FLPA21 • Florida Physician Assistants 2020-2021

Table of Contents

FLPA21 • Florida Physician Assistants 2020-2021

How to Receive Credit

NetCE 2 Hour Course #97922 • Domestic Violence: The Florida Requirement

97922 • Domestic Violence: The Florida Requirement

1. INTRODUCTION

2. DEFINING DOMESTIC VIOLENCE

3. NATIONAL AND STATE STATISTICS AND LEGISLATION

4. IDENTIFYING GROUPS AT RISK FOR DOMESTIC VIOLENCE

5. CHARACTERISTICS OF PERPETRATORS OF DOMESTIC VIOLENCE

6. SCREENING FOR DOMESTIC VIOLENCE AND ABUSE

7. ASSESSING DOMESTIC VIOLENCE AND ABUSE

8. INTERVENTIONS FOR DOMESTIC VIOLENCE AND ABUSE

9. DOCUMENTATION AND FOLLOW-UP

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 2 Hour Course #91333 • Medical Error Prevention and Root Cause Analysis

91333 • Medical Error Prevention and Root Cause Analysis

1. INTRODUCTION

2. DEFINING "MEDICAL ERROR"

3. ROOT CAUSE ANALYSIS PROCESS

4. ERROR REDUCTION AND PREVENTION

5. OTHER CONSIDERATIONS FOR PATIENT SAFETY

6. CONCLUSION

Works Cited

NetCE 3 Hour Course #91151 • Strategies for Appropriate Opioid Prescribing: The Florida APRN/PA Requirement

91151 • Strategies for Appropriate Opioid Prescribing: The Florida APRN/PA Requirement

1. INTRODUCTION

2. DEFINITIONS

3. EPIDEMIOLOGY OF CHRONIC PAIN AND OPIOID MISUSE

4. INITIATION AND MANAGEMENT OF THE PATIENT WITH PAIN

5. CRISIS INTERVENTION: MANAGEMENT OF OVERDOSE

6. COMPLIANCE WITH STATE AND FEDERAL LAWS

7. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

8. INTERVENTIONS FOR SUSPECTED OR KNOWN DRUG DIVERSION

9. CASE STUDY

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 2 Hour Course #97110 • Recognizing and Reporting Human Trafficking in Florida

97110 • Recognizing and Reporting Human Trafficking in Florida

1. INTRODUCTION

2. SCOPE OF HUMAN TRAFFICKING

3. DEFINITIONS OF HUMAN TRAFFICKING

4. FORMS OF TRAFFICKING

5. FACTORS THAT CONTRIBUTE TO HUMAN TRAFFICKING

6. THE TRAFFICKING EXPERIENCE

7. CONSEQUENCES OF HUMAN TRAFFICKING: IMPACT ON VICTIMS

8. IDENTIFICATION AND ASSESSMENT

9. REPORTING

10. INTERVENTIONS AND RESOURCES

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #91783 • Smoking and Secondhand Smoke

91783 • Smoking and Secondhand Smoke

1. INTRODUCTION

2. DEFINITIONS

3. HISTORY OF TOBACCO USE AND RESTRICTION

4. PREVALENCE AND ECONOMIC IMPACT OF SMOKING

5. TOBACCO AND NICOTINE PRODUCTS

6. TOBACCO-RELATED CONCEPTS

7. CIGARETTE SMOKE

8. ANATOMY AND PHYSIOLOGY OF SMOKE INHALATION

9. LEARNING OF BEHAVIOR

10. SMOKING DEPENDENCE

11. HEALTH COMPLICATIONS RELATED TO SMOKING

12. COMORBID CONDITIONS

13. FETAL EXPOSURE

14. PASSIVE SMOKING EFFECTS ON CHILDREN

15. PASSIVE SMOKING EFFECTS ON ADULTS

16. MEASURING SECONDHAND SMOKE EXPOSURE

17. THIRDHAND SMOKE

18. INTERVENTIONS FOR SMOKING CESSATION

19. REDUCING TOBACCO SMOKE EXPOSURE

20. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #94923 • Animal-Related Health Risks

94923 • Animal-Related Health Risks

1. INTRODUCTION

2. HISTORY

3. DEFINITIONS

4. CLASSIFICATION AND REPORTING

5. TICKBORNE DISEASES

6. VIRAL ZOONOTIC DISEASES

7. PROTOZOAL ZOONOTIC DISEASES

8. BACTERIAL ZOONOTIC DISEASES

9. PARASITIC ZOONOTIC DISEASES

10. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

FLPA21 • Florida Physician Assistants 2020-2021

Marjorie Conner Allen, BSN, JD

Alice Yick Flanagan, PhD, MSW

Mark Rose, BS, MA, LP

Mark S. Gold, MD, DFASAM, DLFAPA

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

FLPA21 • Florida Physician Assistants 2020-2021

Expiration Date: 04/30/2021

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

97922 • Domestic Violence: The Florida Requirement

Marjorie Conner Allen, BSN, JD

Alice Yick Flanagan, PhD, MSW

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Domestic violence continues to be a prevalent problem in the United States today. Because of the number of individuals affected, it is likely that most healthcare professionals will encounter patients in their practice who are victims. Accordingly, it is essential that healthcare professionals are taught to recognize and accurately interpret behaviors associated with domestic violence. It is incumbent upon the healthcare professional to establish and implement protocols for early identification of domestic violence victims and their abusers. In order to prevent domestic violence and promote the well-being of their patients, healthcare professionals in all settings must take the initiative to properly assess all women for abuse during each visit and, for those women who are or may be victims, to offer education, counseling, and referral information.

Table of Contents

97922 • Domestic Violence: The Florida Requirement

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. DEFINING DOMESTIC VIOLENCE

3. NATIONAL AND STATE STATISTICS AND LEGISLATION

FLORIDA

4. IDENTIFYING GROUPS AT RISK FOR DOMESTIC VIOLENCE

PREGNANT WOMEN

CHILDREN

ELDERLY

MEN

LESBIAN, GAY, BISEXUAL, AND TRANSGENDER VICTIMS

5. CHARACTERISTICS OF PERPETRATORS OF DOMESTIC VIOLENCE

6. SCREENING FOR DOMESTIC VIOLENCE AND ABUSE

7. ASSESSING DOMESTIC VIOLENCE AND ABUSE

CULTURALLY SENSITIVE ASSESSMENT

8. INTERVENTIONS FOR DOMESTIC VIOLENCE AND ABUSE

9. DOCUMENTATION AND FOLLOW-UP

Works Cited

Evidence-Based Practice Recommendations Citations

97922 • Domestic Violence: The Florida Requirement

Education Category. Ethics - Human Rights

Release Date. 08/01/2019

Expiration Date. 07/31/2022

Course Overview

Domestic violence continues to be a prevalent problem in the United States today. Because of the number of individuals affected, it is likely that most healthcare professionals will encounter patients in their practice who are victims. Accordingly, it is essential that healthcare professionals are taught to recognize and accurately interpret behaviors associated with domestic violence. It is incumbent upon the healthcare professional to establish and implement protocols for early identification of domestic violence victims and their abusers. In order to prevent domestic violence and promote the well-being of their patients, healthcare professionals in all settings must take the initiative to properly assess all women for abuse during each visit and, for those women who are or may be victims, to offer education, counseling, and referral information.

Audience

This course is designed for all Florida healthcare professionals required to complete domestic violence education.

Course Objective

The purpose of this course is to enable healthcare professionals in all practice settings to define domestic violence and identify those who are affected by domestic violence in the United States. This course describes how a victim can be accurately diagnosed and identifies the community resources available in the state of Florida for domestic violence victims.

Learning Objectives

Upon completion of this course, you should be able to:

1. Define domestic violence and its impact on health care.

2. Cite the general prevalence of domestic violence on a national and state level and identify state laws pertaining to the issue.

3. Describe how to screen and assess individuals who may be victims or perpetrators of domestic violence, including the importance of conducting a culturally sensitive assessment.

4. Identify community resources presently available for domestic violence victims and their perpetrators throughout Florida concerning legal aid, shelter, victim and batterer counseling, and child protection services.

Faculty

Marjorie Conner Allen, BSN, JD, received her Bachelor of Science in Nursing degree from the University of Florida, Gainesville, in 1984. She began her nursing career at Shands Teaching Hospital and Clinics at the University of Florida, Gainesville. While practicing nursing at Shands, she gave continuing education seminars regarding the nursing implications for dealing with adolescents with terminal illness. In 1988, Ms. Allen moved to Atlanta, Georgia where she worked at Egleston Children’s Hospital at Emory University in the bone marrow transplant unit. In the fall of 1989, she began law school at Florida State University. After graduating from law school in 1992, Ms. Allen took a two-year job as law clerk to the Honorable William Terrell Hodges, United States District Judge for the Middle District of Florida. After completing her clerkship, Ms. Allen began her employment with the law firm of Smith, Hulsey & Busey in Jacksonville, Florida where she has worked in the litigation department defending hospitals and nurses in medical malpractice actions. Ms. Allen resides in Jacksonville and is currently in-house counsel to the Mayo Clinic Jacksonville.

Alice Yick Flanagan, PhD, MSW, received her Master’s in Social Work from Columbia University, School of Social Work. She has clinical experience in mental health in correctional settings, psychiatric hospitals, and community health centers. In 1997, she received her PhD from UCLA, School of Public Policy and Social Research. Dr. Yick Flanagan completed a year-long post-doctoral fellowship at Hunter College, School of Social Work in 1999. In that year she taught the course Research Methods and Violence Against Women to Masters degree students, as well as conducting qualitative research studies on death and dying in Chinese American families.

Previously acting as a faculty member at Capella University and Northcentral University, Dr. Yick Flanagan is currently a contributing faculty member at Walden University, School of Social Work, and a dissertation chair at Grand Canyon University, College of Doctoral Studies, working with Industrial Organizational Psychology doctoral students. She also serves as a consultant/subject matter expert for the New York City Board of Education and publishing companies for online curriculum development, developing practice MCAT questions in the area of psychology and sociology. Her research focus is on the area of culture and mental health in ethnic minority communities.

Faculty Disclosure

Contributing faculty, Marjorie Conner Allen, BSN, JD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Contributing faculty, Alice Yick Flanagan, PhD, MSW, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

Ronald Runciman, MD

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Domestic violence continues to be a prevalent problem in the United States today. Because of the number of individuals affected, it is likely that most healthcare professionals will encounter patients in their practice who are victims. Accordingly, it is essential that healthcare professionals are taught to recognize and accurately interpret behaviors associated with domestic violence. It is incumbent upon the healthcare professional to establish and implement protocols for early identification of domestic violence victims and their abusers. In order to prevent domestic violence and promote the well-being of their patients, healthcare professionals in all settings should take the initiative to properly assess all women for abuse during each visit and, for those women who are or may be victims, to offer education, counseling, and referral information.

Victims of domestic violence suffer emotional, psychologic, and physical abuse, all of which can result in both acute and chronic signs and symptoms of physical and mental disease, illness, and injury. Frequently, the injuries sustained require abused victims to seek care from healthcare professionals immediately after their victimization. Subsequently, physicians and nurses are often the first healthcare providers that victims encounter and are in a critical position to identify domestic violence victims in a variety of clinical practice settings where victims receive care. Accordingly, each healthcare professional should educate himself or herself to enhance awareness of the presence of abuse victims in his or her particular practice or clinical setting.

Specifically, healthcare professionals should be aware of the signs and symptoms associated with domestic violence. In addition, when family violence cases are identified, there should be a plan of action that includes providing information on, and referral to, local community resources related to legal aid, sheltering, victim counseling, batterer counseling, advocacy groups, and child protection.

2. DEFINING DOMESTIC VIOLENCE

Domestic violence, which is sometimes also referred to as spousal abuse, battering, or intimate partner violence (IPV), refers to the victimization of an individual with whom the abuser has or has had an intimate or romantic relationship. Researchers in the field of domestic violence have not agreed on a uniform definition of what constitutes violence or an abusive relationship. The Centers for Disease Control and Prevention (CDC) defines IPV as, "violence or aggression that occurs in a close relationship" [1]. According to the Florida Department of Children and Families, domestic violence is "a pattern of behaviors that adults or adolescents use against their intimate partners or former partners to establish power and control. It may include physical abuse, sexual abuse, emotional abuse, and economic abuse. It may also include threats, isolation, pet abuse, using children, and a variety of other behaviors used to maintain fear, intimidation, and power over one's partner" [2]. Florida law defines domestic violence as "any assault, aggravated assault, battery, aggravated battery, sexual assault, sexual battery, stalking, aggravated stalking, kidnapping, false imprisonment, or any criminal offense resulting in physical injury or death of one family or household member by another family or household member" [3]. Family or household members, according to Florida definition, must "be currently residing or have in the past resided together in the same single dwelling unit" [3]. Domestic violence knows no boundaries. It occurs in intimate relationships regardless of race, religion, culture, or socioeconomic status [2].

Whatever the definition, it is important for healthcare professionals to understand that domestic violence, in the form of emotional and psychologic abuse, sexual abuse, and physical violence, is prevalent in our society. Because of the similar nature of the definitions, this course will use the terms "domestic violence" and "IPV" interchangeably.

3. NATIONAL AND STATE STATISTICS AND LEGISLATION

Domestic violence is one of the most serious public health problems in the United States [4]. More than 36.4% of women and 33.6% of men have a lifetime history of IPV [4]. In Florida, the weighted lifetime prevalence of IPV (including rape, physical violence, and/or stalking) is 37.3% among women and 30.9% among men [5]. Although many of these incidents are relatively minor and consist of pushing, grabbing, shoving, slapping, and hitting, IPV resulted in approximately 1,300 deaths in the United States in 2017, with 162 deaths reported in Florida [7,8]. One of the difficulties in addressing the problem is that abuse is prevalent in all demographics, regardless of age, ethnicity, race, religious denomination, education, or socioeconomic status [2].

Victims of abuse often suffer severe physical injuries and will likely seek care at a hospital or clinic. The health and economic consequences of domestic violence are significant. Statistics vary from report to report, and due to the lack of studies on the national cost of domestic violence, the U.S. Congress funded the CDC to conduct a study to determine the cost of domestic violence on the healthcare system [9]. The 2003 CDC report, which relied on data from the National Violence Against Women Survey conducted in 1995, estimated the costs of IPV by measuring how many female victims were nonfatally injured; how many women used medical and mental healthcare services; and how many women lost time from paid work and household chores. The estimated total annual cost of IPV against women in the 1995 survey was more than $5.8 billion [9]. When updated to 2017 dollars, the amount was more than $9.3 billion annually. The costs associated with IPV at this time would be considerably more, but no further studies have been conducted [10]. It should be noted that the costs of any one victimization may continue for years; therefore, these statistics most likely underestimate the actual cost of IPV [9].

The national rate of nonfatal domestic violence against women declined 72% between 1993 and 2011 [11]. The rate of overall violent crime fell by nearly 60% in this same time period [11]. Studies reveal that several factors may have contributed to the reduction in violence, including a decline in the marriage rate and decrease of domesticity, better access to federally funded domestic violence shelters, improvements in women's economic status, and demographic trends, such as the aging of the population [13,14]. Of note, declines in the economy and stress associated with financial hardship and unemployment are significant contributors to IPV in the United States. Following the economic downturn in late 2008, there was a significant increase in the use of the National Domestic Violence Hotline in 2009, with more than half of victims reporting a change in household financial situation in the last year [15].

FLORIDA

In response to troubling domestic violence statistics, Governor Lawton Chiles appointed a Task Force on Domestic Violence on September 28, 1993, to investigate the problems associated with domestic violence in Florida and to compile recommendations as to how the problems should be approached and ultimately resolved. On January 31, 1994, the Task Force issued its first report on domestic violence. This report recommended standards to accurately measure the extent of domestic violence and strategies for increasing public awareness and education. It identified programs and resources that are available to victims in Florida, made legislative and budgetary suggestions for needed changes, provided a methodology for implementing these changes, and identified areas of domestic violence that require further study.

As a result of this report, Florida enacted legislation during the 1995 session implementing various suggestions of the Task Force. Specifically, the Legislature amended Section 455.222 of the Florida Statutes to require that all physicians, osteopaths, nurses, dentists, dental hygienists, midwives, psychologists, and psychotherapists obtain, as part of their biennial continuing education requirements, a one-hour continuing education course on domestic violence [17]. In June of 2006, Governor Jeb Bush signed into law House Bill 699. The bill, which went into effect July 1, 2006, changed the domestic violence continuing education requirement from one hour every renewal period to two hours every third renewal period.

In 1997, at the request of the Governor's Task Force, a workgroup was established by the Florida Department of Law Enforcement (FDLE) to evaluate the feasibility of tracking incidents of domestic violence in the state [18]. This resulted in the creation of the Domestic Violence Data Resource Center (DVDRC). The original mission of the DVDRC was to collect information related to domestic violence and to report and maintain the information in a statewide tracking system [19]. Domestic Violence Fatality Review Teams were established to examine those cases of domestic violence that resulted in a fatality and identify potential changes in policy or procedure that might prevent future deaths. The teams were comprised of representatives from law enforcement, the courts, social services, state attorneys, domestic violence centers, and others who may come into contact with domestic violence victims and perpetrators [20]. In 2000, the creation of Florida Statute 741.316 required the FDLE to annually publish a report based on the data gathered by the Fatality Review Teams [19]. Due to budgetary constraints, responsibility of compiling this data transferred to the Department of Children and Families in 2008 [21].

As part of Governor Jeb Bush's initiative, the "Family Protection Act" was signed into law in 2001. The act requires a 5-day mandatory jail term for any crime of domestic battery in which the perpetrator deliberately injures the victim. The law also makes a second battery crime a felony offense, treating offenders as serious criminals. Additional legislation, signed into law in 2002, includes Senate Bills 716 and 1974. Senate Bill 716 protects domestic violence victims by including dating relationships of six months in the definition of domestic violence laws. Senate Bill 1974 requires judges to inform victims of their rights, including the right to appear, be notified, seek restitution, and make a victim-impact statement. Governor Bush also created the Violence Free Florida campaign to increase public awareness of domestic violence issues [22].

In 2003, Governor Bush signed House Bill 1099, which transferred funding authority of the Florida Domestic Violence Trust Fund from the Department of Children and Families to the Florida Coalition Against Domestic Violence. According to the Domestic Violence in Florida 2010–2011 Annual Report to the Legislature, this has strengthened domestic violence services provided by streamlining the process of allocating funds [23].

In 2007, the Domestic Violence Leave Act was signed into law by Governor Charlie Crist [21]. This law requires employers with 50 or more employees to provide guaranteed leave for domestic violence issues.

In 2017, the FDLE reported 106,979 domestic violence offenses [6]. In general, domestic violence rates have been declining since 1998. An estimated 20.2% of domestic violence incidents involved spouses and 28.4% involved cohabitants; 11.5% of the victims were parents of the offenders. Domestic violence offenses resulted in the death of 162 victims in Florida in 2017, a number that has been decreasing since 2014 [6]. Domestic violence accounted for more than 15% of the state's murders in 2017 [6].

In their 2018 Annual Report, Fatality Review Teams summarized 32 cases of domestic violence fatalities and near fatalities [49]. The most significant findings included the following observations [49]:

- The perpetrators were predominantly male (90%) with female victims (84%) and had prior criminal histories, generally (55%) and for domestic violence specifically (48%).

- In 32% of fatalities, the perpetrators had a known "do not contact" order filed against them, and 32% of perpetrators had a known permanent injunction for protection against them filed by someone other than the victim.

- Substance abuse histories by the perpetrator was identified in 62% of the cases and diagnosed mental health disorders in 30%.

- In most cases, neither the decedent nor perpetrator sought help from the various intervention programs available to them.

To obtain a copy of the Executive Summary of the 2018 Florida Domestic Violence Fatality Review Team Annual Report, please visit https://www.fcadv.org/sites/default/files/FACES%20OF%20FATALITY%20VIII%20web.pdf.

4. IDENTIFYING GROUPS AT RISK FOR DOMESTIC VIOLENCE

Healthcare professionals are in a critical position to identify domestic violence victims in a variety of clinical practice settings. Nurses are often the first healthcare provider a victim of domestic violence will encounter in a healthcare setting and should therefore be prepared to provide care and support for these victims. Although women are most often the victims, domestic violence extends to others in the household as well. For example, domestic violence includes abused men, children abused by their parents or parents abused by their children, elder abuse, and abuse among siblings [3].

Many victims of abuse sustain injuries that lead them to present to hospital emergency departments. Research has found that 49.6% of women seen in emergency departments reported a history of abuse and 44% of women who were ultimately killed by their abuser had sought help in an emergency department in the two years prior to their death [25,50]. Another study of 993 police-identified female victims of IPV found that only 28% of the women were identified in the emergency department as being victims of IPV [26]. These alarming statistics demonstrate that healthcare professionals who work in acute care, such as hospital emergency rooms, should maintain a high index of suspicion for battering of the patients that they see. Healthcare professionals who work in these settings should work with hospital administrators to establish and institute assessment mechanisms to accurately detect these victims.

For every victim of abuse, there is also a perpetrator. Like their victims, perpetrators of domestic violence come from all socioeconomic backgrounds, races, religions, and walks of life [27]. Accordingly, healthcare professionals should likewise be aware that seemingly supportive family members may, in fact, be abusers.

PREGNANT WOMEN

Because a gynecologist or obstetrician is frequently a woman's primary care physician, the American College of Obstetricians and Gynecologists (ACOG) recommends that all women be routinely assessed for signs of IPV (i.e., physical and psychologic abuse, reproductive coercion, and progressive isolation), including during prenatal visits, and providers should offer support and referral information for those being abused [28]. According to the ACOG, IPV affects as many as 324,000 pregnant women each year [25]. A meta-analysis of 92 independent studies found that the average reported prevalence of emotional abuse during pregnancy was 28.4%, physical abuse was 13.8%, and sexual abuse was 8% [51]. As with all domestic violence statistics, these estimates are presumed to be lower than the actual incidence as a result of under-reporting and lack of data on women whose pregnancies ended in fetal or maternal death. This makes IPV more prevalent among pregnant women than some of the health conditions included in prenatal screenings, including pre-eclampsia and gestational diabetes [25]. Because 96% of pregnant women receive prenatal care, this is an optimal time to assess for domestic violence and develop trusting relationships with the women. Possible factors that may predispose pregnant women to IPV include being unmarried, lower socioeconomic status, young maternal age, unintended pregnancy, delayed prenatal care, lack of social support, and use of tobacco, alcohol, or illegal drugs [25,51].

The overarching problem of violence against pregnant women cannot be ignored, especially as both mother and fetus are at risk. At this particularly vulnerable time in a woman's life, an organized clinical construct leading to immediate diagnosis and medical intervention will ensure that therapeutic opportunities are available to the pregnant woman and will reduce the potential negative outcomes [29]. Healthcare professionals should also be aware of the possible psychologic consequences of abuse during pregnancy. There is a higher risk of stress, depression, and addiction to alcohol and drugs in abused women. These conditions may result in damage to the fetus from tobacco, drugs, and alcohol and a loss of interest on the part of the mother in her or her baby's health [16,30]. Possible direct injuries to the fetus may result from maternal trauma [25].

Control of reproductive or sexual health is also a recognized trend in IPV. This type of abuse includes trying to impregnate or become pregnant against a partner's wishes, refusal to use birth control (e.g., condoms, oral contraceptives), or stopping a partner from using birth control [4].

CHILDREN

Children exposed to family violence are at high risk for abuse and for emotional damage that may affect them as they grow older. The Department of Justice estimates that of the 76 million children in the United States, 46 million will be exposed to some type of violence during their childhood [52]. Results of the National Survey of Children's Exposure to Violence indicated that 11% of children were exposed to IPV at home within the last year, and as many as 26% of children were exposed to at least one form of family violence during their lifetimes [31]. Of those children exposed to IPV, 90% were direct eyewitnesses of the violence; the remaining children were exposed by either hearing the violence or seeing or being told about injuries [31]. Of note, according to Florida criminal law, witnessing domestic violence is defined as "violence in the presence of a child if an offender is convicted of a primary offense of domestic violence, and that offense was committed in the presence of a child under age 16 who is a family or household member with the victim or perpetrator" [32].

A number of studies indicate that child witnesses are at increased risk for post-traumatic stress disorder, impaired development, aggressive behavior, anxiety, difficulties with peers, substance abuse, and academic problems than the average child [33,54,55]. Children exposed to violence may also be more prone to dating violence (as a perpetrator or a victim), and the ability to effectively cope with partnerships and parenting later in life may be affected, continuing the cycle of violence into the next generation [34,56].

In addition to witnessing violence, various studies have shown that these children may also become direct victims of violence, and children who both witness and experience violence are at the greatest risk for adverse psychosocial outcomes [53]. Research indicates that between 30% and 60% of husbands who batter their wives also batter their children [35]. Moreover, victims of abuse will often turn on their children; statistics demonstrate that 85% of domestic violence victims abuse or neglect their children. The 2017 Crime in Florida report found that more than 16% of domestic homicide victims were children killed by a parent [6]. Teenage children are also victimized. According to the U.S. Department of Justice, between 1980 and 2008, 17.5% of all homicides against female adolescents 12 to 17 years of age were committed by an intimate partner [36]. Among young women (18 to 24 years of age), the rate is 42.9%. Abused teens often do not report the abuse. Individuals 12 to 19 years of age report only 35.7% of crimes against them, compared with 54% in older age groups [37]. Accordingly, healthcare professionals who see young children and adolescents in their practice (e.g., pediatricians, family physicians, school nurses, pediatric nurse practitioners, community health nurses) should have the tools necessary to detect these "silent victims" of domestic violence and to intervene quickly to protect young children and adolescents from further abuse. Without such critical intervention, the cycle of violence will never end.

ELDERLY

Abused and neglected elders, who may be mistreated by their spouses, partners, children, or other relatives, are among the most isolated of all victims of family violence. In a national study conducted by the National Institute of Justice in 2010, 4.6% of participants (community dwelling adults 60 years of age or older) were victims of emotional abuse in the past year, 1.6% physical abuse, 0.6% sexual abuse, 5.1% potential neglect, and 5.2% current financial abuse by a family member [38]. The estimated annual incidence of all elder abuse types is 2% to 10%, but it is believed to be severely under-measured. According to one study, only 1 in 14 cases of elder abuse are reported to the authorities [39].

The prevalence rate of elder abuse in institutional settings is not clear. However, in a 2019 review of nine studies, 64% of elder care facility staff disclosed to having perpetrated abuse against an elderly resident in the past year [40]. In a random sample survey, 24.3% of respondents reported at least one incident of elder physical abuse perpetrated by a nursing home staff member [57].

As healthcare professionals in Florida, which leads the nation in percentage of older residents, it is important to understand that the needs of older Floridians will increase as will the numbers of elder victims of domestic violence. Because elder abuse can occur in family homes, nursing homes, board and care facilities, and even medical facilities, healthcare professionals should remain keenly aware of the potential for abuse. When abuse occurs between elder partners, it is primarily manifested in one of two ways: either as a long-standing pattern of marital violence or as abuse originating in old age. In the latter case, abuse may be precipitated by issues related to advanced age, including the stress that accompanies disability and changing family relationships [39].

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening all elderly or vulnerable adults (physically or mentally dysfunctional) for abuse and neglect.

https://annals.org/aim/fullarticle/1558517/screening-intimate-partner-violence-abuse-elderly-vulnerable-adults-u-s

Last Accessed: July 26, 2019

Strength of Recommendation: I (Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.)

It is important to understand that the domestic violence dynamic involves not only a victim but a perpetrator as well. For example, an adult son or daughter who lives in the parents' home and depends on the parents for financial support may be in a position to inflict abuse. This abuse may not always manifest itself as violence, but can lead to an environment in which the elder parent is controlled and isolated. The elder may be hesitant to seek help because the abuser's absence from the home may leave the elder without a caregiver [39]. Because these elderly victims are often isolated, dependent, infirm, or mentally impaired, it is easy for the abuse to remain undetected. Healthcare professionals in all settings should remain aware of the potential for abuse and keep a watchful eye on this particularly vulnerable group.

MEN

Statistics confirm that domestic violence is predominantly perpetrated by men against women; however, there is evidence to suggest that women also exhibit violent behavior against their male partners [4]. Studies demonstrate approximately 5% of murdered men are killed by intimate partners [36]. It is persuasively argued that the impact on the health of female victims of domestic violence is generally much more severe than the impact on the health of male victims [42]. Approximately 512,770 women were raped and/or physically assaulted by an intimate partner in 2008, compared to 101,050 men [58]. In addition, 1 in 4 women has been physically assaulted, raped, and/or stalked by an intimate partner, compared with 1 out of every 10 men [1]. Rape, non-contact unwanted sexual experiences, and stalking against men are primarily perpetrated by other men, while other forms of violence against men were perpetrated mostly by women [5]. Male victims of IPV experienced 3 victimizations per 1,000 boys and men 12 years of age or older in 1994, and this rate decreased by 64%, to 1.1 per 1,000, in 2010 [11]. Of all homicides committed against men between 1980 and 2008, 7.1% were committed by an intimate partner [36]. Although women are more often victims of IPV, healthcare professionals should always keep in mind that men can also be victimized and assess accordingly.

LESBIAN, GAY, BISEXUAL, AND TRANSGENDER VICTIMS

Domestic violence exists in lesbian, gay, bisexual, and transgender (LGBT) communities, and the rates are thought to mirror those of heterosexual women—approximately 25% [43]. However, women living with female intimate partners experience less IPV than women living with men [6]. Conversely, men living with male intimate partners experience more IPV than do men who live with female intimate partners [6]. In addition, 78% of IPV homicide victims reported in 2017 were transgender women or cisgender men [24]. This supports other statistics indicating that IPV is perpetrated primarily by men. A form of abuse specific to the gay community is for an abuser to threaten or to proceed with "outing" a partner to others [41,43].

Transgender individuals appear to be at particular risk for violence. According to a large national report, transgender victims of IPV were 1.9 times more likely to experience physical violence and 3.9 times more likely to experience discrimination than other members of the LGBT community [24].

In 2017, an annual national report recorded 52 incidences of hate violence-related homicides of LGBT+ people, the highest incident number recorded in its 20-year history [24]. This increasing prevalence of anti-LGBT+ violence can exacerbate IPV in LGBT+ communities. For example, a person who loses their job because of anti-trans bias may be more financially reliant on an unhealthy relationship. An abusive partner may also use the violence that an LGBT+ person experiences from their family as a way of isolating that person further [24].

Because of the stigma of being LGBT, victims may be reticent to report abuse and afraid that their sexual orientation or biologic sex will be revealed. In one study, the three major barriers to seeking help were a limited understanding of the problem of LGBT IPV, stigma, and systemic inequities [41]. Many in this community feel that support services (e.g., shelters, support groups, crisis hotlines) are not available to them due to homophobia of the service providers. Unfortunately, this results in the victim feeling isolated and unsupported. Healthcare professionals should strive to be sensitive and supportive when working with homosexual patients.

5. CHARACTERISTICS OF PERPETRATORS OF DOMESTIC VIOLENCE

Abuser characteristics have been studied far less frequently than victim characteristics. Some studies suggest a correlation between the occurrence of abuse and the consumption of alcohol. A man who abuses alcohol is also likely to abuse his mate, although the abuser may not necessarily be inebriated at the time the abuse is inflicted [44]. Domestic violence assessment questionnaires should include questions that explore social drinking habits of both victims and their mates.

Other studies demonstrate that abusive mates are generally possessive and jealous. Another characteristic related to the abuser's dependency and jealousy is extreme suspiciousness. This characteristic may be so extreme as to border on paranoia [12]. Domestic violence victims frequently report that abusers are extremely controlling of the everyday activities of the family. This domination is generally all encompassing and often includes maintaining complete control of finances and activities of the victim (e.g., work, school, social interactions) [12].

In addition, abusers often suffer from low self-esteem and their sense of self and identity is directly connected to their partner [12]. Extreme dependence is common in both abusers and those being abused. Due to low self-esteem and self-worth, emotional dependence often occurs in both partners, but even more so in the abuser. Emotional dependence in the victim stems from both physical and psychologic abuse, which results in a negative self-image and lack of self-worth. Financial dependence is also very common, as the abuser often withholds or controls financial resources to maintain power over the victim [27].

6. SCREENING FOR DOMESTIC VIOLENCE AND ABUSE

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends that clinicians screen women of childbearing age for intimate partner violence, such as domestic violence, and provide or refer women who screen positive to intervention services. This recommendation applies to women who do not have signs or symptoms of abuse.

https://annals.org/aim/fullarticle/1558517/screening-intimate-partner-violence-abuse-elderly-vulnerable-adults-u-s

Last Accessed: July 26, 2019

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

There is no universal guideline for identifying and responding to domestic violence, but it is universally accepted that a plan for screening, assessing, and referring patients of suspected abuse should be in place at every healthcare facility. Guidelines should review appropriate interview techniques for a given setting and should also include the utilization of assessment tools. Furthermore, protocols within each facility or healthcare setting should include referral, documentation, and follow-up. This section relies heavily on the guidelines outlined in the Family Violence Prevention Fund's National Consensus Guidelines on Identifying and Responding to Domestic Violence Victimization in Health Care Settings; however, protocols should be customized based on individual practice settings and resources available [35]. The CDC has provided a compilation of assessment tools for healthcare workers to assist in recognizing and accurately interpreting behaviors associated with domestic violence and abuse, which may be accessed at https://www.cdc.gov/violenceprevention/pdf/ipv/ipvandsvscreening.pdf [45].

Several barriers to screening for domestic violence have been noted, including a lack of knowledge and training, time constraints, lack of privacy for asking appropriate questions, and the sensitive nature of the subject [35]. Although awareness and assessment for IPV has increased among healthcare providers, many are still hesitant to inquire about abuse [46]. At a minimum, those exhibiting signs of domestic violence should be screened. Although victims of IPV may not display typical signs and symptoms when they present to healthcare providers, there are certain cues that may be attributed to abuse. The obvious cues are physical. Injuries range from bruises, cuts, black eyes, concussions, broken bones, and miscarriages to permanent injuries such as damage to joints, partial loss of hearing or vision, and scars from burns, bites, or knife wounds. Typical injury patterns include contusions or minor lacerations to the head, face, neck, breast, or abdomen and musculoskeletal injuries. These are often distinguishable from accidental injuries, which are more likely to involve the extremities of the body. Abuse victims are also more likely to have multiple injuries than accident victims. When this pattern of injuries is seen, particularly in combination with evidence of old injury, physical abuse should be suspected [44].

In addition to physical signs and symptoms, domestic violence victims also exhibit psychologic cues that resemble an agitated depression. As a result of prolonged stress, various psychosomatic symptoms that generally lack an organic basis often manifest. For example, complaints of backaches, headaches, and digestive problems are common. Often, there are reports of fatigue, restlessness, insomnia, or loss of appetite. Great amounts of anxiety, guilt, and depression or dysphoria are also typical. Women who experienced IPV are also more likely to report asthma, irritable bowel syndrome, and diabetes [4]. Healthcare professionals should look beyond the typical symptoms of a domestic violence victim and work within their respective practice settings to develop appropriate assessment mechanisms to detect victims who exhibit less obvious symptoms.

The unique relationship dynamics of the abuser and abused are not easily detected under the best of circumstances. They may be especially difficult to uncover in circumstances in which the parties are suspicious and frightened, as might be expected when a victim presents to the emergency department. The key to detection, however, is to establish a proper assessment tool that can be utilized in the particular setting and to maintain a keen awareness for the cues described in this course. Screening for IPV should be carried out at the entry points of contact between victims and medical care (e.g., primary care, emergency services, obstetric and gynecologic services, psychiatric services, and pediatric care) [35].

The key to an initial assessment is to obtain an adequate history. Establishing that a patient's injuries are secondary to abuse is the first task. Clearly, there will be times when a victim is injured so severely that treatment of these injuries becomes the first priority. After such treatment is rendered, however, it is important that healthcare professionals not ignore the reasons that brought the victim to the emergency department [35].

7. ASSESSING DOMESTIC VIOLENCE AND ABUSE

Healthcare providers have reported that even if routine screening and inquiry results in a positive identification of IPV, the next steps of assessing and referring are often difficult, and many feel that they are not adequately prepared [46]. According to the Family Violence Prevention Fund, the goals of the assessment are to create a supportive environment, gather information about health problems associated with the abuse, and assess the immediate and long-term health and safety needs for the patient to develop an intervention [35].

Assessment of domestic violence victims should occur immediately after disclosure of abuse and at any follow-up appointments. Assessing immediate safety is priority. Having a list of questions readily available and well-practiced can help alleviate the uncertainty of how to begin to the assessment (Table 1). If the patient is in immediate danger, referral to an advocate, support system, hotline, or shelter is indicated [35].

Table 1: ASSESSMENT OF IMMEDIATE SAFETY FOR DOMESTIC VIOLENCE VICTIMS

Are you in immediate danger?

Is your partner at the health facility now?

Do you want to (or have to) go home with your partner?

Do you have somewhere safe to go?

Have there been threats or direct abuse of the children (if s/he has children)?

Are you afraid your life may be in danger?

Has the violence gotten worse or is it getting scarier? Is it happening more often?

Has your partner used weapons, alcohol or drugs?

Has your partner ever held you or your children against your will?

Does your partner ever watch you closely, follow you or stalk you?

Has your partner ever threatened to kill you, him/herself or your children?

Source: [35]

If the patient is not in immediate danger, the assessment may continue with a focus on the impact of IPV on the patient's mental and physical health and the pattern of history and current abuse [35]. These responses will help formulate an appropriate intervention.

CULTURALLY SENSITIVE ASSESSMENT

During the assessment process, a practitioner should be open and sensitive to the patient's worldview, cultural belief systems and how he/she views the illness [47]. This may reduce the tendency to over-pathologize or minimize health concerns of ethnic minority patients.

Pachter proposed a dynamic model that involves several tiers and transactions [48]. The first component of Pachter's model calls for the practitioner to take responsibility for cultural awareness and knowledge. The professional should be willing to acknowledge that he/she does not possess enough or adequate knowledge in health beliefs and practices among the different ethnic and cultural groups he/she comes in contact with. Reading and becoming familiar with medical anthropology is a good first step.

The second component emphasizes the need for specifically tailored assessment [48]. Pachter advocates the notion that there is tremendous diversity within groups. For example, one cannot automatically assume that a Cuban immigrant adheres to traditional beliefs. Often, there are many variables, such as level of acculturation, age at immigration, educational level, and socioeconomic status, that influence health ideologies. Finally, the third component involves a negotiation process between the patient and the professional [48]. The negotiation consists of a dialogue that involves a genuine respect of beliefs. It is important to remember that these beliefs may affect symptoms or appropriate interventions in the case of domestic violence.

Culturally sensitive assessment involves a dynamic framework whereby the practitioner engages in a continual process of questioning. By incorporating cultural sensitivity into the assessment of individuals with a history of being victims or perpetrators of domestic violence, it may be possible to intervene and offer treatment more effectively.

8. INTERVENTIONS FOR DOMESTIC VIOLENCE AND ABUSE

After the assessment is complete, the patient may or may not want immediate assistance or referral. It is important for healthcare providers to assure patients in a nonjudgmental manner that the decision of what they would like in terms of assistance is their choice and that the provider will help regardless of the decisions they are currently ready to make [35].

If the patient would like to immediately implement a plan of action, information for referral to a local domestic violence shelter to assist the victim and the victim's family should be readily available. The acute situation should be referred immediately to local law enforcement officials. Other resources in an acute situation include crisis hotlines and rape relief centers. After a victim is introduced into the system, counseling and follow-up are generally available by individual counselors who specialize in the care of battered women and their spouses and children. These may include social workers, psychologists, psychiatrists, other mental health workers, and community mental health services. The goals are to make the resources accessible and safe and to enhance support for those who are unsure of their options [35].

In Florida, a 24-hour domestic violence hotline is available for toll-free counseling and information. The number is 800-500-1119. The counselors answering the toll-free line may refer the victim to her or his local domestic violence center. A list of Florida certified domestic violence centers organized by county and city may also be found on the Florida Coalition Against Domestic Violence website at https://www.fcadv.org/local-center-services. As of 2018, Florida had 72 certified domestic violence centers that provide information and referral services, counseling and case management services, a 24-hour hotline, temporary emergency shelter for more than 24 hours, educational services for community awareness relative to domestic violence, assessment and appropriate referral of resident children, and training for law enforcement personnel.

9. DOCUMENTATION AND FOLLOW-UP

It is imperative that healthcare professionals document all findings and recommendations regarding domestic violence in the victim's medical record, including a patient's denial of abuse, if applicable. If domestic violence is disclosed, documentation should include relevant history, results of the physical examination, findings of laboratory and other diagnostic procedures, and results of the assessment, intervention, and referral. The medical record can be an invaluable document in establishing the credibility of the victim's story when seeking legal aid [35].

Healthcare professionals should offer a follow-up appointment if disclosure of past or current abuse is present. Reassurance that assistance is available to the patient at any time is critical in helping to break the cycle of abuse [35].

Works Cited

1. Centers for Disease Control and Prevention. Preventing Intimate Partner Violence. Available at https://www.cdc.gov/ViolencePrevention/intimatepartnerviolence/fastfact.html. Last accessed July 18, 2019.

2. Florida Department of Children and Families. What Is Domestic Violence? Available at https://www.myflfamilies.com/service-programs/domestic-violence/what-is-domestic-violence.shtml. Last accessed July 18, 2019.

3. Florida Statutes. Section 741.28 (2018): Domestic Violence; Definitions. Available at http://www.leg.state.fl.us/statutes/index.cfm?App_mode=Display_Statute&URL=0700-0799/0741/Sections/0741.28.html. Last accessed July 18, 2019.

4. Smith, SG, Zhang, X, Basile, KC, et al. The National Intimate Partner and Sexual Violence Survey (NISVS): 2015 Data Report: Updated Release. Atlanta, GA: National Center for Injury Prevention and Control, Centers for Disease Control and Prevention; 2015.

5. Smith, SG, Chen, J, Basile, KC, et al. The National Intimate Partner and Sexual Violence Survey (NISVS): 2010–2012 State Report. Atlanta, GA: National Center for Injury Prevention and Control, Centers for Disease Control and Prevention; 2014.

6. Florida Department of Law Enforcement. Crime in Florida, 2017: Florida Uniform Crime Report. Available at https://www.fdle.state.fl.us/FSAC/UCR/2017/CIFAnnual17.aspx. Last accessed July 18, 2019.

7. Federal Bureau of Investigation. Crime in the United States, 2017. Available at https://ucr.fbi.gov/crime-in-the-u.s/2017. Last accessed July 18, 2019.

8. Florida Department of Law Enforcement. Crime in Florida, 2017: Florida Uniform Crime Report. Available at https://www.fdle.state.fl.us/FSAC/UCR/2017/2017SA_CIF.aspx. Last accessed July 18, 2019.

9. National Center for Injury Prevention and Control. Costs of Intimate Partner Violence Against Women in the United States. Atlanta, GA: Centers for Disease Control and Prevention; 2003.

10. Institute for Women's Policy Research. The Economic Cost of Intimate Partner Violence, Sexual Assault, and Stalking. Available at https://iwpr.org/wp-content/uploads/2017/08/B367_Economic-Impacts-of-IPV-08.14.17.pdf. Last accessed July 18, 2019.

11. Catalano S. Intimate Partner Violence: Attributes of Victimization, 1993–2011. Washington, DC: Bureau of Justice Statistics, U.S. Department of Justice; 2013.

12. Capaldi DM, Knoble NB, Shortt JW, Kim HK. A systematic review of risk factors for intimate partner violence. Partner Abuse. 2012;3(2):231-280.

13. National Institute of Justice. The decline of intimate partner homicide. National Institute of Justice Journal. 2005;252.

14. Farmer A, Tiefenthaler J. Explaining the recent decline in domestic violence. Contemp Econ Policy. 2003;21(s):158-172.

15. National Domestic Violence Hotline. Increased Financial Stress Affects Domestic Violence Victims. Available at https://www.thehotline.org/2009/01/30/increased-financial-stress-affects-domestic-violence-victims-2. Last accessed July 18, 2019.

16. Crane CA, Hawes SW, Weinberger AH. Intimate partner violence victimization and cigarette smoking: a meta-analytic review. Trauma Violence Abuse. 2013;14(4):305-315.

17. 1995 Florida Session Law Service Chapter 95-187, Domestic Violence, General Provisions.

18. Florida Governor's Task Force on Domestic and Sexual Violence. Florida Mortality Review Project. Jacksonville, FL: Office of the Governor; 1997.

19. Florida Department of Law Enforcement. Florida Domestic Violence Fatality Review Team Annual Report, 2001. Available at https://www.dcf.state.fl.us/programs/domesticviolence/publications/docs/FatalityReview2001.pdf. Last accessed July 18, 2019.

20. Florida Department of Law Enforcement. Florida Domestic Violence Fatality Review Team Annual Report, 2002. Available at http://www.ndvfri.org/reports/florida/Florida_Statewide_AnnualReport_2002.pdf. Last accessed July 18, 2019.

21. Florida Department of Law Enforcement. Florida Domestic Violence Fatality Review Team 2008 Annual Report: Executive Summary. Available at http://www.dcf.state.fl.us/programs/domesticviolence/publications/docs%5CFatalityReview2008.pdf. Last accessed July 18, 2019.

22. Florida Department of Children and Families. Violence Free Florida! Ending Abuse—Improving Lives. Available at https://www.dcf.state.fl.us/programs/domesticviolence/publications/docs/DVAnnualReport0102.pdf. Last accessed July 18, 2019.

23. Florida Coalition against Domestic Violence. Domestic Violence in Florida: 2010–2011 Annual Report to the Legislature. Available at http://www.dcf.state.fl.us/programs/domesticviolence/publications/docs/DVAnnualReport1011.pdf. Last accessed November 21, 2017.

24. National Coalition of Anti-Violence Programs. Lesbian, Gay, Bisexual, Transgender, Queer, and HIV-Affected Intimate Partner Violence in 2015. Available at http://avp.org/wp-content/uploads/2019/01/NCAVP-HV-IPV-2017-report.pdf. Last accessed July 18, 2019.

25. American College of Obstetricians and Gynecologists. Committee Opinion: Intimate Partner Violence. Available at http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Health-Care-for-Underserved-Women/Intimate-Partner-Violence. Last accessed July 18, 2019.

26. Rhodes KV, Kothari CL, Dichter M, Cerulli C, Wiley J, Marcus S. Intimate partner violence identification and response: time for a change in strategy. J Gen Intern Med. 2011;26(8):894-899.

27. National Center for Victims of Crime. Intimate Partner Violence. Available at http://victimsofcrime.org/docs/default-source/ncvrw2015/2015ncvrw_stats_ipv.pdf?sfvrsn=2. Last accessed July 18, 2019.

28. American College of Obstetricians and Gynecologists. Committee Opinion: Intimate Partner Violence. Available at https://www.acog.org/-/media/Committee-Opinions/Committee-on-Health-Care-for-Underserved-Women/co518.pdf?dmc=1&ts=20190624T1711014545. Last accessed July 18, 2019.

29. Cook J, Bewley S. Acknowledging a persistent truth: domestic violence in pregnancy. J R Soc Med. 2008;101:358-363.

30. Newberger EH, Barkan SE, Lieberman ES, et al. Abuse of pregnant women and adverse birth outcome: current knowledge and implications for practice. JAMA. 1992;267(17):2370-2372.

31. Hamby S, Finkelhor D, Turner H, Ormrod R. Children's Exposure to Intimate Partner Violence and Other Family Violence. Rockville, MD: U.S. Department of Justice Office of Juvenile Justice and Delinquency Prevention; 2011.

32. Child Welfare Information Gateway. Child Witnesses to Domestic Violence. Available at https://www.childwelfare.gov/pubPDFs/witnessdv.pdf. Last accessed July 18, 2019.

33. Kitzman KM, Gaylord NK, Holt AR, Kenny ED. Child witnesses to domestic violence: a meta-analytic review. J Consult Clin Psychol. 2003;71(2):339-352.

34. Finkelhor D, Turner H, Ormrod R, Hamby S, Kracke K. Children's Exposure to Violence: A Comprehensive National Survey. Rockville, MD: U.S. Department of Justice Office of Juvenile Justice and Delinquency Prevention; 2009.

35. Family Violence Prevention Fund. National Consensus Guidelines on Identifying and Responding to Domestic Violence Victimization in Health Care Settings. San Francisco, CA: Family Violence Prevention Fund; 2007.

36. Cooper A, Smith EL. Homicide Trends in the United States, 1980–2008. Washington, DC: Bureau of Justice Statistics; 2011.

37. U.S. Bureau of Justice. Press Release: Violence Rates Among Intimate Partners Differ Greatly According to Age. Available at https://www.bjs.gov/content/pub/press/ipva99pr.cfm. Last accessed July 18, 2019.

38. Acierno R, Hernandez MA, Amstadter AB, et al. Prevalence and correlates of emotional, physical, sexual, and financial abuse and potential neglect in the United States: the National Elder Mistreatment Study. Am J Public Health. 2010;100(2):292-297.

39. National Council on Aging. Elder Abuse Facts. Available at https://www.ncoa.org/public-policy-action/elder-justice/elder-abuse-facts/. Last accessed July 18, 2019.

40. Yon Y, Ramiro-Gonzalez M, Mikton CR, et al. The prevalence of elder abuse in institutional settings: a systematic review and meta-analysis. Eur J Public Health. 2019;29(1):58-67.

41. Calton JM, Cattaneo LB, Gebhard KT. Barriers to help seeking for lesbian, gay, bisexual, transgender, and queer survivors of intimate partner violence. Trauma Violence Abuse. 2016;17(5):585-600.

42. Compton MT. Clinical Manual of Prevention in Mental Health. 5th ed. Washington, DC: American Psychiatric Publishing; 2010.

43. Ard KL, Makadon HJ. Addressing intimate partner violence in lesbian, gay, bisexual, and transgender patients. J Gen Intern Med. 2011;26(8):930-933.

44. Bhandari M, Dosanjh S, Tornetta P 3rd, Matthews D, Violence Against Women Health Research Collaborative. Musculoskeletal manifestations of physical abuse after intimate partner violence. J Trauma. 2006;61(6):1473-1479.

45. Basile KC, Hertz MF, Back SE. Intimate Partner Violence and Sexual Violence Victimization Assessment Instruments for Use in Healthcare Settings: Version 1. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2007.

46. Sprague S, Madden K, Simunovic N, et al. Barriers to screening for intimate partner violence. Women Health. 2012;52(6):587-605.

47. Panos PT, Panos AJ. A model for a culture-sensitive assessment of patients in health care settings. Soc Work Health Care. 2000;31(1):49-62.

48. Pachter LM. Culture and clinical care: folk illness beliefs and behaviors and their implications for health care delivery. JAMA. 1994;271(9):690-695.

49. Florida Domestic Violence Fatality Review Team. Faces of Fatality, 2018. Available at https://www.fcadv.org/sites/default/files/FACES%20OF%20FATALITY%20VIII%20web.pdf Last accessed July 18, 2019.

50. de Boinville M. Screening for Domestic Violence in Health Care Settings. Available at https://aspe.hhs.gov/report/screening-domestic-violence-health-care-settings. Last accessed July 18, 2019.

51. James L, Brody D, Hamilton Z. Risk factors for domestic violence during pregnancy: a meta-analytic review. Violence Vict. 2013;28(3):359-380.

52. U.S. Department of Justice. Report of the Attorney General's National Task Force on Children Exposed to Violence. Available at https://www.justice.gov/defendingchildhood/cev-rpt-full.pdf. Last accessed July 18, 2019.

53. Ellonen N, Piispa M, Peltonen K, Oranen M. Exposure to parental violence and outcomes of child psychosocial adjustment. Violence Vict. 2013;28(1):3-15.

54. Yount KM, DiGirolamo AM, Ramakrishnan U. Impacts of domestic violence on child growth and nutrition: a conceptual review of the pathways of influence. Soc Sci Med. 2011;72(9):1534-1554.

55. Schiff M, Plotnikova M, Dingle K, Williams GM, Najman J, Clavarino A. Does adolescent's exposure to parental intimate partner conflict and violence predict psychological distress and substance use in young adulthood? A longitudinal study. Child Abuse Neglect. 2014;38(12):1945-1954.

56. Narayan AJ, Englund MM, Carlson EA, Egeland B. Adolescent conflict as a developmental process in the prospective pathway from exposure to interparental violence to dating violence. J Abnorm Child Psychol. 2014;42(2):239-250.

57. Schiamberg LB, Oehmke J, Zhang Z, et al. Physical abuse of older adults in nursing homes: a random sample survey of adults with an elderly family member in a nursing home. J Elder Abuse Negl. 2012;24(1):65-83.

58. Catalano S, Smith E, Snyder H, Rand M. Female Victims of Violence. Available at https://www.bjs.gov/content/pub/pdf/fvv.pdf. Last accessed July 18, 2019.

Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Screening for intimate partner violence and abuse of elderly and vulnerable adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;158(6):478-486. Available at http://annals.org/aim/fullarticle/1558517/screening-intimate-partner-violence-abuse-elderly-vulnerable-adults-u-s. Last accessed July 26, 2019.

91333 • Medical Error Prevention and Root Cause Analysis

Marjorie Conner Allen, BSN, JD

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

The Institute of Medicine's (IOM) 1999 publication To Err is Human: Building a Safer Health System, illuminated the unfortunate reality of medical errors in the healthcare industry. The report reviewed the prevalence of medical errors in the United States and highlighted measures that should be taken to prevent them. Specifically, the authors of the report noted that at least 44,000 and perhaps as many as 98,000 Americans were dying in hospitals each year as a result of medical errors. A 2016 report stated that the average number of annual in-hospital deaths attributable to medical error might actually be much higher, at around 400,000. Certainly, these numbers must be balanced against the millions of admissions to hospitals in the United States, which is in excess of 35 million annually. Healthcare professionals should commit to continuing to pay attention to evaluating current approaches for reducing errors and to building new systems to reduce the incidence of medical errors.

Table of Contents

91333 • Medical Error Prevention and Root Cause Analysis

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. DEFINING "MEDICAL ERROR"

3. ROOT CAUSE ANALYSIS PROCESS

FLORIDA LAW

4. ERROR REDUCTION AND PREVENTION

UNINTENDED RETENTION OF A FOREIGN BODY

WRONG-SITE SURGERY

DELAYS IN TREATMENT

OPERATIVE AND POSTOPERATIVE COMPLICATIONS

PATIENT SUICIDE

PATIENT FALLS

MEDICATION ERRORS

COMMON MISDIAGNOSES

5. OTHER CONSIDERATIONS FOR PATIENT SAFETY

USE OF AN INTERPRETER

6. CONCLUSION

Works Cited

91333 • Medical Error Prevention and Root Cause Analysis

Education Category. Management

Release Date. 09/01/2019

Expiration Date. 08/31/2022

Course Overview

The Institute of Medicine's (IOM) 1999 publication To Err is Human: Building a Safer Health System, illuminated the unfortunate reality of medical errors in the healthcare industry. The report reviewed the prevalence of medical errors in the United States and highlighted measures that should be taken to prevent them. Specifically, the authors of the report noted that at least 44,000 and perhaps as many as 98,000 Americans were dying in hospitals each year as a result of medical errors. A 2016 report stated that the average number of annual in-hospital deaths attributable to medical error might actually be much higher, at around 400,000. Certainly, these numbers must be balanced against the millions of admissions to hospitals in the United States, which is in excess of 35 million annually. Healthcare professionals should commit to continuing to pay attention to evaluating current approaches for reducing errors and to building new systems to reduce the incidence of medical errors.

Audience

This course is designed for all licensed healthcare professionals.

Course Objective

The purpose of this course is to satisfy the requirement of the Florida law and provide all licensed healthcare professionals with information regarding the root cause process, error reduction and prevention, and patient safety.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe how the Institute of Medicine defines "medical error."

2. Describe the types of sentinel events the Joint Commission has identified.

3. Discuss what factors must be included in a root cause analysis in order for the Joint Commission to consider it "thorough" and "credible."

4. Identify what types of adverse incidents must be reported to the Florida Agency for Healthcare Administration.

5. Identify the most common sentinel events reported to the Joint Commission.

6. Evaluate the most common misdiagnoses, as recognized by the Florida Board of Medicine, and outline the safety needs of special populations, including non-English-proficient patients.

Faculty

Marjorie Conner Allen, BSN, JD, received her Bachelor of Science in Nursing degree from the University of Florida, Gainesville, in 1984. She began her nursing career at Shands Teaching Hospital and Clinics at the University of Florida, Gainesville. While practicing nursing at Shands, she gave continuing education seminars regarding the nursing implications for dealing with adolescents with terminal illness. In 1988, Ms. Allen moved to Atlanta, Georgia where she worked at Egleston Children’s Hospital at Emory University in the bone marrow transplant unit. In the fall of 1989, she began law school at Florida State University. After graduating from law school in 1992, Ms. Allen took a two-year job as law clerk to the Honorable William Terrell Hodges, United States District Judge for the Middle District of Florida. After completing her clerkship, Ms. Allen began her employment with the law firm of Smith, Hulsey & Busey in Jacksonville, Florida where she has worked in the litigation department defending hospitals and nurses in medical malpractice actions. Ms. Allen resides in Jacksonville and is currently in-house counsel to the Mayo Clinic Jacksonville.

Faculty Disclosure

Contributing faculty, Marjorie Conner Allen, BSN, JD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

The Institute of Medicine's (IOM) 1999 publicationTo Err is Human: Building a Safer Health System, illuminated the unfortunate reality of medical errors in the healthcare industry. The report reviewed the prevalence of medical errors in the United States and highlighted measures that should be taken to prevent them. Specifically, the authors of the report noted that at least 44,000 and perhaps as many as 98,000 Americans were dying in hospitals each year as a result of medical errors and many more were being seriously injured [1]. They further noted that, even when using the lower estimate of 44,000, deaths in hospitals due to medical errors exceeded the annual deaths attributable to motor vehicle accidents (43,458), breast cancer (42,297), or AIDS (16,516) [1]. A 2016 report stated that the average number of annual in-hospital deaths attributable to medical error might actually be much higher, at around 400,000 [2]. This report places medical errors as the third leading cause of death in the United States. Certainly, these numbers must be balanced against the millions of admissions to hospitals in the United States, which is in excess of 35 million annually [1,3].

It does appear that some progress has been made in the past decade. The Agency for Healthcare Research and Quality found a 17% decline in hospital-acquired conditions between 2010 and 2013, or 1.3 million fewer conditions and 50,000 fewer deaths than if the 2010 rate had remained steady [4]. Though the precise mechanism(s) responsible for this decline is not clear, it occurred following a concerted effort by federal agencies, organizations, and individual providers to curtail medical errors. However, the statistics indicate that medical errors continue to be an issue. Healthcare professionals should commit to continuing to pay greater attention to evaluating approaches for reducing errors and to building new systems to reduce the incidence of medical errors.

Spurred by a commitment to reducing medical error incidents, the Florida Legislature mandates that all healthcare professionals in Florida complete a two-hour course on the topic of prevention of medical errors [5]. This continuing education course is designed to satisfy the requirements of the Florida law and provide all licensed healthcare professionals with information regarding the root cause analysis process, error reduction and prevention, and patient safety, as well as information regarding the five most misdiagnosed conditions as determined by the Florida Board of Medicine.

2. DEFINING "MEDICAL ERROR"

The IOM Committee on Quality of Healthcare in America defines error as "the failure of a planned action to be completed as intended or the use of a wrong plan to achieve an aim" [1]. It is important to note that medical errors are not defined as intentional acts of wrongdoing and that not all medical errors rise to the level of medical malpractice or negligence. Errors depend on two kinds of failures: either the correct action does not proceed as intended, which is described as an "error of execution," or the original intended action is not correct, which is described as an "error of planning" [1]. A medical error can occur at any stage in the process of providing patient care, from diagnosis to treatment, and even while providing preventative care. Not all errors will result in harm to the patient. Medical errors that do result in injury are sometimes called preventable adverse events or sentinel events—sentinel because they signal the need for immediate investigation and response [6].

Preventable adverse events or sentinel events are defined as those events that cause an injury to a patient as a result of medical intervention or inaction on the part of the healthcare provider whereby the injury cannot reasonably be said to be related to the patient's underlying medical condition. Thus, for example, if a patient has a surgical procedure and dies postoperatively from pneumonia, the patient has suffered an adverse event. But was that adverse event preventable; was it caused by medical intervention or inaction? The specific facts of this case must be analyzed to determine whether the patient acquired the pneumonia as a result of poor handwashing techniques of the medical staff (i.e., an error of execution), which would indicate a preventable adverse event, or whether the patient acquired the pneumonia because of age and comorbidities, which would indicate a nonpreventable adverse event.

Healthcare professionals can learn much by closely scrutinizing and evaluating adverse events that lead to serious injury or death. The evaluation of such events would also enable healthcare professionals to improve the delivery of health care and reduce future mistakes. In addition, healthcare professionals should have a process in place to evaluate those instances in which a medical error occurred and did not cause harm to the patient. By reviewing these processes, healthcare professionals are afforded the unique opportunity to identify system improvements that have the potential to prevent future adverse events. The Joint Commission, recognizing the importance of analyzing both preventable adverse events and near-misses, has established guidelines for recognizing these events and requires healthcare facilities to conduct a root cause analysis to determine the underlying cause of the event [7].

3. ROOT CAUSE ANALYSIS PROCESS

The Joint Commission is a national organization with a mission to improve the quality of care provided at healthcare institutions in the United States. It accomplishes this mission by providing accredited status to healthcare facilities. Accreditors play an important role in encouraging and supporting actions within healthcare organizations by holding them accountable for ensuring a safe environment for patients. Healthcare organizations should actively engage in a cooperative relationship with the Joint Commission through this accreditation process and participate in the process to reduce risk and facilitate desired outcomes of care.

The Joint Commission defines a sentinel event as "an unexpected occurrence involving the death or serious physical or psychological injury, or the risk thereof. Serious injury specifically includes loss of limb or function. The phrase 'or the risk thereof' includes any process variation for which a recurrence would carry a significant chance of a serious adverse outcome" [6]. Root cause analysis, as defined by the Joint Commission, is "a process for identifying the basic or causal factors that underlie variation in performance, including the occurrence or possible occurrence of a sentinel event" [6].

The following subsets of sentinel events are subject to review by the Joint Commission [6]:

- The event has resulted in an unanticipated death or major permanent loss of function, not related to the natural course of the patient's illness or underlying condition

or

- The event is one of the following (even if the outcome was not death or major permanent loss of function unrelated to the natural course of the patient's illness or underlying condition):

- Suicide of any patient receiving care, treatment, and services in a staffed around-the-clock care setting or within 72 hours of discharge

- Unanticipated death of a full-term infant

- Abduction of any patient receiving care, treatment, and services

- Discharge of an infant to the wrong family

- Rape, assault (leading to death or permanent loss of function), or homicide of any patient receiving care, treatment, and services

- Rape, assault (leading to death or permanent loss of function), or homicide of a staff member, licensed independent practitioner, visitor, or vendor while on site at the healthcare organization

- Hemolytic transfusion reaction involving administration of blood or blood products having major blood group incompatibilities (e.g., ABO, Rh, other blood groups)

- Invasive procedure, including surgery, on the wrong patient or wrong site

- Unintended retention of a foreign object in a patient after surgery or other invasive procedures

- Severe neonatal hyperbilirubinemia (bilirubin >30 mg/dL)

- Prolonged fluoroscopy with cumulative dose >1,500 rads to a single field or any delivery of radiotherapy to the wrong body region or >25% above the planned radiotherapy dose

- Fire, flame, or unanticipated smoke, heat, or flashes occurring during an episode of patient care

- Any intrapartum (related to the birth process) maternal death

- Severe maternal morbidity

Alternatively, the following examples are events that are NOT considered reviewable under the Joint Commission's sentinel event policy [6]:

- Any close call ("near miss")

- Full or expected return of limb or bodily function to the same level as prior to the adverse event by discharge or within two weeks of the initial loss of said function, whichever is the longer period

- Any sentinel event that has not affected a recipient of care (e.g., patient, individual, resident)

- Medication errors that do not result in death or major permanent loss of function

- Suicide other than in an around-the-clock care setting or following elopement from such a setting

- A death or loss of function following a discharge against medical advice

- Unsuccessful suicide attempts unless resulting in major permanent loss of function

- Minor degrees of hemolysis not caused by a major blood group incompatibility and with no clinical sequelae

(For further definition of terms, please refer to the Joint Commission's Sentinel Event Policy and Procedures at https://www.jointcommission.org/sentinel_event_policy_and_procedures.)

As part of the accreditation requirement, the Joint Commission requires that healthcare organizations have a process in place to recognize these sentinel events, conduct thorough and credible root cause analyses that focus on process and system factors, and document a risk-reduction strategy and internal corrective action plan that includes measurement of the effectiveness of process and system improvements to reduce risk [6]. This process must be completed within 45 days of the organization having become aware of the sentinel event.

The Joint Commission will consider a root cause analysis acceptable for accreditation purposes if it focuses primarily on systems and processes, not individual performance [6]. In other words, the healthcare organization should minimize the individual blame or retribution for involvement in a medical error. In addition, the root cause analysis should progress from special causes in clinical processes to common causes in organizational processes, and the analysis should repeatedly dig deeper by asking why, then, when answered, why again, and so on. The analysis should also identify changes that can be made in systems and processes, either through redesign or development of new systems or processes, which would reduce the risk of such events occurring in the future. The Joint Commission requires that the analysis be thorough and credible. To be considered thorough, the root cause analysis must include [6]:

- A determination of the human and other factors most directly associated with the sentinel event and the process(es) and systems related to its occurrence

- Analysis of the underlying systems and processes through a series of "why" questions to determine where redesign might reduce risk

- Inquiry into all areas appropriate to the specific type of event

- Identification of risk points and their potential contributions to this type of event

- A determination of potential improvement in processes or systems that would tend to decrease the likelihood of such events in the future, or a determination, after analysis, that no such improvement opportunities exist

To be considered credible, the root cause analysis must meet the following standards [6]:

- The organization's leadership and the individuals most closely involved in the process and systems under review must participate in the analysis.

- The analysis must be internally consistent; that is, it must not contradict itself or leave obvious questions unanswered.

- The analysis must provide an explanation for all findings of "not applicable" or "no problem."

- The analysis must include consideration of any relevant literature.

Finally, as previously discussed, after conducting this root cause analysis, the organization must prepare an internal corrective action plan. The Joint Commission will accept this action plan if it identifies changes that can be implemented to reduce risk or formulate a rationale for not undertaking such changes, and if, where improvement actions are planned, it identifies who is responsible for implementation, when the action will be implemented, and how the effectiveness of the actions will be evaluated [6].

FLORIDA LAW

Healthcare professionals have an obligation to report adverse events to leadership and ensure that organizations have processes in place to satisfy the Joint Commission requirement. In Florida, certain serious adverse incidents must also be reported to Florida's Agency for Health Care Administration (AHCA). Florida law requires that licensed facilities, such as hospitals, establish an internal risk management program. As part of that program, licensed facilities must develop and implement an incident reporting system, which requires the development of appropriate measures to minimize the risk of adverse incidents to patients, as well as imposes an affirmative duty on all healthcare providers and employees of the facility to report adverse incidents to the risk manager or to his or her designee. The risk manager must receive these incident reports within 3 business days of the incident, and depending on the type of incident, the risk manager may have to report the incident to AHCA within 15 days of receipt of the report.

Florida Statute 395.0197 specifically defines an adverse incident as [8]:

For purposes of reporting to the agency pursuant to this section, the term "adverse incident" means an event over which health care personnel could exercise control and which is associated in whole or in part with medical intervention, rather than the condition for which such intervention occurred, and which:

1. Results in one of the following injuries:

1. Death;

2. Brain or spinal damage;

3. Permanent disfigurement;

4. Fracture or dislocation of bones or joints;

5. A resulting limitation of neurological, physical, or sensory function which continues after discharge from the facility;

6. Any condition that required specialized medical attention or surgical intervention resulting from nonemergency medical intervention, other than an emergency medical condition, to which the patient has not given his or her informed consent; or

7. Any condition that required the transfer of the patient, within or outside the facility, to a unit providing a more acute level of care due to the adverse incident, rather than the patient's condition prior to the adverse incident

2. Was the performance of a surgical procedure on the wrong patient, a wrong surgical procedure, a wrong-site surgical procedure, or a surgical procedure otherwise unrelated to the patient's diagnosis or medical condition;

3. Required the surgical repair of damage resulting to a patient from a planned surgical procedure, where the damage was not a recognized specific risk, as disclosed to the patient and documented through informed-consent process; or

4. Was a procedure to remove unplanned foreign objects remaining from a surgical procedure.

In 2018, the Florida AHCA reported that a total of 131 deaths occurred as a result of hospital error, 20.6% of 636 adverse incidents reported for the year. The next most common incidents during this period were surgical procedure to remove foreign object from a previous surgical procedure (16.5%), transfer of the patient to a unit providing a more acute level of care due to the adverse incident (14.2%), surgical procedures unrelated to the patient's diagnosis or medical needs (10%), and surgical procedure performed on the wrong site (5.3%) [9]. The following adverse incidents must be reported to the AHCA within 15 calendar days after their occurrence [8]:

- The death of a patient

- Brain or spinal damage to a patient

- The performance of a surgical procedure on the wrong patient

- The performance of a wrong-site surgical procedure

- The performance of a wrong surgical procedure

- The performance of a surgical procedure that is medically unnecessary or otherwise unrelated to the patient's diagnosis or medical condition

- The surgical repair of damage resulting to a patient from a planned surgical procedure, where the damage is not a recognized specific risk, as disclosed to the patient and documented through the informed-consent process

- The performance of procedures to remove unplanned foreign objects remaining from a surgical procedure

Each incident will be reviewed by the AHCA, who will then determine the penalty to be imposed upon the responsible party [8]. All Florida healthcare professionals who practice in licensed facilities should familiarize themselves with these requirements and ensure that the facility in which they practice has processes in place to ensure compliance.

Unlike Florida's mandatory reporting of serious adverse incidents, the Joint Commission recommends that healthcare organizations voluntarily report sentinel events, and it encourages the facilities to communicate the results of their root cause analyses and their corrective action plans. As a result of the sentinel events that have been reported, the Joint Commission has compiled Sentinel Event Alerts. These alerts are intended to provide healthcare organizations with important information regarding reported trends and, by doing so, highlight areas of potential concern so an organization may review its own internal processes to maximize error reduction and prevention with regard to a particular issue [7].

4. ERROR REDUCTION AND PREVENTION

Between 2005 and 2018, the Joint Commission reviewed 11,622 sentinel events [11]. Some events, such as fire, impacted multiple patients. Sentinel event reviews during this time period were frequently conducted for unintended retention of a foreign body; wrong-patient, wrong-site, wrong-procedure surgery; delay in treatment; operative and postoperative complications; patient suicide; patient fall; and medication error [11].

UNINTENDED RETENTION OF A FOREIGN BODY

In 2017–2018, the most frequently reported sentinel event reported to the Joint Commission was unintended retained foreign objects [11]. The prevalence of these events has remained relatively stable since 2009, indicating that preventing these errors remains difficult for practitioners and facilities. The most commonly retained items are sponges, followed by catheter guidewires and other (a broad category encompassing a wide variety of items) [10].

In addition to harming patients and contributing to distrust in the medical system, the unintended retention of foreign objects significantly contributes to patient care costs [13]. The average total cost of care related to unintended retained foreign objects is $166,000 to $200,000 [13].

According to the sentinel event data, the most common root causes of unintended retained foreign objects reported to the Joint Commission are [13]:

- The absence of policies and procedures

- Failure to comply with existing policies and procedures

- Problems with hierarchy and intimidation

- Failure in communication with physicians

- Failure of staff to communicate relevant patient information

- Inadequate or incomplete education of staff

WRONG-SITE SURGERY

Operating on the wrong part of a patient's body is an obvious sign that there is a problem in the operating room system. Interestingly, wrong-site surgery occurred more commonly in orthopedic procedures than in all other surgical specialties combined. The American Academy of Orthopaedic Surgeons takes this issue seriously, and it has taken special steps to eliminate the problem. For example, it recommends that a surgeon sign their initials at the correct site of surgery with an indelible pen. Unless the initials are visible, the surgeon should not make an incision [12]. Writing "NO" in large black letters on the side not to be operated on was suggested in the past, but this is discouraged due to possible confusion with the surgeon's initials. In spinal surgery, the Academy recommends that an intraoperative radiograph and radiopaque marker be used to determine the exact vertebral level of spinal surgery [12]. Whatever the mechanism used to prevent and reduce the incidence of this error, it is clear that this is not just the surgeon's problem. All of the operating room personnel, including physicians, nurses, technicians, anesthesiologists, and other preoperative allied health personnel, should monitor procedures to ensure verification procedures are followed, especially for high-risk procedures.

Due to the prevalence of wrong-site, wrong-procedure, and wrong-person surgeries, the Joint Commission, along with more than 50 professional healthcare organizations, convened two summits to help reduce the occurrence of these errors. The first summit, convened in 2003, developed a Universal Protocol that consisted of the following: a preprocedure verification process; marking the operative/procedure site with an indelible marker; taking a "time-out" with all team members immediately before starting the procedure; and adaptation of the requirements to all procedure settings, including bedside procedures. However, the incidence of wrong-site surgeries continued to increase, and in 2007 and 2010, additional summits were organized to pinpoint barriers in compliance and discover new strategies to eliminate these errors [14]. As of 2019, the Universal Protocol has been incorporated into the National Patient Safety Goal chapter of the Joint Commission accreditation manual [15].

DELAYS IN TREATMENT

According to the Joint Commission, more than half of all reported delays in treatment sentinel events in 2010–2014 resulted in patient death [16]. It is important to keep in mind that delays in treatment can occur in any healthcare setting. The most common reason for a delay in treatment is misdiagnosis; however, delays can also result from delayed test results, physician availability, delayed administration of ordered care, incomplete treatment, and even inability to get an initial appointment or follow-up appointment in a timely manner [16]. The main root causes contributing to delays in treatment are inadequate assessments, poor planning, communication failures, and human factors. Recommendations from the Joint Commission include avoiding cognitive shortcuts, improving health information technology, incorporating diagnostic checklists into the electronic record, promoting provider-to-provider communication, engaging leadership in developing solutions, focusing organization attention on the scheduling process and on ordering tests and reporting test results, improving access to care, implementing a standardized communications method, maintaining adequate staffing levels, and increasing patient and family engagement/activation [16].

OPERATIVE AND POSTOPERATIVE COMPLICATIONS

Many of the sentinel events reported to the Joint Commission regarding operative and postoperative complications occurred in relation to nonemergent procedures, such as interventional imaging and/or endoscopy, tube or catheter insertion, open abdominal surgery, head and neck surgery, orthopedic surgery, and thoracic surgery [17]. The majority of the reporting healthcare facilities cited miscommunication as the primary root cause. Other identified causes include failure to follow established procedures, incomplete preoperative assessment, inconsistent postoperative monitoring procedures, and failure to question inappropriate orders. In order to reduce the risk, reporting facilities have identified a number of strategies, including improving staff orientation and training, increasing educational opportunities for physicians, clearly defining expected channels of communication, and monitoring consistency of compliance with procedures. Healthcare facilities should review postoperative patient monitoring procedures to ensure an adequate level appropriate to the needs of the patient, regardless of the setting (e.g., operating room, endoscopy suite, radiology department) [17]. Based upon these findings, it is clear that direct communication among healthcare providers is key to preventing operative and postoperative complications. Healthcare facilities should provide more staff education regarding preventative measures, and healthcare providers can do their part by engaging in a healthy and mutual respect for all of the members of the healthcare team [17].

PATIENT SUICIDE

It is estimated that between 48 and 65 hospital inpatient suicides occur per year in the United States. Most of these cases (31 to 52) occur in psychiatric units or involve psychiatric inpatients. The most common method is hanging [50]. Times of care transition are particularly risky, with a 200% increase in risk in the week after discharge from a psychiatric facility; the elevated risk continues for four years [18]. Other risk factors include previous suicide attempt or self-injury, mental or emotional disorders, history of trauma or loss, serious illness or chronic pain, substance use disorder, social isolation, and access to lethal means.

The most common root cause documented for patient suicide reported between 2010 and 2014 was shortcomings in assessment, most commonly psychiatric assessment [18]. In addition, nearly 25% of behavioral health facilities accredited by the Joint Commission were found noncompliant with the requirement to conduct an adequate suicide risk assessment in 2014.

The Joint Commission has recommended a number of suicide risk reduction strategies, including [18]:

- Review each patient's personal and family medical history for suicide risk factors.

- Screen all patients for suicide ideation, using a brief, standardized, evidence-based screening tool.

- Review screening questionnaires before the patient leaves the appointment or is discharged.

- Establish a collaborative, ongoing, and systematic assessment and treatment process with the patient involving the patient's other providers, family, and friends, as appropriate.

- To improve outcomes for at-risk patients, develop treatment and discharge plans that directly target suicidality.

- Educate all staff in patient care settings about how to identify and respond to patients with suicide ideation.

- Document decisions regarding the care and referral of patients with suicide risk.

A simple review of these measures demonstrates that healthcare providers can avoid the devastating impact of an inpatient suicide by implementing fairly routine preventative strategies, such as removing harmful items and careful screening through the admission and discharge processes.

PATIENT FALLS

Patient falls are a constant challenge in healthcare facilities. Patients who are at highest risk include the elderly, those who have an altered mental status due to chronic mental illness or acute intoxication, and those who have a history of prior falls. It is obvious from these factors that a thorough and complete patient history may be the key to identifying those at risk. The root causes of those patient falls that healthcare facilities identified as sentinel events and reported to the Joint Commission included inadequate assessment, communication failures, lack of adherence to protocols and safety practices, inadequate staff orientation, supervision, staffing levels or skill mix, deficiencies in the physical environment, and lack of leadership [19]. Risk reduction strategies to these root causes are fairly straightforward, although in practice, preventing falls is difficult. The most important are the use of a standardized assessment tool to identify fall and injury risk factors, assessing an individual patient's risks that may not have been captured through the tool, and interventions tailored to an individual patient's identified risks [19].

Because patient falls often result in morbidity, mortality, immobility, and early nursing home placement for patients, it is imperative that healthcare facilities initiate adequate fall prevention programs, which will ultimately reduce injuries. Failure to do so will result in a spiraling increase in the number of falls in healthcare facilities, particularly among the elderly who are at highest risk. As more Americans live beyond 65 years of age, the need to develop mobility protocols and programs to reduce the risk of falls and injuries for the older adult grows more urgent.

MEDICATION ERRORS

Unquestionably, medication errors are one of the most common causes of avoidable harm to patients. These errors may occur at three critical points: when ordered by a physician, dispensed by a pharmacist, or administered by a nurse.

The National Coordinating Council for Medication Error Reporting and Prevention defines a medication error as [20]:

Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient or consumer. Such events may be related to professional practice, healthcare products, procedures, and systems, including prescribing: order communication; product labeling; packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use.

A number of medication errors can be linked to the prescriber who continually uses potentially dangerous abbreviations and dose expressions. Despite repeated warnings by the Institute for Safe Medication Practices about the dangers associated with using certain abbreviations when prescribing medications, this practice continues. To eliminate this factor, there are fairly simple steps that can eliminate much confusion. Prescribers should [21]:

- Avoid the use of the symbol "U" or "u" but rather spell "units" when ordering drugs, such as insulin.

- Spell out medication names completely rather than using abbreviations and acronyms.

- Avoid using abbreviations for "daily" (QD), "every other day" (QOD), or "four times daily" (QID), which are easily confused.

- Use leading zeros before a decimal point (e.g., 0.2 mg instead of .2 mg), and do not use trailing zeros (e.g., 2 mg instead of 2.0 mg).

- Write out "morphine sulfate" and "magnesium sulfate" instead of using the abbreviations (MS, MSO_4, MgSO_4).

The Institute for Safe Medication Practices publishes a list of error-prone abbreviations, symbols, and dose designations online at https://www.ismp.org/Tools/errorproneabbreviations.pdf.

Other factors contributing to prescriber errors are illegible or confusing handwriting and, a frequently cited cause of many adverse and sentinel events, the failure of healthcare providers to assess risk and prevent errors. Addressing illegibility may include developing appropriate policies and procedures, tracking and trending patterns, and evaluating results through peer review committees. Improving communication might include developing protocols for the use of verbal orders to assure that those from an onsite practitioner would be limited to an emergency situation only. No verbal orders should be taken for certain medications, such as for chemotherapy, and all verbal orders should be repeated for clarification and, whenever possible, reiterated to a third person. Another method of improving communication might involve reviewing the hospital formulary in collaboration with the Pharmacy and Therapeutics Committee of the medical staff to limit, where appropriate, the number of therapeutically and generically equivalent products [22].

It has been estimated that between 0.2% and 10% of prescriptions are dispensed incorrectly [23]. The most common type of medication error is wrong drug (43.8%), followed by wrong dose (31.5%), failure to consult with prescriber (4.9%), and compounding error (3.7%) [24]. Safe medication dispensing practices may include a number of risk reduction strategies to reduce the incidence of errors that may cause harm to patients [22,25,54]:

- Ensure that appropriate and current drug reference texts and/or online resources are immediately available to pharmacy personnel.

- Ensure that essential patient information, such as allergies, age, weight, current diagnoses, pertinent lab values, and current medication regimen, is available to the pharmacist prior to the dispensing of a new medication order.

- Require clarification of any order that is incomplete, illegible, or otherwise questionable using an established process for resolving questions.

- Whenever possible, dispense dosage units in a ready-to-administer form.

- Dispense single-dose vials and ampoules rather than multidose vials.

- Select oral rather than injectable routes, when possible.

- Require that a pharmacist double-check all mathematical calculations for neonatal and pediatric dilutions, parenteral nutrition solutions, and other compounded pharmaceutical products.

- Create an environment for the dispensing area that minimizes distractions and interruptions, provides appropriate lighting, air conditioning, and air flow, safe noise levels, and includes ergonomic consideration of equipment, fixtures, and technology.

- Require that a second pharmacist double-check the accuracy of order entry and dose calculations for all orders involving antineoplastic agents and other high-risk drugs dispensed by the pharmacy.

- Enhance the awareness of look-alike and sound-alike medications, and use warning signs to help differentiate medications from one another, especially when confusion exists between or among strengths, similar looking labels, or similar sounding names.

- Separate look-alike and sound-alike medications in pharmacy dispensing areas or consider repackaging or using different vendors.

- Follow-up and periodically evaluate the need for continued drug therapy for individual patients.

Once again, communication is likely the key to avoiding dispensing errors. Pharmacists should work closely with their staff to ensure that proper protocols are followed, and most importantly, when questions arise regarding a prescription, the pharmacist should take the time to contact the prescriber directly to obtain clarification.

The healthcare provider who has the responsibility to administer a medication has the final opportunity to avoid a mistake. In most cases, particularly in inpatient settings, this responsibility falls to the nurse. Nurses are often taught in nursing school to review the five "rights" prior to administering any medication: the right patient is given the right drug in the right dose by the right route at the right time [26]. Medication errors generally fall into four categories, which mimic these five "rights." The first is the failure to follow procedural safeguards, such as ensuring that essential patient information, including allergies, age, weight, and current medication regimen, is available. The second is unfamiliarity with a drug. In one case, a jury determined that a nurse was negligent for giving a drug without having reviewed the literature, which stated that the necessary precautions for the administration of the drug required the specialized skill of an anesthesiologist. The third category of drug administration is failure to use the correct mode of administration. A nurse in Delaware was held liable for administering a medication by injection after an order had been written to change the route to oral. The final category involves failure to obtain clarification if an order is incomplete, illegible, or otherwise questionable. In a case tried in Louisiana, a nurse was held liable for administering a medication that a physician ordered, notwithstanding that the dose was excessive. The nurse's administration of the drug led to the patient's death [27].

In addition, healthcare facilities should implement appropriate guidelines, policies, and procedures to ensure safe medication administration practice. These policies should require that staff members who administer medications [25,54]:

- Are knowledgeable about the drug's uses, precautions, contraindications, potential adverse reactions, interactions, and proper method of administration

- Resolve questions prior to medication administration

- Only administer medications that have been properly labeled with medication name, dose to be administered, dosage form, route, and expiration date

- Utilize a standard medication administration time schedule and receive education on how and when to incorporate newly started medication orders safely into the standardized schedule

- Have a second person verify a dosage calculation if a mathematical calculation of a dose is necessary

- Receive adequate education on the operation and use of devices and equipment used for medication administration (for example, patient-controlled anesthesia pumps and other types of infusion pumps)

- Have another person double-check infusion pump settings when critical, high-risk drugs are infused

- Document all medications immediately after administration

Finally, healthcare facilities should have proper quality assurance measures in place to monitor medication administration practices. Included among these would be protocols and guidelines for use with critical and problem-prone medications to help optimize therapies and minimize the possibility of adverse events and to integrate "triggers" to indicate the need for additional clinical monitoring [25].

It is important to note that the pediatric population is especially vulnerable to medication errors. When children are prescribed adult medications, care must be taken to adjust dosage according to weight, requiring the physician to use pediatric-specific calculations. Also, many healthcare settings are not trained to care for the pediatric patient. Intolerance due to physiologic immaturity is also a factor in adverse response to medications, and in many cases, this population cannot communicate their discomfort due to adverse reactions. Risk reduction strategies include standardizing and effectively identifying medications and processes for drug administration, ensuring pharmacy oversight, and using technology, such as medication dispensing programs, infusion pumps, and bar-coding, judiciously [28].

COMMON MISDIAGNOSES

As Florida healthcare professionals, it is important to be aware that in addition to wrong-site/wrong-procedure surgery, several medical conditions also continue to be misdiagnosed. As of 2022, the Florida Board of Medicine has determined the five most misdiagnosed conditions to be [29]:

- Cancer-related conditions

- Neurologic conditions

- Cardiac-related issues

- Missed spinal cord compression

- Gastroenterology-related issues

It is important to be aware of the possibility of misdiagnosis and incorporate this knowledge into practice.

Cancer

The early detection and diagnosis of cancers is crucial for selecting the appropriate treatment approach and to ensure an optimum outcome. However, an estimated 12% of cancer patients are initially misdiagnosed, and the missed or delayed diagnosis of cancers remains a significant cause of medical malpractice claims [30,31]. The causes of missed diagnoses vary widely among cancers in different parts of the body. In many cases, patients who do not fit the typical profile for a specific cancer (e.g., young age) may be underdiagnosed, and it is important that cancer is considered as part of the differential diagnosis in ambiguous cases [31,32,33]. In order to prevent missed or delayed cancer diagnosis, practitioners may take steps to ensure adherence to clinical guidelines for screening and diagnosis, use tools to facilitate communication, and engage strategies to ensure appropriate follow-up [55].

Neurologic/Spinal Cord-Related Conditions

Delayed or missed diagnoses of neurologic conditions may result in serious morbidity and mortality. Headaches are a common presenting condition in acute and primary care, and an estimated 5% of all patients admitted to emergency departments have neurologic symptoms [34]. Acute headache with neurologic symptoms may be misdiagnosed as stroke [35]. In addition, missed spinal fracture diagnoses are one of the leading causes of malpractice claims against radiologists [48].

One of the most common neurologic conditions is headache; however, it has been estimated that 50% of migraine patients remain undiagnosed or misdiagnosed, and only a small number (8% to 10%) of individuals with migraine take migraine-specific medications such as triptans or ergotamines [65,66]. Patients suffering from daily migraines may be misdiagnosed with chronic sinusitis or rhinitis and repeatedly and unsuccessfully treated with broad-spectrum antibiotics [67,68]. The diagnosis of migraine is based solely on a constellation of signs and symptoms, and a comprehensive medical and neurological examination is required to exclude secondary headache [69]. Useful evidence-based clinical guidelines for migraine screening have been developed and are summarized in the mnemonic POUND: pulsatile headache; one-day duration (4 to 72 hours); unilateral location; nausea or vomiting; and disabling intensity [70]. Competence of the clinician and effective communication with the patient play a crucial role in the diagnosis of migraine.

Cardiac-Related Issues

The clinical presentation of chest pain has many possible etiologies, ranging from benign (e.g., panic/anxiety, pneumonia, peptic ulcer, gastroesophageal reflux disease, and pericarditis) to life-threatening (e.g., pulmonary embolism, acute coronary syndrome [ACS], aortic dissection, and pneumothorax). In many cases, it is best to rule out the more urgently threatening possibilities before testing for other causes.

Of the potentially life-threatening causes of chest pain, ACS is the most prevalent. Although a large percentage of individuals with suspected ACS will be seen initially in emergency departments, patients in any healthcare setting, regardless of other diagnoses, may abruptly develop chest pain suspicious for ACS. When a patient presents with clinical signs suspicious for myocardial infarction, immediate medical intervention is directed at confirming a diagnosis and stratifying the person's risk for adverse events such as cardiac arrest and severe/significant damage to the myocardium [41]. It is important to note that while some patients will present with classic ACS-related chest pain (tightness, sensation of pressure, heaviness, crushing, vise-like, aching pain in the substernal or upper left chest), many patients, particularly women and older patients, will present with "atypical" ACS-related chest pain [45,46]. Words commonly used to describe "atypical" chest pain associated with ACS include numbness, tingling, burning, stabbing, or pricking. Atypical chest pain location includes any area other than substernal or left sided, such as the back, area between shoulder blades, upper abdomen, shoulders, elbows, axillae, and ears [43,44,45,46]. Aside from atypical clinical presentation, other possible causes of missed ACS diagnosis include failure of interpretation of the history, failure to correctly interpret the electrocardiogram, failure to perform an electrocardiogram when necessary, and lack of proper use of cardiac enzyme test [47].

Missed Spinal Cord Compression

Epidural compression syndrome is an umbrella term that encompasses spinal cord compression, cauda equina syndrome, and conus medullaris syndrome. While these conditions differ in the level of neurologic deficit at presentation, they are otherwise similar in symptoms, evaluation, and management. Massive herniation of a midline disk, typically at the L4 to L5 disk level, is the most common cause of epidural compression syndrome. Tumor, epidural abscess, spinal canal hematoma, or lumbar spine spondylosis represent other causes [37].

Spinal cord compression is often secondary to herniated disk, vertebral fracture, or space-occupying lesion. Missing this diagnosis, typically by attributing the associated pain to muscle or nerve causes, will miss potentially catastrophic conditions [38,39,40,41]. In a study of 3,786 individuals, the estimated prevalence of asymptomatic spinal cord compression in a healthy population was 24.2%, with a significantly higher prevalence in older populations compared with younger populations and American/European populations compared with Asian populations [42].

In patients with spinal cord compression, neurologic status at diagnosis is the greatest predictor of ultimate neurologic outcome and underscores the importance of early accurate diagnosis. The dominant symptom is back pain with accelerating pain severity. Pain from epidural spinal cord compression is made worse with recumbent positioning, and unilateral or bilateral radiculopathy may develop over time. For many patients, leg pain or neurologic symptoms are more dominant than back pain. Also common at diagnosis is symmetrical lower extremity weakness that may have progressed to gait disturbance or paralysis. Decreased lower extremity reflexes are associated with cauda equina syndrome [37].

Gastroenterology-Related Conditions

Gasteroenterologic conditions may present with nonspecific complaints (e.g., abdominal pain, nausea) common to a variety of illnesses, complicating and delaying diagnosis. In one study of patients with pancreatic cancer, more than 30% were initially misdiagnosed, most commonly with gall bladder disease [71]. Diagnosis and screening for GI disorders may be complicated by a lack of definitive test (e.g., irritable bowel syndrome) or by limits on screening recommendations (e.g., colorectal cancer). However, delayed diagnosis can lead to worsening conditions and poorer prognosis.

In general, gastrointestinal syndromes/symptoms may be classified into three general diagnostic categories: organic, motility, or functional disorders [72,73]. Functional GI disorders are idiopathic disorders of gut-brain interaction and, unlike organic and motility disorders, diagnosis involves identification of symptom clusters. As such, misdiagnosis is more common.

Another important consideration is GI symptom-specific anxiety, an important perpetuating factor that describes threatening interpretation and out-of-proportion behavioral response to GI sensations. This anxiety to real GI symptoms and the frequency of psychiatric comorbidity can lead to functional GI syndromes being dismissed as psychological or psychosomatic in nature.

5. OTHER CONSIDERATIONS FOR PATIENT SAFETY

The most important issue to improving patient safety is being aware of the particular safety hazards that may exist for various patient populations and on particular specialty units. In addition, education of the patient and the family should be a priority.

Infants and young children are not developmentally or cognitively able to participate in care and decision making, thus putting them at higher risk, especially for medication errors. In addition, when a medication error occurs in this population, infants and young children are at higher risk because of their physical immaturity and increased sensitivity to the effects of drugs. The family or guardian of a pediatric patient should be encouraged to ask questions, especially if something seems wrong. In addition, a meta-analysis found that computerized provider order entry with clinical decision support reduced pediatric medication errors by 36% to 87% [51]. As such, the adoption of electronic support systems may help to reduce or eliminate these errors.

An estimated 30% of individuals 65 years of age or older who are living in the community fall each year [52]. Older patients may have poor vision, as a result of cataracts, glaucoma, and/or macular degeneration, and cardiovascular problems, which might result in syncope or postural hypotension. These conditions may affect patients' balance and stability. Bladder dysfunction, such as nocturia, may cause an elderly patient to have to ambulate more during the night in an unfamiliar environment, thereby increasing the risk of a fall. Lower extremity dysfunctions, such as arthritis, muscle weakness, or peripheral neuropathy, may make it more difficult to ambulate at any time. In addition to being at greater risk for falls, the elderly are also more prone to medication errors as their ability to understand instructions or to recognize an unfamiliar medication may be affected by dementia or other cognitive disorders. Interventions that can help prevent falls in the elderly include exercise programs, tai chi, vision improvement (e.g., first cataract surgery), and multifactorial assessment and intervention [52].

There are also unique factors that increase the risk of medical errors on specialty units. For instance, in critical care units, patients may be suffering from environmental psychosis, which could inhibit participation in their care. This is also true of lethargic and comatose patients. These patients are at particular risk because they cannot participate in the identification process. On psychiatric wards, patients may be suicidal or depressed, which may cause them to act out or attempt to harm themselves or others. Patients may also experience orthostatic side effects due to certain psychiatric medications, which may increase the incidence of falls. Obstetric patients are at higher risk for falls because they may have decreased sensation and mobility due to administration of epidural anesthesia, and they may also suffer from excessive blood loss, which could lead to postural hypotension [49]. Again, the key is identifying the unique needs of the particular population.

With regard to education, a number of organizations have developed guidelines to facilitate the role of patients as their own safety advocates. These guidelines are not intended to shift the burden of monitoring medical error to patients. Rather, they encourage patients to share responsibility for their own safety. As healthcare professionals, we should ensure that all of our patients are familiar with these guidelines. The Agency for Healthcare Research and Quality has developed a "Patient Fact Sheet" that outlines 20 tips for patients to help prevent medical errors [53]. Although some of these suggestions may seem extreme, many patients now desire to have a more active role in their care. Some of these items have become routine or are currently required, such as consultations by pharmacists when a patient picks up a prescribed medication.

USE OF AN INTERPRETER

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient education is such a vital aspect of preventing medical errors, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

Interpreters are more than passive agents who translate and transmit information back and forth from party to party. They should be professionally trained in ethics, accuracy, completeness, and impartiality. Furthermore, it is the interpreter's role to negotiate cultural differences and promote culturally responsive communication and practice. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. In any case in which information regarding diagnostic procedures, treatment options, or medication/treatment measures is being provided, the use of an interpreter should be considered.

6. CONCLUSION

Although the United States has one of the top 40 healthcare systems in the world, it is apparent that the numbers of medical errors are at unacceptably high levels. The consequences of medical errors are often more severe than the consequences of mistakes in other industries. They may lead to death or to serious and long-term disability, which underscores the need for aggressive action in this area. As a starting point, we should become an active part of the solution. This will only happen if all healthcare professionals voice their concerns when they identify problems in a system or process. In addition, we should actively participate in the root cause analysis process, understanding that the goal is not to assign blame, but rather to identify how we can improve the process to provide the best quality care to our patients. Medical errors are costly, not only because patients may lose their lives or livelihoods, but also because patients lose trust in the system and colleagues lose faith in each other. To preserve the integrity of our system, we must correct this problem, and the solution begins with each of us.

Works Cited

1. Committee on Quality of Health Care in American. To Err is Human: Building a Safer Health System. Washington, DC: National Academy Press; 1999.

2. Makary MA, Daniel M. Medical error: the third leading cause of death in the U.S. BMJ. 2016;353:i2139.

3. Centers for Disease Control and Prevention. Hospital Utilization (in Non-Federal Short-Stay Hospitals). Available at https://www.cdc.gov/nchs/fastats/hospital.htm. Last accessed August 1, 2019.

4. Agency for Healthcare Research and Quality. Efforts To Improve Patient Safety Result in 1.3 Million Fewer Patient Harms: Interim Update on 2013 Annual Hospital-Acquired Condition Rate and Estimates of Cost Savings and Deaths Averted From 2010 to 2013. Available at https://www.ahrq.gov/professionals/quality-patient-safety/pfp/interimhacrate2013.html. Last accessed August 1, 2019.

5. Florida Statutes. 456.013 Department; General Licensing Provisions. Available at http://www.leg.state.fl.us/Statutes/index.cfm?App_mode=Display_Statute&Search_String=&URL=0400-0499/0456/Sections/0456.013.html. Last accessed August 1, 2019.

6. The Joint Commission. Sentinel Events. Available at https://www.jointcommission.org/assets/1/6/CAMH_2012_Update2_24_SE.pdf. Last accessed August 1, 2019.

7. The Joint Commission. Sentinel Event Policy and Procedures. Available at https://www.jointcommission.org/sentinel_event_policy_and_procedures. Last accessed August 1, 2019.

8. Florida Legislature. The 2018 Florida Statutes: 395.0197 Internal Risk Management Program. Available at http://www.leg.state. fl.us/Statutes/index.cfm?App_mode=Display_Statute&Search_String=&URL=0300-0399/0395/Sections/0395.0197.html. Last accessed June 25, 2019.

9. Florida Agency for Health Care Administration. AHCA Incident Reporting System: Quarterly Report—Detail Data. Available at https://bi.ahca.myflorida.com/t/ABICC/views/QuarterlyReport_ASC-HOSP-HMO/DetailData?:embed=y&:showAppBanner=false&:showShareOptions=true&:display_count=no&:showVizHome=no. Last accessed August 6, 2019.

10. The Joint Commission. Most Commonly Reviewed Sentinel Event Types. Available at https://www.jointcommission.org/assets/1/18/Event_type_2Q_2016.pdf. Last accessed August 9, 2019.

11. The Joint Commission. Sentinel Event Data: General Information. Available at https://www.jointcommission.org/sentinel_ event_data_general. Last accessed August 9, 2019.

12. American Academy of Orthopedic Surgeons. Information Statement: Surgical Site and Procedure Confirmation. Available athttps://aaos.org/uploadedFiles/PreProduction/About/Opinion_Statements/advistmt/1043%20Surgical%20Site%20and%20Procedure%20Confirmation.pdf. Last accessed August 9, 2019.

13. The Joint Commission. Preventing unintended retained foreign objects. Sentinel Event Alert. 2013;51:1-5.

14. The Joint Commission. Performance of the Correct Procedure at the Correct Body Site. Available at https://www.who.int/patientsafety/solutions/patientsafety/PS-Solution4.pdf. Last accessed August 9, 2019.

15. The Joint Commission. Universal Protocol. Available at https://www.jointcommission.org/standards_information/up.aspx. Last accessed August 9, 2019.

16. The Joint Commission. Quick Safety: Preventing Delays in Treatment. Available athttps://www.jointcommission.org/assets/1/23/Quick_Safety_Issue_Nine_Jan_2015_FINAL.pdf. Last accessed August 9, 2019.

17. AHC Media. JCAHO Data Show Surgical Complications, Causes. Available at https://www.reliasmedia.com/articles/45354-jcaho-data-show-surgical-complications-causes. Last accessed August 9, 2019.

18. The Joint Commission. Detecting and treating suicide ideation in all settings. Sentinel Event Alert. 2016;56:1-7.

19. The Joint Commission. Preventing falls and fall-related injuries in health care facilities. Sentinel Event Alert. 2015;55:1-5.

20. National Coordinating Council for Medication Error Reporting and Prevention. About Medication Errors. Available at https://www.nccmerp.org/about-medication-errors. Last accessed August 9, 2019.

21. The Joint Commission. Facts About the Official "Do Not Use" List of Abbreviations. Available at https://www.jointcommission.org/facts_about_do_not_use_list/. Last accessed August 9, 2019.

22. Cohen MR (ed). Medication Errors. 2nd ed. Washington, DC: American Pharmacists Association; 2007.

23. Flynn EA, Barker KN, Carnahan BJ. National observational study of prescription dispensing accuracy and safety in 50 pharmacies.J Am Pharm Assoc (Wash). 2003;43(2):191-200.

24. O'Donnell J, Vogenberg FR. Legal risk management opportunities, pharmacy practice, and P&T committees. Part 1: deconstructing dispensing errors. P T. 2014;39(8):559-562, 579.

25. Breland BD. Strategies for the prevention of medication errors. Hospital Pharmacy Report. 2000;14(8):56-65.

26. Federico F. The Five Rights of Medication Administration. Available at http://www.ihi.org/resources/pages/improvementstories/fiverightsofmedicationadministration.aspx. Last accessed August 9, 2019.

27. Pozgar GD. Legal Aspects of Health Care Administration. 13th ed. Sudbury, MA: Jones & Bartlett Learning; 2018.

28. The Joint Commission. Sentinel Event Alert, Issue 39: Preventing Pediatric Medication Errors. Available at https://www.jointcommission.org/assets/1/18/SEA_39.pdf. Last accessed August 9, 2019.

29. Florida Administrative Code. 64B8-13.005. Continuing Education for Biennial Renewal. Available at https://www.flrules.org/gateway/ruleno.asp?id=64B8-13.005. Last accessed March 15, 2022.

30. Zarick AL. Leadership in Legal Education Symposium X. Damage deferred: determining when a cause of action begins to accrue for a cancer misdiagnosis claim. Univ Toledo Law Rev. 2010;41:445.

31. Lyratzopoulos G, Vedsted P, Singh H. Understanding missed opportunities for more timely diagnosis of cancer in symptomatic patients after presentation. Br J Cancer. 2015;112(Suppl 1):S84-S91.

32. Lydiatt DD. Medical malpractice and cancer of the larynx. Laryngoscope. 2010;112(3):445-448.

33. Lydiatt DD. Cancer of the oral cavity and medical malpractice. Laryngoscope. 2010;112(5):816-819.

34. Pope JV, Edlow JA. Avoiding misdiagnosis in patients with neurological emergencies. Emergency Medicine International. 2012;(2012):949275.

35. Kamalian S, Kamalian S, Boulter DJ, Lev MH, Gonzalez RG, Schaefer PW. Stroke differential diagnosis and mimics: part 1. Applied Radiology. 2015;44(11):26-39.

36. Kahn RL, Stanton MA, Tong-Ngork S, Liguori GA, Edmonds CR, Levine DS. One-year experience with day-of-surgery pregnancy testing before elective orthopedic procedures. Anesth Analg. 2006;106(4):1127-1131.

37. Corwell BN. The emergency department evaluation, management, and treatment of back pain. Emerg Med Clin North Am. 2010;28(4):811-839.

38. Ruckdeschel JC. Early detection and treatment of spinal cord compression. Oncology (Williston Park). 2005;19(1):81-86, 89-92.

39. Arce D, Sass P, Abul-Khoudoud H. Recognizing spinal cord emergencies. Am Fam Physician. 2001;64(4):631-638.

40. Lawton AJ, Lee KA, Cheville AL, et al. Assessment and management of patients with metastatic spinal cord compression: a multidisciplinary review. J Clin Oncol. 2018;37(1):61-71.

41. Boussios S, Cooke D, Hayward C, et al. Metastatic spinal cord compression: unraveling the diagnostic and therapeutic challenges. Anticancer Res. 2018;38(9):4987-4997.

42. Smith SS, Stewart ME, Davies BM, Kotter MRN. The prevalence of asymptomatic and symptomatic spinal cord compression on magnetic resonance imaging: a systematic review and meta-analysis. Global Spine J. 2021;11(4):597-607.

43. Roffi M, Patrono C, Collet JP, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(3):267-315.

44. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. Circulation. 2011;123(11):1243-1262.

45. El-Menyar A, Zubaid M, Sulaiman K, et al. Atypical presentation of acute coronary syndrome: a significant independent predictor of in-hospital mortality. J Cardiol. 2011;57(2):165-171.

46. Khan NA, Daskalopoulou SS, Karp I, et al. Sex differences in acute coronary syndrome symptom presentation in young patients. JAMA Intern Med. 2013;173(20):1863-1871.

47. Darawshe A, Rabkin Y, Batsheva Z, Abdelhadi F, Feldman A, Rosenfeld R. Misdiagnosed acute coronary syndrome: characteristics of patients with acute coronary syndrome discharged home from the emergency department. Israeli Journal of Emergency Medicine. 2007;7(3):3-10.

48. Whang JS, Baker SR, Patel R, Luk L, Castro A 3rd. The causes of medical malpractice suits against radiologists in the United States. Radiology. 2013;266(2):548-554.

49. Cooke LJ, Becker WJ. Migraine prevalence, treatment and impact: the Canadian Women Migraine Study. Can J Neurol Sci. 2010;37(5):580-587.

50. Williams SC, Schmaltz SP, Castro GM, Baker DW. Incidence and method of suicide in hospitals in the United States. Jt Comm J Qual Patient Saf. 2018;44(11):643-650.

51. Rinke ML, Bundy DG, Velasquez CA, et al. Interventions to reduce pediatric medication errors: a systematic review. Pediatrics. 2014;134(2):338-360.

52. Gillespie LD, Robertson MC, Gillespie WJ, et al. Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev. 2012;(9):CD007146.

53. Agency for Healthcare Research and Quality. 20 Tips to Help Prevent Medical Errors: Patient Fact Sheet. Available at https://www.ahrq.gov/patients-consumers/care-planning/errors/20tips/index.html. Last accessed August 9, 2019.

54. Lupoli TA, Lockey RF, Temporomandibular dysfunction: an often overlooked cause of chronic headaches. Ann Allergy Asthma Immunol. 2007;99(4):314-318.

55. Cady RK, Farmer K. Migraine. In: Jay GW (ed). Clinician's Guide to Chronic Headache and Facial Pain. New York, NY: Informa Healthcare USA; 2010: 1-15.

56. Beithon J, Gallenberg M, Johnson K, et al. Diagnosis and Treatment of Headache. Bloomington, MN: Institute for Clinical Systems Improvement; 2013.

57. McDonald C, Hernandez M, Gofman Y, Suchecki S, Schreier W. The five most common misdiagnoses: a meta-analysis of autopsy and malpractice data. Internet J Fam Pract. 2008;7(2).

58. Deaño RC, Glassner-Kolmin C, Rubenfire M, et al. Referral of patients with pulmonary hypertension diagnoses to tertiary pulmonary hypertension centers: the multicenter RePHerral study. JAMA Intern Med. 2013;173(10):887-893.

59. Lahey MB; Graul A, Meyers S, Ferrarello D, Oxford CM. Keeping our newborns safe: effectively decreasing the rate of neonatal falls during the postpartum period. Obstetrics & Gynecology. 2015;125(Suppl 1):108S-109S.

60. Jabbarpour YM, Jayaram G. Suicide risk: navigating the failure modes. Quality and Professionalism in Psychiatry. 2011;9(2):186-193.

61. American Society of Health-System Pharmacists. ASHP Guidelines on Preventing Medication Errors in Hospitals. Available at https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/preventing-medication-errors-hospitals.ashx?la=en&hash=CFDD375E109297517C3CB96BDADE7B0D59E2560A. Last accessed August 9, 2019.

62. Poon EG, Kachalia A, Puopolo AL, Gandhi TK, Studdert DM. Cognitive errors and logistical breakdowns contributing to missed and delayed diagnoses of breast and colorectal cancers: a process analysis of closed malpractice claims. J Gen Intern Med. 2012;27(11):1416-1423.

63. Pope JV, Edlow JA. Avoiding misdiagnosis in patients with neurological emergencies. Emergency Medicine International. 2012;(2012):949275.

64. Newman-Toker DE, Moy E, Valente E, Coffey R, Hines AL. Missed diagnosis of stroke in the emergency department: a cross-sectional analysis of a large population-based sample. Diagnosis. 2014;1(2):155-166.

65. Dahlf C, Maassen Van Den Brink A. Dihydroergotamine, ergotamine, methysergide and sumatriptan: basic science in relation to migraine treatment. Headache. 2012;52(4):707-714.

66. Cooke LJ, Becker WJ. Migraine prevalence, treatment and impact: the Canadian Women Migraine Study. Can J Neurol Sci. 2010;37(5):580-587.

67. Graff-Radford SB. Facial pain, cervical pain, and headache. Continuum (Minneap Minn). 2012;18(4):869-882.

68. Lupoli TA, Lockey RF, Temporomandibular dysfunction: an often overlooked cause of chronic headaches. Ann Allergy Asthma Immunol. 2007;99(4):314-318.

69. Cady RK, Farmer K. Migraine. In: Jay GW (ed). Clinicians Guide to Chronic Headache and Facial Pain. New York, NY: Informa Healthcare USA; 2010: 1-15.

70. Beithon J, Gallenberg M, Johnson K, et al. Diagnosis and Treatment of Headache. Bloomington, MN: Institute for Clinical Systems Improvement; 2013.

71. Mechcatie E. DDW: Study Finds Pancreatic Cancer Misdiagnosis Rate at 31%. Available at https://www.mdedge.com/gihepnews/article/101026/gastroenterology/ddw-study-finds-pancreatic-cancer-misdiagnosis-rate-31. Last accessed February 27, 2020.

72. Drossman DA. Functional gastrointestinal disorders: history, pathophysiology, clinical features, and Rome IV. Gastroenterology. 2016;150:1262-1279.

73. Drossman DA, Hasler WL. Rome IVfunctional GI disorders: disorders of gut-brain interaction. Gastroenterology. 2016;150(6):1257-1261.

91151 • Strategies for Appropriate Opioid Prescribing: The Florida APRN/PA Requirement

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Table of Contents

91151 • Strategies for Appropriate Opioid Prescribing: The Florida APRN/PA Requirement

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. DEFINITIONS

3. EPIDEMIOLOGY OF CHRONIC PAIN AND OPIOID MISUSE

OPIOID MISUSE IN FLORIDA

4. INITIATION AND MANAGEMENT OF THE PATIENT WITH PAIN

ACUTE PAIN

PATIENT EVALUATION AND ASSESSMENT OF ADDICTION RISK

CREATING A TREATMENT PLAN

PERIODIC REVIEW AND MONITORING

CONSULTATION AND REFERRAL

MEDICAL RECORDS

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

DISCONTINUING OPIOID THERAPY

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. CRISIS INTERVENTION: MANAGEMENT OF OVERDOSE

OPIOID ANTAGONISTS

6. COMPLIANCE WITH STATE AND FEDERAL LAWS

CONTROLLED SUBSTANCES LAWS/RULES

THE ELECTRONIC FLORIDA ONLINE REPORTING OF CONTROLLED SUBSTANCES EVALUATION PROGRAM

7. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

8. INTERVENTIONS FOR SUSPECTED OR KNOWN DRUG DIVERSION

9. CASE STUDY

ASSESSMENT

FOLLOW-UP

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

91151 • Strategies for Appropriate Opioid Prescribing: The Florida APRN/PA Requirement

Education Category. Management

Release Date. 09/01/2019

Expiration Date. 08/31/2022

Course Overview

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Audience

This course is designed for all nurses and physician assistants who may alter prescribing practices or intervene to prevent drug diversion and inappropriate opioid use.

Course Objective

The purpose of this course is to provide clinicians who prescribe or distribute opioids with an appreciation for the complexities of opioid prescribing and the dual risks of litigation due to inadequate pain control and drug diversion or misuse in order to provide the best possible patient care and to prevent a growing social problem.

Learning Objectives

Upon completion of this course, you should be able to:

1. Define opioid prescribing and opioid misuse.

2. Apply epidemiologic trends in opioid use and misuse to current practice so at-risk patient populations can be more easily identified, assessed, and treated.

3. Create comprehensive treatment plans for patients with chronic pain that address patient needs as well as drug diversion prevention.

4. Identify state and federal laws governing the proper prescription and monitoring of controlled substances.

5. Evaluate behaviors that may indicate drug seeking or diverting as well as approaches for patients suspected of misusing opioids.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Pain is the leading reason for seeking medical care, and pain management is a large part of many healthcare professionals' practice. Opioid analgesics are approved by the U.S. Food and Drug Administration (FDA) for moderate and severe pain and are broadly accepted in acute pain, cancer pain, and end-of-life care, but are controversial in chronic noncancer pain. In response to the long-standing neglect of severe pain, indications for opioid analgesic prescribing were expanded in the 1990s, followed by inappropriate prescribing and increasing abuse, addiction, diversion, and overdose through the 2000s. In tandem with the continued under-treatment of pain, these practice patterns led to needless suffering from uncontrolled pain, opioid analgesic addiction, and overdose. Opioid analgesic prescribing and associated overdose peaked in 2010 with both now in multi-year decline, but information on these important trends is largely absent in the medical literature and media reporting.

Patients show substantial opioid response variations in analgesia and tolerability and may exhibit a range of psychologic, emotional, and behavioral responses that reflect inadequate pain control, an emerging opioid use problem, or both. Clinician delivery of best possible care to patients with pain requires appreciation of the complexities of opioid prescribing and the dual risks of inadequate pain control and inappropriate use, drug diversion, or overdose. A foundation for appropriate opioid prescribing is the understanding of factual data that clarify the prevalence, causality, and prevention of serious safety concerns with opioid prescribing.

2. DEFINITIONS

Definitions and use of terms describing opioid analgesic misuse, abuse, and addiction have changed over time, and their current correct use is inconsistent not only among healthcare providers, but also by federal agencies reporting epidemiologic data such as prevalence of opioid analgesic misuse, abuse, or addiction. Misuse and misunderstanding of these concepts and their correct definitions have resulted in misinformation and represent an impediment to proper patient care.

Inappropriate opioid analgesic prescribing for pain is defined as the non-prescribing, inadequate prescribing, excessive prescribing, or continued prescribing despite evidence of ineffectiveness of opioids [1]. Appropriate opioid prescribing is essential to achieve pain control; to minimize patient risk of abuse, addiction, and fatal toxicity; and to minimize societal harms from diversion. The foundation of appropriate opioid prescribing is thorough patient assessment, treatment planning, and follow-up and monitoring. Essential for proper patient assessment and treatment planning is comprehension of the clinical concepts of opioid abuse and addiction, their behavioral manifestations in patients with pain, and how these potentially problematic behavioral responses to opioids both resemble and differ from physical dependence and pseudo-addiction. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [2]. For example, a 2013 survey measuring 200 primary care physicians' understanding of opioids and addiction found that [3]:

- 35% admitted knowing little about opioid addiction.

- 66% and 57% viewed low levels of education and income, respectively, as causal or highly contributory to opioid addiction.

- 30% believed opioid addiction "is more of a psychologic problem," akin to poor lifestyle choices rather than a chronic illness or disease.

- 92% associated prescription analgesics with opioid addiction, but only 69% associated heroin with opioid addiction.

- 43% regarded opioid dependence and addiction as synonymous.

This last point is very important because confusion and conflation of the clinical concepts of dependence and addiction has led to accusations of many non-addicted patients with chronic pain of misusing or abusing their prescribed opioid and in the failure to detect treatment-emergent opioid problems [4]. Knowledge gaps concerning opioid analgesics, addiction, and pain are related to attitude gaps, and negative attitudes may interfere with appropriate prescribing of opioid analgesics. For example, when 248 primary care physicians were asked of their prescribing approach in patients with headache pain with either a past or current history of substance abuse, 16% and 42%, respectively, would not prescribe opioids under any circumstance [5]. Possibly contributing to healthcare professionals' knowledge deficit in pain treatment is the extent of educational exposure in school. A 2011 study found that U.S. medical school students received a median seven hours of pain education and Canadian medical students a median 14 hours, in contrast to the median 75 hours received by veterinarian school students in the United States [6]. Additionally, less than 3% of medical schools incorporate pain management into their curriculum, yet chronic pain is the most common reason patients see a provider, accounting for 40% of all visits in primary care [7].

The terms related to addiction are often inconsistent, inaccurate, and confusing, partially reflecting the diverse perspectives of those working in the related fields of health care, law enforcement, regulatory agencies, and reimbursement/payer organizations. Changes over time in the fundamental understanding of addiction have also contributed to the persistent misuse of obsolete terminology [8]. The Diagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association, is the standard reference for the diagnosis of addiction and all other psychiatric disorders. Prior to the 2013 release of the DSM-5, versions of the DSM eschewed the term "addiction" in favor of "substance dependence," with a separate diagnostic entity of "substance abuse" representing a less severe version of dependence [9]. Also, in earlier DSM versions, physiologic dependence, manifesting as substance tolerance and withdrawal, was considered a diagnostic criterion of substance dependence. The result was the perpetuation of patient and healthcare professional confusion between physical and substance dependence and the belief that tolerance and withdrawal meant addiction. This confusion also enhanced provider and patient fears over addiction developing from opioid analgesics and contributed to the undertreatment of pain. The DSM-5 has eliminated substance dependence and substance abuse by combining them into the single diagnostic entity of substance use disorder. The disorder is measured on a continuum from mild to severe [9].

In 2011, the American Society of Addiction Medicine (ASAM) published their latest revision in defining the disease of addiction. In the abbreviated version, the ASAM states [10]:

Addiction is a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biologic, psychologic, social, and spiritual manifestations. This is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors. Addiction is characterized by inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of significant problems with one's behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death.

According to the ASAM, the five characteristics of addiction are [10]:

- Inability to consistently abstain

- Impairment in behavioral control

- Craving or increased "hunger" for drug or reward experiences

- Diminished recognition of significant problems with one's behaviors and interpersonal relationships

- A dysfunctional emotional response

The ASAM emphatically states this summary of addiction should not be used as diagnostic criteria for addiction because the core symptoms vary substantially among addicted persons, with some features more prominent than others [10].

3. EPIDEMIOLOGY OF CHRONIC PAIN AND OPIOID MISUSE

Chronic pain affects about 100 million American adults—more than the total affected by heart disease, cancer, and diabetes combined [2]. It also costs the nation up to $635 billion each year in medical treatment and lost productivity and is the leading reason for receiving disability insurance [3,11]. The lifetime prevalence of chronic pain ranges from 54% to 80%, and among adults 21 years of age and older, 14% report pain lasting 3 to 12 months and 42% report pain that persists longer than one year [2]. While 5 to 8 million Americans receive long-term opioids for the management of chronic pain, an estimated 41% of patients with chronic pain report their pain is uncontrolled, and 10% of all adults with pain suffer from severe, disabling chronic pain [11].

The increasing prevalence of chronic pain is the result of multiple factors, including the aging population; rising rates of obesity and obesity-related pain conditions, such as joint deterioration; advances in life-saving trauma interventions; poorly managed post-surgical pain; and greater public awareness of pain as a condition warranting medical attention [2]. In addition, many armed forces veterans have been returning from military action in Afghanistan and Iraq with traumatic injuries and chronic pain, and veterans' care clinicians have been reporting the perception that long-term pain management is lacking support in the veteran healthcare infrastructure [12].

There is a widespread misperception that opioid analgesic prescribing and overdose continues to grow, fueling an opioid epidemic [13,14,15,16,17]. Data from a 2018 Centers for Disease Control and Prevention (CDC) surveillance report show that between 2006 and 2017, the annual prescribing rate per 100 persons decreased from 72.4 to 58.5 for all opioids, an overall reduction of 19.2% [18]. (Opioid prescriptions, including codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, propoxyphene, tapentadol, tramadol, and buprenorphine, were identified using the National Drug Code. Cough and cold formulations containing opioids were not included.) The rate for all opioid prescriptions initially increased annually by 3.0% from 2006 to 2010, but then decreased annually by 1.6% from 2010 to 2014, and continued to decrease annually by 8.2% from 2014 to 2017 [18].

Although the epidemic of drug overdoses that began in the 1990s primarily involved prescription opioids prescribed for analgesia, the rapid increase in overdose deaths in 2010 was primarily attributed to heroin, and in 2013, to synthetic opioids, particularly illicitly manufactured fentanyl [18]. A record number (63,632) of drug overdose deaths occurred in 2016, a rate of 19.8 per 100,000 persons. Although deaths might have involved more than one drug, prescription and/or illicit opioids were involved in 66.4% of these drug overdose fatalities. Among opioid-involved deaths, the most commonly involved drugs were synthetic opioids other than methadone (primarily illicitly manufactured fentanyl [19,413 deaths]), prescription opioids (17,087 deaths), and heroin (15,469 deaths). Prescription opioid deaths included those involving natural and semisynthetic opioids (14,487 deaths) and methadone (3,373 deaths). Cocaine was involved in 10,375 deaths. The increase in overdose deaths in 2016 was attributed to heroin, synthetic opioids other than methadone (mostly illicitly manufactured fentanyl), cocaine, and psychostimulants with abuse potential [18].

There is nearly universal agreement that opioid analgesics were injudiciously overprescribed during the 2000s. Interpretation of the broader trend of increased prescribing from 1990 might be viewed by public health professionals as entirely problematic and by pain medicine professionals as necessary in part, given the past neglect of patients in pain. This reflects the polarized nature of pain care and opioid analgesic prescribing in particular. Efforts to reduce opioid analgesic overprescribing and associated overdose have been successful but have come at a cost to patients who have faced increasing barriers to access, including stigma and abuse in a healthcare system, tapering of opioids without consideration for pain or functional improvements, and difficulty finding a physician [14,19,20].

Worldwide consumption of opioid analgesics increased dramatically over the past few decades, driven primarily by U.S. consumption. For example, the global consumption of oxycodone was 3 tons (2,722 kg) in 1990 and 77 tons (69,853 kg) in 2009, with 62 tons (81%) consumed in the United States [21]. However, in line with a decrease in global manufacture of the drug, global consumption of oxycodone also decreased, from 79.7 tons in 2016 to 62.6 tons in 2017. Consumption remained concentrated in the United States, which consumed 42.4 tons (67.7%) of the world total [22]. In 2017, the United States had 4.3% of the world population but consumed 80% of global opioid supplies and 99.2% of hydrocodone supplies [22]. This is partially because access to opioid analgesics is virtually or entirely non-existent for much of the world's population. An estimated 3.6 billion people (50% of the global population who reside in the poorest countries) receive less than 1% of the distributed opioids [23]. Other countries with adequate opioid access prefer dihydrocodeine or low-dose morphine over hydrocodone for use in moderate or moderately severe pain [24].

Many prescribed opioid analgesic fatalities result from the co-ingestion of central nervous system (CNS)/respiratory depressants (especially benzodiazepines) or prescribed methadone. The National Institute on Drug Abuse reported benzodiazepines contributed to 24% of opioid analgesic fatalities in 2017 (compared with 18.4% in 2004), but this may underestimate the true contribution [25]. A Canadian study evaluated 607,156 adults prescribed opioids for noncancer pain, and of those whose deaths were related to opioids, co-prescribed benzodiazepines were detected in 84.5% [26]. In another study of 2,182,374 North Carolina residents receiving one or more opioid analgesics in 2010, benzodiazepines were present in 61.4% who fatally overdosed [27]. A cross-sectional study of 386,457 ambulatory care visits in the United States from 2003 through 2015 found that the use of benzodiazepines increased substantially from 3.8% to 7.4% of visits, including co-prescribing with other sedating medications [28]. Use for back and chronic pain increased more significantly than use for anxiety and insomnia, which remained relatively unchanged. This increase likely reflects not only a growing number of individuals receiving benzodiazepines, but also an increase in those receiving them on a long-term basis, despite the lack of evidence supporting their use past 8 or 10 weeks [28].

OPIOID MISUSE IN FLORIDA

In Florida, misuse of prescription opioids became a serious problem in the 1990s and 2000s, but efforts to stem the problem appear to be working. The rate of drug overdose deaths increased 58.9% during 2003–2010, and in 2009, one in eight deaths in Florida was attributable to drug overdose [29,30]. As of 2017, 6% of all deaths in Florida were found to have a drug present [31]. Oxycodone-caused deaths accounted for 2.9% of all drug-related deaths (8,646) in 2017 [29]. These trends resulted in the enactment of several measures to address prescribing that was inconsistent with best practices, and partnership with the U.S. Drug Enforcement Administration (DEA) to close and prevent "pill mills" from introducing millions of opioid dose units into illicit markets [32,33]. In May 2017, former Florida Governor Rick Scott signed an executive order declaring the opioid epidemic a public health emergency, providing additional funding and empowering state health professions to take steps to address this pressing issue [33]. As part of this order, the State Health Officer has issued a standing order for opioid antagonists to ensure emergency responders have access [33]. The order has been extended several times and, as of August 2019, is still in place [34].

Drug overdose fatalities in Florida have continued rising from increased use of heroin, synthetic cannabinoids, and novel psychoactive substances such as alpha-PVP ("flakka"). An influx of clandestine fentanyl into Florida in early 2014, and several fentanyl analogs and other novel non-pharmaceutical opioids more recently, has largely driven the increases in opioid overdose fatalities. Several overdose fatalities in Florida were linked to counterfeit alprazolam, oxycodone, and hydrocodone tablets that contained fentanyl [35]. The decrease in prescription opioid fatalities, offset by increasing overdose fatalities from other opioid and non-opioid agents, reflects the intervention focus on the supply side ("pill mill laws") and neglect of treatment funding that would address the demand side of problematic drug use [36].

In Florida, fatalities with benzodiazepines present peaked in 2010 with 6,188, falling to 5,064 in 2017 (37% were alprazolam) [31]. Of the 28,031 deaths investigated by Florida authorities, toxicology results determined that drugs were present at the time of death in 12,439 individuals, with the vast majority revealing more than one drug occurrence [31]. Other primary contributors to opioid analgesic-related fatalities include alcohol and prescribed methadone [37,38].

In addition to the executive order issued in 2017, several new state laws were passed in 2018 to impose additional legal requirements on controlled substance prescribers [39]. These laws will be discussed in detail later in this course.

4. INITIATION AND MANAGEMENT OF THE PATIENT WITH PAIN

In 2016, the CDC issued updated opioid prescribing guidelines for chronic pain that address when to initiate or continue opioids for chronic pain; opioid selection, dosage, duration, follow-up, and discontinuation; and assessing risk and addressing harms of opioid use [40]. Some of the recommendations are standard risk mitigation approaches, but others have been criticized by pain medicine physicians and patient advocates. A common criticism is the sole focus on curtailing prescribing and patient access [41,42,43,44].

It can be difficult to balance the benefits and harms of prescription opioids. This is exacerbated by inadequate education and by opioid prescribing guidelines based on expert opinion instead of scientific evidence. This has resulted in wide variation in clinical practice, inconsistent prescriber guidance, and clinician confusion [45]. For instance, the CDC and other opioid guidelines state that opioids should be considered only after non-opioid therapy fails. However, when pain is severe and patients require powerful analgesic control, there is little choice because no other pain medications are as effective as opioids with lower addiction risk [46].

However, many guidelines do share common recommendations. These represent the current "conventional wisdom" in opioid analgesic prescribing and can inform healthcare professionals of the best clinical practices in opioid prescribing that include approaches to the assessment of pain and function and pain management modalities. Pharmacologic and nonpharmacologic approaches should be used on the basis of current evidence or best clinical practice. Patients with moderate-to-severe chronic pain without adequate pain relief from non-opioid or nonpharmacologic therapy can be considered for a trial of opioid therapy [40,47]. Initial treatment should always be considered individually determined and as a trial of therapy, not a definitive course of treatment [48].

ACUTE PAIN

Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids in a quantity no greater than that needed for the expected duration of severe pain. In most cases, three days or less will be sufficient; more than seven days will rarely be needed [40]. Florida law dictates that, for the treatment of acute pain, a prescription for an opioid drug may not exceed a three-day supply; an exception may be made for a seven-day supply if [49]:

- The prescriber, in his or her professional judgment, believes that more than a three-day supply of such an opioid is medically necessary to treat the patient's pain as an acute medical condition.

- The prescriber indicates "ACUTE PAIN EXCEPTION" on the prescription. (For the treatment of pain other than acute pain, a practitioner must indicate "NONACUTE PAIN" on a prescription.)

- The prescriber adequately documents in the patient's medical records the acute medical condition and lack of alternative treatment options that justify deviation from the three-day supply limit.

With postoperative, acute, or intermittent pain, analgesia often requires frequent titration, and the two- to four-hour analgesic duration with short-acting hydrocodone, morphine, and oxycodone is more effective than extended-release formulations. Short-acting opioids are also recommended in patients who are medically unstable or with highly variable pain intensity [50,51,52].

As part of House Bill 21, passed in 2018, the Florida Board of Medicine and the Board of Osteopathic Medicine are required to establish guidelines for prescribing controlled substances for acute pain; these guidelines are forthcoming [49].

PATIENT EVALUATION AND ASSESSMENT OF ADDICTION RISK

Information obtained by patient history, physical examination, and interview, from family members, a spouse, or state prescription drug monitoring program (PDMP), and from the use of screening and assessment tools can help the clinician to stratify the patient according to level of risk for developing problematic opioid behavioral responses (Table 1). Low-risk patients receive the standard level of monitoring, vigilance, and care. Moderate-risk patients should be considered for an additional level of monitoring and provider contact, and high-risk patients are likely to require intensive and structured monitoring and follow-up contact, additional consultation with psychiatric and addiction medicine specialists, and limited supplies of short-acting opioid formulations [40,53].

Table 1: RISK STRATIFICATION FOR PATIENTS PRESCRIBED OPIOIDS

Low Risk

No past or current personal history of alcohol/substance use disorder (AUD/SUD)

No or minimal co-occurring psychiatric disorders

No family history of alcoholism or substance abuse

Medium Risk

Past history of AUD or SUD

Moderate concomitant psychiatric disorders

Family history of alcoholism or substance abuse/addiction

Patient history of physical, emotional or sexual abuse, especially in childhood

High Risk

Patient actively addicted to or abusing opioids, illicit drugs or alcohol

Untreated or poorly controlled major psychiatric disorder

History of diversion, prescription forgery, selling their prescription drugs

Source: [54,55,56]

Anxiety disorders, major depressive disorder, and intense emotional distress alter pain perception and response. Intensity and perception of reported pain is also influenced by factors such as mood, cultural background, social supports, and financial resources. A biopsychosocial model is required to inform pain assessment in order to address the biologic basis of pain and presence of social and psychologic contributors [46].

Before deciding to prescribe an opioid analgesic, clinicians should perform and document a detailed patient assessment that includes [1]:

- Pain indications for opioid therapy

- Nature and intensity of pain

- Past and current pain treatments and patient response

- Comorbid conditions

- Pain impact on physical and psychologic function

- Social support, housing, and employment

- Home environment (i.e., stressful or supportive)

- Pain impact on sleep, mood, work, relationships, leisure, and substance use

- Patient history of physical, emotional, or sexual abuse

Evidence Based Practice Recommendation

Despite limited evidence for reliability and accuracy, screening for opioid use is recommended by the American Society of Interventional Pain Physicians, as it will identify opioid abusers and reduce opioid abuse.

https://painphysicianjournal.com/2012/july/2012;%2015;S67-S116.pdf

Last Accessed: August 14, 2019

Level of Evidence: Limited (Evidence is insufficient to assess effects on health outcomes because of limited number or power of studies, large and unexplained inconsistency between higher-quality trials, important flaws in trial design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.)

Depression is perhaps the single most important comorbidity in patients with chronic pain and is vastly underdiagnosed and untreated. Patients with unrecognized and untreated depression are unlikely to respond to opioids and other pain therapies, but successful treatment of depression can promote analgesia [57].

If substance abuse is active, in remission, or in the patient's history, consult an addiction specialist before starting opioids [1]. In active substance abuse, do not prescribe opioids until the patient is engaged in treatment/recovery program or other arrangement made, such as addiction professional co-management and additional monitoring. When considering an opioid analgesic (particularly those that are extended-release or long-acting), one must always weigh the benefits against the risks of overdose, abuse, addiction, physical dependence and tolerance, adverse drug interactions, and accidental exposure by children [40,58].

Screening and assessment tools can help guide patient stratification according to risk level and inform the appropriate degree of structure and monitoring in the treatment plan. It should be noted that despite widespread endorsement of screening tool use to help determine patient risk level, most tools have not been extensively evaluated, validated, or compared to each other, and evidence of their reliability is poor [59].

Opioid Risk Tool (ORT)

The Opioid Risk Tool (ORT) is a five-item assessment to help predict aberrant drug-related behavior. The ORT is also used to establish patient risk level through categorization into low, medium, or high levels of risk for aberrant drug-related behaviors based on responses to questions of previous alcohol/drug abuse, psychologic disorders, and other risk factors [60].

Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R)

The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a patient-administered, 24-item screen with questions addressing history of alcohol/substance use, psychologic status, mood, cravings, and stress. Like the ORT, the SOAPP-R helps assess risk level of aberrant drug-related behaviors and the appropriate extent of monitoring [61].

CAGE and CAGE-AID

The original CAGE (Cut down, Annoyed, Guilty, and Eye-opener) Questionnaire consisted of four questions designed to help clinicians determine the likelihood that a patient was misusing or abusing alcohol. These same four questions were modified to create the CAGE-AID (adapted to include drugs), revised to assess the likelihood of current substance abuse [62,63].

Diagnosis, Intractability, Risk, and Efficacy (DIRE) Tool

The Diagnosis, Intractability, Risk, and Efficacy (DIRE) risk assessment tool is a clinician-rated questionnaire that is used to predict patient compliance with long-term opioid therapy [64,65]. Patients scoring lower on the DIRE tool are poor candidates for long-term opioid analgesia.

Mental Health Screening Tool

The Mental Health Screening Tool is a five-item screen that asks about a patient's feelings of happiness, calmness, peacefulness, nervousness, and depression in the past month [66]. A lower score on this tool is an indicator that the patient should be referred to a specialist for pain management.

CREATING A TREATMENT PLAN

Opioid therapy should be presented as a trial for a pre-defined period (e.g., ≤30 days). The goals of treatment should be established with all patients prior to the initiation of opioid therapy, including reasonable improvements in pain, function, depression, anxiety, and avoidance of unnecessary or excessive medication use [1,40]. The treatment plan should describe therapy selection, measures of progress, and other diagnostic evaluations, consultations, referrals, and therapies. All patients prescribed an opioid for pain related to a traumatic injury (severity score ≥9) should be concurrently prescribed an antagonist (e.g., naloxone) [49].

In opioid-naïve patients, start at the lowest possible dose and titrate to effect. Dosages for opioid-tolerant patients should always be individualized and titrated by efficacy and tolerability [1]. The need for frequent progress and benefit/risk assessments during the trial should be included in patient education. Patients should also have full knowledge of the warning signs and symptoms of respiratory depression.

Prescribers should be knowledgeable of federal and state opioid prescribing regulations. Issues of equianalgesic dosing, close patient monitoring during all dose changes, and incomplete cross-tolerance with opioid conversion should be considered. If necessary, treatment may be augmented, with preference for non-opioid and immediate-release opioids over long-acting/extended-release opioids. Taper opioid dose when no longer needed [58].

Non-Opioid Pain Management Options

Nonpharmacologic Approaches

Several nonpharmacologic approaches are therapeutic complements to pain-relieving medication, lessening the need for higher doses and perhaps minimizing side effects. These interventions can help decrease pain or distress that may be contributing to the pain sensation. Approaches include palliative radiotherapy, complementary/alternative methods, manipulative and body-based methods, and cognitive/behavioral techniques. The choice of a specific nonpharmacologic intervention is based on the patient's preference, which, in turn, is usually based on a successful experience in the past.

Methods to provide distraction from pain come in a wide variety, including reciting poetry, meditating with a calm phrase, watching television or movies, playing cards, visiting with friends, or participating in crafts. Music therapy and art therapy are also becoming more widely used as nonpharmacologic options for pain management.

Non-Opioid Analgesics

Non-opioid analgesics, such as aspirin, acetaminophen (Tylenol), and nonsteroidal anti-inflammatory drugs (NSAIDs), are primarily used for mild pain and may also be helpful as coanalgesics for moderate and severe pain. Acetaminophen is among the safest of analgesic agents, but it has essentially no anti-inflammatory effect. Toxicity is a concern at high doses, and the maximum recommended dose is 3–4 g per day [67]. Acetaminophen should be avoided or given at lower doses in people with a history of alcohol abuse or renal or hepatic insufficiency [67].

NSAIDs are most effective for pain associated with inflammation. Among the commonly used NSAIDs are ibuprofen (Motrin, Advil), naproxen (Aleve, Naprosyn), and indomethacin (Indocin). There are several classes of NSAIDs, and the response differs among patients; trials of drugs for an individual patient may be necessary to determine which drug is most effective [68]. NSAIDs inhibit platelet aggregation, increasing the risk of bleeding, and also can damage the mucosal lining of the stomach, leading to gastrointestinal bleeding. There is a ceiling effect to the non-opioid analgesics; that is, there is a dose beyond which there is no further analgesic effect. In addition, many side effects of non-opioids can be severe and may limit their use or dosing.

Informed Consent and Treatment Agreements

The initial opioid prescription is preceded by a written informed consent or "treatment agreement" [1]. This agreement should address potential side effects, tolerance and/or physical dependence, drug interactions, motor skill impairment, limited evidence of long-term benefit, misuse, dependence, addiction, and overdose. Informed consent documents should include information regarding the risk/benefit profile for the drug(s) being prescribed. The prescribing policies should be clearly delineated, including the number/frequency of refills, early refills, and procedures for lost or stolen medications.

The treatment agreement also outlines joint physician and patient responsibilities. The patient agrees to using medications safely, refraining from "doctor shopping," and consenting to routine urine drug testing (UDT). The prescriber's responsibility is to address unforeseen problems and prescribe scheduled refills. Reasons for opioid therapy change or discontinuation should be listed. Agreements can also include sections related to follow-up visits, monitoring, and safe storage and disposal of unused drugs.

PERIODIC REVIEW AND MONITORING

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [1]. This can include input from family members and/or the state PDMP. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. At every visit, chronic opioid response may be monitored according to the "5 A's" [1]:

- Analgesia

- Activities of daily living

- Adverse or side effects

- Aberrant drug-related behaviors

- Affect (i.e., patient mood)

Signs and symptoms that, if present, may suggest a problematic response to the opioid and interference with the goal of functional improvement include [69]:

- Excessive sleeping or days and nights turned around

- Diminished appetite

- Short attention span or inability to concentrate

- Mood volatility, especially irritability

- Lack of involvement with others

- Impaired functioning due to drug effects

- Use of the opioid to regress instead of re-engaging in life

- Lack of attention to hygiene and appearance

The decision to continue, change, or terminate opioid therapy is based on progress toward treatment objectives and absence of concerning adverse effects and risks of overdose or diversion [1]. Satisfactory therapy is indicated by improvements in pain, function, and quality of life. It is important to remember that for some patients with severe chronic pain, improved function may take longer than pain control. Either pain or function (not both) will improve. In some cases, preventing worsening pain/functional impairment is the best achievable outcome. Brief assessment tools to assess pain and function may be useful, as may UDTs. Treatment plans may include periodic pill counts to confirm adherence and minimize diversion.

Involvement of Family

Family members or the partner of the patient can provide the clinician with valuable information that better informs decision making regarding continuing opioid therapy. Family members can observe whether a patient is losing control of his or her life or becoming less functional or more depressed during the course of opioid therapy. They can also provide input regarding positive or negative changes in patient function, attitude, and level of comfort. The following questions can be asked of family members or a spouse to help clarify whether the patient's response to opioid therapy is favorable or unfavorable [69]:

- Is the person's day centered around taking the opioid medication? Response can help clarify long-term risks and benefits of the medication and identify other treatment options.

- Does the person take pain medication only on occasion, perhaps three or four times per week? If yes, the likelihood of addiction is low.

- Have there been any other substance (alcohol or drug) abuse problems in the person's life? An affirmative response should be taken into consideration when prescribing.

- Does the person in pain spend most of the day resting, avoiding activity, or feeling depressed? If so, this suggests the pain medication is failing to promote rehabilitation. Daily activity is essential, and the patient may be considered for enrollment in a graduated exercise program

- Is the person in pain able to function (e.g., work, do household chores, play) with pain medication in a way that is clearly better than without? If yes, this suggests the pain medication is contributing to wellness.

Assessment Tools

VIGIL

VIGIL is the acronym for a five-step risk management strategy designed to empower clinicians to appropriately prescribe opioids for pain by reducing regulatory concerns and to give pharmacists a framework for resolving ambiguous opioid analgesic prescriptions in a manner that preserves legitimate patient need while potentially deterring diverters. The components of VIGIL are:

- Verification: Is this a responsible opioid user?

- Identification: Is the identity of this patient verifiable?

- Generalization: Do we agree on mutual responsibilities and expectations?

- Interpretation: Do I feel comfortable allowing this person to have controlled substances?

- Legalization: Am I acting legally and responsibly?

The foundation of VIGIL is a collaborative physician/pharmacist relationship [70,71].

Current Opioid Misuse Measure (COMM)

The Current Opioid Misuse Measure (COMM) is a 17-item patient self-report assessment designed to help clinicians identify misuse or abuse in patients with chronic pain. Unlike the ORT and the SOAPP-R, the COMM identifies aberrant behaviors associated with opioid misuse in patients already receiving long-term opioid therapy [53]. Sample questions include: In the past 30 days, how often have you had to take more of your medication than prescribed? In the past 30 days, how much of your time was spent thinking about opioid medications (e.g., having enough, taking them, dosing schedule)?

Pain Assessment and Documentation Tool (PADT)

Guidelines by the Federation of State Medical Boards (FSMB) and the Joint Commission stress the importance of documentation from both a healthcare quality and medicolegal perspective. Research has found widespread deficits in chart notes and progress documentation for patients with chronic pain who are receiving opioid therapy, and the Pain Assessment and Documentation Tool (PADT) was designed to address these shortcomings [72]. The PADT is a clinician-directed interview, with most sections (e.g., analgesia, activities of daily living, adverse events) consisting of questions asked of the patient [73]. However, the potential aberrant drug-related behavior section must be completed by the physician based on his or her observations of the patient.

The Brief Intervention Tool

The Brief Intervention Tool is a 26-item, "yes-no," patient-administered questionnaire used to identify early signs of opioid abuse or addiction. The items assess the extent of problems related to drug use in several areas, including drug use-related functional impairment [66].

Urine Drug Tests

UDTs may be used to monitor adherence to the prescribed treatment plan and to detect unsanctioned drug use. They should be used more often in patients receiving addiction therapy, but clinical judgment is the ultimate guide to testing frequency (Table 2) [74]. The CDC recommends clinicians should use UDT before starting opioid therapy and consider UDT at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs [40]. However, this recommendation was based on low-quality evidence that indicates little confidence in the effect estimate.

Table 2: PATIENT RISK LEVEL AND FREQUENCY OF MONITORING

Monitoring Tool

Patient Risk Level

Low

Medium

High

Urine drug test

Every 1 to 2 years

Every 6 to 12 months

Every 3 to 6 months

State prescription drug monitoring program

Twice per year

3 times per year

4 times per year

Source: [74]

Initially, testing involves the use of class-specific immunoassay drug panels [1]. If necessary, this may be followed with gas chromatography/mass spectrometry for specific drug or metabolite detection. It is important that testing identifies the specific drug rather than the drug class, and the prescribed opioid should be included in the screen. Any abnormalities should be confirmed with a laboratory toxicologist or clinical pathologist. Immunoassay may be used point-of-care for "on-the-spot" therapy changes, but the high error rate prevents its use in major clinical decisions except with liquid chromatography coupled to tandem mass spectrometry confirmation.

Urine test results suggesting opioid misuse should be discussed with the patient using a positive, supportive approach. The test results and the patient discussion should be documented.

CONSULTATION AND REFERRAL

It is important to seek consultation or patient referral when input or care from a pain, psychiatry, addiction, or mental health specialist is necessary. Clinicians who prescribe opioids should become familiar with opioid addiction treatment options (including licensed opioid treatment programs for methadone and office-based opioid treatment for buprenorphine) if referral is needed [1].

Ideally, providers should be able to refer patients with active substance abuse who require pain treatment to an addiction professional or specialized program. In reality, these specialized resources are scarce or non-existent in many areas [1]. Therefore, each provider will need to decide whether the risks of continuing opioid treatment while a patient is using illicit drugs outweigh the benefits to the patient in terms of pain control and improved function [75].

MEDICAL RECORDS

As noted, documentation is a necessary aspect of all patient care, but it is of particular importance when opioid prescribing is involved. All clinicians should maintain accurate, complete, and up-to-date medical records, including all written or telephoned prescription orders for opioid analgesics and other controlled substances, all written instructions to the patient for medication use, and the name, telephone number, and address of the patient's pharmacy [1]. Good medical records demonstrate that a service was provided to the patient and that the service was medically necessary. Regardless of the treatment outcome, thorough medical records protect the prescriber.

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

Patients and caregivers should be counseled regarding the safe use and disposal of opioids. As part of its mandatory Risk Evaluation and Mitigation Strategy (REMS) for extended-release/long-acting opioids, the FDA has developed a patient counseling document with information on the patient's specific medications, instructions for emergency situations and incomplete pain control, and warnings not to share medications or take them unprescribed [58]. A copy of this form may be accessed online at https://www.fda.gov/media/79776/download.

When prescribing opioids, clinicians should provide patients with the following information [58]:

- Product-specific information

- Taking the opioid as prescribed

- Importance of dosing regimen adherence, managing missed doses, and prescriber contact if pain is not controlled

- Warning and rationale to never break or chew/crush tablets or cut or tear patches prior to use

- Warning and rationale to avoid other central nervous system depressants, such as sedative-hypnotics, anxiolytics, alcohol, or illicit drugs

- Warning not to abruptly halt or reduce the opioid without physician oversight of safe tapering when discontinuing

- The potential of serious side effects or death

- Risk factors, signs, and symptoms of overdose and opioid-induced respiratory depression, gastrointestinal obstruction, and allergic reactions

- The risks of falls, using heavy machinery, and driving

- Warning and rationale to never share an opioid analgesic

- Rationale for secure opioid storage

- Warning to protect opioids from theft

- Instructions for disposal of unneeded opioids, based on product-specific disposal information

There are no universal recommendations for the proper disposal of unused opioids, and patients are rarely advised of what to do with unused or expired medications [76]. According to the Office of National Drug Control Policy, most medications that are no longer necessary or have expired should be removed from their containers, mixed with undesirable substances (e.g., cat litter, used coffee grounds), and put into an impermeable, nondescript container (e.g., disposable container with a lid or a sealed bag) before throwing in the trash [77]. Any personal information should be obscured or destroyed. The FDA recommends that certain medications, including oxycodone/acetaminophen (Percocet), oxycodone (OxyContin tablets), and transdermal fentanyl (Duragesic Transdermal System), be flushed down the toilet instead of thrown in the trash [77]. Patients should be advised to flush prescription drugs down the toilet only if the label or accompanying patient information specifically instructs doing so and no other disposal method is appropriate.

The American College of Preventive Medicine has established best practices to avoid diversion of unused drugs and educate patients regarding drug disposal [76]:

- Consider writing prescriptions in smaller amounts.

- Educate patients about safe storing and disposal practices.

- Give drug-specific information to patients about the temperature at which they should store their medications. Generally, the bathroom is not the best storage place. It is damp and moist, potentially resulting in potency decrements, and accessible to many people, including children and teens, resulting in potential theft or safety issues.

- Ask patients not to advertise that they are taking these types of medications and to keep their medications secure.

- Refer patients to community "take back" services overseen by law enforcement that collect controlled substances, seal them in plastic bags, and store them in a secure location until they can be incinerated. Contact your state law enforcement agency or visit https://www.dea.gov to determine if a program is available in your area.

DISCONTINUING OPIOID THERAPY

The decision to continue or end opioid prescribing should be based on a physician-patient discussion of the anticipated benefits and risks. An opioid should be discontinued with resolution of the pain condition, intolerable side effects, inadequate analgesia, lack of improvement in quality of life despite dose titration, deteriorating function, or significant aberrant medication use [1,40].

Clinicians should provide physically dependent patients with a safely structured tapering protocol. Withdrawal is managed by the prescribing physician or referral to an addiction specialist. Patients should be reassured that opioid discontinuation is not the end of treatment; continuation of pain management will be undertaken with other modalities through direct care or referral.

As a side note, cannabis use by patients with chronic pain receiving opioid therapy has traditionally been viewed as a treatment agreement violation that is grounds for termination of opioid therapy. However, some now argue against cannabis use as a rationale for termination or substantial treatment and monitoring changes, especially considering the increasing legalization of medical use at the state level [75]. Cannabis use for chronic pain in patients receiving opioid therapy continues to receive increased interest and support; however, experts caution that more evidence of improved patient outcomes is needed [78,79,80].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For patients who are not proficient in English, it is important that information regarding the risks associated with the use of opioids and available resources be provided in their native language, if possible. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

5. CRISIS INTERVENTION: MANAGEMENT OF OVERDOSE

Individuals who have first contact with persons suspected of experiencing an opioid-related overdose are in the position to intervene to prevent the potentially devastating consequences. In these cases, care begins with crisis intervention directed at immediate survival by reversing the potentially lethal effects of overdose with an opioid antagonist.

Opioid antagonists have obvious therapeutic value in the treatment of opioid overdose. A 2012 study found that wider distribution of naloxone and training in its administration might have prevented numerous deaths from opioid overdoses in the United States [81]. Since the first community-based opioid overdose prevention program began distributing naloxone in 1996, more than 10,000 overdoses have been reversed [81].

In Florida, licensed healthcare providers may prescribe and pharmacists may dispense opioid antagonists (even as a standing order) for at-risk individuals, these individuals' relatives or other caregivers, and emergency responders to be used in their course of duties [82]. Emergency responders include (but are not limited to) law enforcement officers, paramedics, and emergency medical technicians [82]. As noted, there is a statewide standing order for naloxone for all emergency responders in Florida [33].

OPIOID ANTAGONISTS

Relatively minor changes in the structure of an opioid can convert an agonist drug into one with antagonistic actions at one or more opioid receptor types. Opioid antagonists include naloxone, naltrexone, and nalmefene. Interestingly, naloxone also appears to block the analgesic effects of placebo medications and acupuncture. These agents have no abuse potential [83].

In response to acute overdose, the short-acting opioid antagonist naloxone is considered the gold standard, and it remains the most widely used opioid antagonist for the reversal of overdose and opioid-related respiratory depression. It acts by competing with opioids at receptor sites in the brain stem, reversing desensitization to carbon dioxide, and reversing or preventing respiratory failure and coma. There is no evidence that subcutaneous or intramuscular use is inferior to intravenous naloxone. This has prompted some states to pass laws allowing opioid antagonists to be available to the general public for administration outside the healthcare setting to treat acute opioid overdose [84].

When used for opioid overdose, a dose of 0.4–2 mg of naloxone is administered intravenously, intramuscularly, or subcutaneously [85]. If necessary, the dose may be repeated every two to three minutes for full reversal. For ease of use, naloxone is also available in a pre-filled auto-injection device. An intranasal formulation is also available in doses of 2 mg, 4 mg, or 8 mg [85]. It is important that standard Advanced Cardiac Life Support (ACLS) protocols be continued while naloxone is being administered and that medical treatment (at a healthcare facility) be given immediately.

6. COMPLIANCE WITH STATE AND FEDERAL LAWS

In response to the rising incidence in prescription opioid abuse, addiction, diversion, and overdose in the late 1990s and 2000s, the FDA has mandated opioid-specific REMS to reduce the potential negative patient and societal effects of prescribed opioids. Other elements of opioid risk mitigation include FDA partnering with other governmental agencies, state professional licensing boards, and societies of healthcare professionals to help improve prescriber knowledge of appropriate and safe opioid prescribing and safe home storage and disposal of unused medication [69].

Several regulations and programs at the state level have been enacted in an effort to reduce prescription opioid abuse, diversion, and overdose, including [86]:

- Physical examination required prior to prescribing

- Tamper-resistant prescription forms

- Pain clinic regulatory oversight

- Prescription limits

- Prohibition from obtaining controlled substance prescriptions from multiple providers

- Patient identification required before dispensing

- Immunity from prosecution or mitigation at sentencing for individuals seeking assistance during an overdose

CONTROLLED SUBSTANCES LAWS/RULES

The DEA is responsible for formulating federal standards for the handling of controlled substances. In 2011, the DEA began requiring every state to implement electronic databases that track prescribing habits, referred to as PDMPs. Specific policies regarding controlled substances are administered at the state level [87].

According to the DEA, drugs, substances, and certain chemicals used to make drugs are classified into five distinct categories or schedules depending upon the drug's acceptable medical use and the drug's abuse or dependency potential [88]. The abuse rate is a determinate factor in the scheduling of the drug; for example, Schedule I drugs are considered the most dangerous class of drugs with a high potential for abuse and potentially severe psychologic and/or physical dependence.

In Florida, the prescribing, dispensing, and consumption of certain controlled substances are governed by Chapter 893 of the Florida Statutes [89]. This law establishes the standards for controlled substance prescribing, including reporting system requirements, for prescribers and pharmacists in Florida. As of 2019, the Florida schedule of controlled substances aligns with the DEA schedule [39].

THE ELECTRONIC FLORIDA ONLINE REPORTING OF CONTROLLED SUBSTANCES EVALUATION PROGRAM

Emerging trends and patterns of prescription opioid abuse, addiction, and overdose are monitored by several industry and government agencies through data collection from a variety of sources. These include health insurance claims; the Automation of Reports and Consolidated Orders System, a DEA-run program that monitors the flow of controlled substances from manufacturing through distribution to retail sale or dispensing; the Treatment Episode Data Set, which monitors treatment admissions; the National Center for Health Statistics state mortality data; and the Researched Abuse, Diversion, and Addiction-Related Surveillance System, which monitors prescription drug abuse, misuse, and diversion [90].

Almost all states, including Florida, have enacted PDMPs to facilitate the collection, analysis, and reporting of information on controlled substances prescribing and dispensing [1]. All prescribers must consult the Electronic Florida Online Reporting of Controlled Substances Evaluation (E-FORCSE) to review a patient's controlled substance dispensing history before prescribing or dispensing a controlled substance to a patient 16 years of age or older [39,91]. This is mandated even for existing patients and should be done each time a controlled substance is prescribed or dispensed [39]. If the system is nonoperational or cannot be accessed due to a temporary technologic or electrical failure, the prescription may be issued (with documentation of the exception) for up to a maximum three-day supply.

All clinicians who prescribe or dispense controlled substances are required to report the action to E-FORCSE as soon as possible, but no later than the close of the next business day [39]. This should be repeated each time the substance is dispensed. This reporting requirement is waived in certain circumstances, including for [92]:

- The dispensing of a controlled substance in the healthcare system of the Department of Corrections

- The dispensing of a controlled substance to a person younger than 16 years of age

7. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

Research has more closely defined the location of prescribed opioid diversion into illicit use in the supply chain from the manufacturer to the distributor, retailer, and the end user (the patient with pain). This information carries with it substantial public policy and regulatory implications. The 2016 National Survey on Drug Use and Health asked 11.5 million non-medical users of prescription opioids how they obtained their most recently used drugs [93]. Among persons 12 years of age or older, 53% obtained their prescription opioids from a friend or relative. Of this 53%, 40.4% got the prescription opioids from a friend or relative for free, 8.9% bought them from a friend or relative, and 3.7% took them from a friend or relative without asking; 35.4% got them through a prescription from one doctor (vs. 19.7% in 2012) [93]. Less frequent sources included a drug dealer or other stranger (6%); multiple doctors (1.4%); theft from a doctor's office, clinic, hospital, or pharmacy (0.7%) (vs. 0.8% in 2012); and some other way (3.4%) [93].

As discussed, UDTs can give insight into patients who are misusing opioids. A random sample of UDT results from 800 patients with pain treated at a Veterans Affairs facility found that 25.2% were negative for the prescribed opioid while 19.5% were positive for an illicit drug/unreported opioid [94]. Negative UDT results for the prescribed opioid do not necessarily indicate diversion, but may indicate the patient halted his/her use due to side effects, lack of efficacy, or pain remission. The concern arises over the increasingly stringent climate surrounding clinical decision-making regarding aberrant UDT results and that a negative result for the prescribed opioid or a positive UDT may serve as the pretense to terminate a patient rather than guide him/her into addiction treatment or an alternative pain management program [95].

In addition to aberrant urine screens, there are certain behaviors that are suggestive of an emerging opioid use disorder. The most suggestive behaviors are [75,96,97]:

- Selling medications

- Prescription forgery or alteration

- Injecting medications meant for oral use

- Obtaining medications from nonmedical sources

- Resisting medication change despite worsening function or significant negative effects

- Loss of control over alcohol use

- Using illegal drugs or non-prescribed controlled substances

- Recurrent episodes of:

- Prescription loss or theft

- Obtaining opioids from other providers in violation of a treatment agreement

- Unsanctioned dose escalation

- Running out of medication and requesting early refills

Behaviors with less association with opioid misuse include [75,96,97]:

- Aggressive demands for more drug

- Asking for specific medications

- Stockpiling medications during times when pain is less severe

- Using pain medications to treat other symptoms

- Reluctance to decrease opioid dosing once stable

- In the earlier stages of treatment:

- Increasing medication dosing without provider permission

- Obtaining prescriptions from sources other than the pain provider

- Sharing or borrowing similar medications from friends/family

8. INTERVENTIONS FOR SUSPECTED OR KNOWN DRUG DIVERSION

There are a number of actions that prescribers and dispensers can take to prevent or intervene in cases of drug diversion. These actions can be generally categorized based on the various mechanisms of drug diversion.

Prevention is the best approach to addressing drug diversion. As noted, the most common source of nonmedical use of prescribed opioids is from a family member or friend, through sharing, buying, or stealing. To avoid drug sharing among patients, healthcare professionals should educate patients on the dangers of sharing opioids and stress that "doing prescription drugs" is the same as "using street drugs" [76]. In addition, patients should be aware of the many options available to treat chronic pain aside from opioids. As stated, to prevent theft, patients should be advised to keep medications in a private place and to refrain from telling others about the medications being used.

Communication among providers and pharmacies can help to avoid inappropriate attainment of prescription drugs through "doctor shopping." Prescribers should keep complete and up-to-date records for all controlled substance prescribing. When possible, electronic medical records should be integrated between pharmacies, hospitals, and managed care organizations [76]. It is also best practice to periodically request a report from the E-FORCSE to evaluate the prescribing of opioids to your patients by other providers [76].

When dealing with patients suspected of drug seeking/diversion, first inquire about prescription, over-the-counter, and illicit drug use and perform a thorough examination [76,98]. Pill counting and/or UDT may be necessary to investigate possible drug misuse. Photo identification or other form of identification and social security number may be required prior to dispensing the drug, with proof of identity documented fully. If a patient is displaying suspicious behaviors, consider prescribing for limited quantities [98].

If a patient is found to be abusing prescribed opioids, this is considered a violation of the treatment agreement and the clinician must make the decision whether or not to continue the therapeutic relationship. If the relationship is terminated, it must be done ethically and legally. The most significant issue is the risk of patient abandonment, which is defined as ending a relationship with a patient without consideration of continuity of care and without providing notice to the patient. The American Medical Association Code of Ethics states that "physicians' fiduciary responsibility to patients entails an obligation to support continuity of care for their patients" [99]. While physicians have the option of withdrawing from a case, they cannot do so without giving notice to the patient, the relatives, or responsible friends sufficiently long in advance of withdrawal to permit another medical attendant to be secured or to facilitate the transfer of care, when appropriate [99]. The notice of termination should be sent in writing, should specifically note the cause(s) for the termination, and should give a period of time prior to termination, usually 30 days [100]. Patients may also be given resources and/or recommendations to help them locate a new clinician.

Patients with chronic pain found to have an ongoing substance abuse problem or addiction should be referred to a pain specialist for continued treatment. Theft or loss of controlled substances is reported to the DEA. If drug diversion has occurred, the activity should be documented and a report to law enforcement should be made [101].

9. CASE STUDY

An unemployed man, 64 years of age, is brought to an emergency department by ambulance, after his wife returned from work to find him lying on the couch, difficult to arouse and incoherent. He has a past history of hypertension, diabetes (non-insulin dependent), mild chronic obstructive pulmonary disease, and chronic back and shoulder pain, for which he has been prescribed hydrocodone/acetaminophen for many years. His wife reports that while he seemed his usual self when she left for work that morning, he had, in recent weeks, been more withdrawn socially, less active, and complained of greater discomfort from the back and shoulder pain. She knows little about his actual medication usage and expresses concern that he may have been taking more than the prescribed amount of "pain medicine."

On evaluation, the patient is somnolent and arouses to stimulation but is non-communicative and unable to follow commands. His blood pressure is normal, he is afebrile, and there are no focal neurologic deficits. Oxygen saturation, serum glucose, and routine laboratory studies (blood counts and metabolic profile) are normal except for mild elevation in blood urea nitrogen (BUN) and creatinine; the urine drug screen is negative except for opioids. Additional history from the family indicates that the patient has been admitted to other hospitals twice in the past three years with a similar presentation and recovered rapidly each time "without anything being found."

Following admission, the patient remains stable-to-improved over the next 12 to 18 hours. By the following day, he is awake and conversant and looks comfortable. On direct questioning, he reports recent symptoms of depression but no suicidal ideation. The patient describes an increased preoccupation with his pain syndrome, difficulty sleeping at night, and little physical activity during the day, in part because of physical discomfort. He is vague about his medication regimen and admits to taking "occasional" extra doses of hydrocodone for pain relief.

The family is instructed to bring in all his pill bottles from home, which they do. In addition to the hydrocodone prescribed by his primary care physician, there is a recent refill of a prescription for the medication given to the patient at the time of his last hospital discharge six months earlier.

ASSESSMENT

A full evaluation, including radiographic studies and consultation with psychiatry and physical therapy, is completed. The working diagnosis for the patient's acute illness is toxic encephalopathy caused by the sedative side effects of opioid medication on the CNS. It is explained that the combination of his advancing age and diabetes likely reduced the efficiency of his kidneys in clearing the medication and its metabolites, making him more susceptible to CNS sedation. It is noted that the patient and his wife have little understanding of the rationale, proper use and safeguards, potential side effects, and limited effectiveness of opioid use for chronic pain.

In addition, the patient is diagnosed with poorly controlled chronic pain syndrome secondary to osteoarthritis and degenerative disc disease; exacerbating factors include deconditioning and reactive depression. The use of an opioid analgesic, at least for the near term, is considered appropriate, if dosed properly, monitored closely, and integrated into a comprehensive, multidisciplinary plan that includes treatment of depression and the use of adjunctive, nonpharmacologic modalities of care. In the setting of possible early diabetic nephropathy, the option of utilizing an NSAID, except for very brief periods of break-through pain, is not considered to be a safe option.

At discharge, and in consultation with his primary care physician, a written treatment and management plan addressing all aspects of the patient's care is presented to the patient and his wife for discussion and consent. Among the key issues addressed are:

- Goals: Improvement in subjective pain experience; improved function of daily living manifested by regular walking exercise and improved social interaction with family and friends; relief of depression; and in the long-term, anticipated withdrawal of opioid medication and resumption of part-time work and/or volunteer community activity

- Outpatient physical therapy and back exercise program to increase core muscular strength, improve flexibility, reduce pain, and increase exercise tolerance

- Patient and family counseling regarding the safe use, dosage regulation, side effects, and proper disposal of opioid medication

- Joint patient-physician responsibilities as regards to regular follow-up, monitoring of goals and treatment effectiveness, avoidance of "doctor-shopping," and assent to single provider for prescription medication

FOLLOW-UP

On follow-up six weeks after discharge, the patient is noticeably improved. He reports that he feels stronger and is sleeping better. His affect is brighter, and he is getting out more. He has maintained his physical therapy and exercise routine and is compliant with his medication. Though he still has pain, it is noticeably less and he is coping better. He and his wife are encouraged by his progress, particularly in regard to his improved functional status.

10. CONCLUSION

For patients suffering from pain, prescribed opioid analgesics may substantially lessen pain, distress, and impairment. Inappropriate overprescribing and overdose related to opioid analgesics increased dramatically in the 2000s. These trends are in multi-year reversal, but patient safety and risk mitigation remains no less important, and clinical tools, guidelines, and recommendations are available for use when prescribing opioids to patients with pain. By implementing these tools, the clinician can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Works Cited

1. Federation of State Medical Boards. Model Policy for the Use of Opioid Analgesics in the Treatment of Chronic Pain. Washington, DC: The Federation of State Medical Boards; 2013.

2. Institute of Medicine, Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011.

3. PR Newswire. U.S. Public and Doctors' Misperceptions Revealed in National Survey Demonstrate Urgent Need for Increased Opioid Dependence Awareness. Available at https://www.prnewswire.com/news-releases/us-public-and-doctors-misperceptions-revealed-in-national-survey-demonstrate-urgent-need-for-increased-opioid-dependence-awareness-210981471.html. Last accessed August 6, 2019.

4. American Society of Addiction Medicine. Definitions Related to the Use of Opioids for the Treatment of Pain: Consensus Statement of the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine. Available at https://www.asam.org/docs/default-source/public-policy-statements/1opioid-definitions-consensus-2-011.pdf. Last accessed August 1, 2019.

5. Bhamb B, Brown D, Hariharan J, et al. Survey of select practice behaviors by primary care physicians on the use of opioids for chronic pain. Curr Med Res Opin. 2006;22(9):1859-1865.

6. Mezei L, Murinson BB. Pain education in North American medical schools. J Pain. 2011;12:1199-1208.

7. Vadivelu N, Mitra S, Hines R, Elia M, Rosenquist R. Acute pain in undergraduate medical education: an unfinished chapter!Pain Pract. 2012;12(8):663-671.

8. Oliver J, Coggins C, Compton P, et al. American Society for Pain Management Nursing position statement: pain management in patients with substance use disorders. Pain Manage Nurs. 2012;13(3):169-183.

9. Psychiatry Online. Highlights of Changes from DSM-IV-TR to DSM-5. Available at https://dsm.psychiatryonline.org/doi/10.1176/appi.books.9780890425596.changes. Last accessed August 6, 2019.

10. American Society of Addiction Medicine. Definition of Addiction. Available at https://www.asam.org/resources/definition-of-addiction. Last accessed August 6, 2019.

11. Reuben DB, Alvanzo AAH, Ashikaga T, et al. National Institutes of Health Pathways to Prevention Workshop: the role of opioids in the treatment of chronic pain. Ann Intern Med. 2015;162(4):295-300.

12. Giordano J, Schatman ME, Höver G. Ethical insights to rapprochement in pain care: bringing stakeholders together in the best interest(s) of the patient. Pain Physician. 2009;12:E265-E275.

13. Atkinson TJ, Schatman ME, Fudin J. The damage done by the war on opioids: the pendulum has swung too far. J Pain Res. 2014;7:265-268.

14. Webster LR. Pain and suicide: the other side of the opioid story. Pain Med. 2014;15(3):345-346.

15. Ziegler SJ. Patient abandonment in the name of opioid safety. Pain Med. 2013;14(3):323-324.

16. Schatman ME, Webster LR. The health insurance industry: perpetuating the opioid crisis through policies of cost-containment and profitability. J Pain Res. 2015;8:153-158.

17. Fudin J, Pratt Cleary J, Schatman ME. The MEDD myth: the impact of pseudoscience on pain research and prescribing-guideline development. J Pain Res. 2016;9:153-156.

18. Centers for Disease Control and Prevention. 2018 Annual Surveillance Report of Drug-Related Risks and Outcomes: United States. Available at https://www.cdc.gov/drugoverdose/pdf/pubs/2018-cdc-drug-surveillance-report.pdf. Last accessed August 1, 2019.

19. Jamison RN, Scanlan E, Matthews ML, Jurcik DC, Ross EL. Attitudes of primary care practitioners in managing chronic pain patients prescribed opioids for pain: a prospective longitudinal controlled trial. Pain Med. 2016;17(1):99-113.

20. Anson P. Health Officials Call for Better Access to Addiction Treatment. Available at http://nationalpainreport.com/health-officials-call-for-better-access-to-addiction-treatment-8823738.html. Last accessed August 6, 2019.

21. Kenen K, Mack K, Paulozzi L. Trends in prescriptions for oxycodone and other commonly used opioids in the United States, 2000–2010. Open Med. 2012;6(2)e41-e47.

22. International Narcotics Control Board. Narcotic Drugs, 2018: Estimated World Requirements for 2019. Available at http://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2018/INCB-Narcotics_Drugs_Technical_Publication_2018.pdf. Last accessed August 2, 2019.

23. Bhadelia A, De Lima L, Arreola-Ornelas H, Kwete XJ, Rodriquez NM, Knaul FM. Solving the global crisis in access to pain relief: lessons from country actions. Am J Public Health. 2019;109(1):58-60.

24. Fudin J. The Hydrocodone Question. Available at https://www.drugtopics.com/chains-business/hydrocodone-question. Last accessed August 6, 2019.

25. National Institute on Drug Abuse. Overdose Death Rates: Revised January 2019. Available at https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates. Last accessed August 2, 2019.

26. Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med. 2011;171(7):686-691.

27. Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S. Cohort study of the impact of high-dose opioid analgesics on overdose mortality. Pain Med. 2016;17(1):85-98.

28. Agarwal SD, Landon BE. Patterns in outpatient benzodiazepine prescribing in the United States. JAMA Netw Open. 2019;2(1):e1873999.

29. Florida Department of Health. 2017-2018 Prescription Drug Monitoring Program Annual Report. Available at http://www.floridahealth.gov/statistics-and-data/e-forcse/health_care_practitioners/_documents/2018-pdmp-annual-report.pdf. Last accessed August 2, 2019.

30. Rudd RA, Aleshire N, Zibbell JE, Gladden RM. Increases in drug and opioid overdose deaths—United States, 2000–2014. MMWR. 2016;64(50):1378-1382.

31. Florida Department of Law Enforcement. Drugs Identified in Deceased Persons by Florida Medical Examiners: 2017 Annual Report. Available at https://www.fdle.state.fl.us/MEC/Publications-and-Forms/Documents/Drugs-in-Deceased-Persons/2017-Annual-Drug-Report.aspx. Last accessed August 6, 2019.

32. Johnson H, Paulozzi L, Porucznik C, Mack K, Herter B. Decline in drug overdose deaths after state policy changes—Florida, 2010–2012. MMWR. 2014;63(26):569-574.

33. Florida Governor Rick Scott. 17-146 Executive Order directing a Public Health Emergency re: Opioid Epidemic. Available at https://www.flgov.com/wp-content/uploads/orders/2017/EO_17-146.pdf. Last accessed August 6, 2019.

34. Ron DeSantis, 46th Governor of Florida. 2018 Executive Orders. #2018-362 Executive Order extends Executive Order 18-279 re: Opioid Epidemic: December 5, 2018. Available at https://www.flgov.com/2018-executive-orders/#header. Last accessed August 2, 2019.

35. Hall J. Florida Drug Trends Update: November 2015. Available at https://slideplayer.com/slide/12804922/. Last accessed August 6, 2019.

36. Popovich N. A Deadly Crisis: Mapping the Spread of America's Drug Overdose Epidemic. Available at https://www.theguardian.com/society/ng-interactive/2016/may/25/opioid-epidemic-overdose-deaths-map. Last accessed August 6, 2019.

37. Jones CM, Paulozzi LJ, Mack KA. Alcohol involvement in opioid pain reliever and benzodiazepine drug abuse-related emergency department visits and drug-related deaths—United States, 2010. MMWR. 2014;63(40):881-885.

38. Ruhm CJ. Drug poisoning deaths in the United States, 1999–2012: a statistical adjustment analysis. Popul Health Metr. 2016;14:2.

39. Scott J. Florida's New Law on Controlled Substance Prescribing. Available at https://flmedical.org/Florida/Florida_Public/Docs/FMA-Opioid-HB21.pdf. Last accessed August 6, 2019.

40. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR. 2016;65(1):1-49.

41. Webster L. Will CDC Opioid Guidelines Help Reduce Overdoses? Available at https://www.painnewsnetwork.org/stories/2016/4/25/will-cdc-opioid-guidelines-help-reduce-overdoses. Last accessed August 6, 2019.

42. Ciccone TG, Kean N. Responses and Criticisms Over New CDC Opioid Prescribing Guidelines. Available at https://www.practicalpainmanagement.com/resources/news-and-research/responses-criticisms-over-new-cdc-opioid-prescribing-guidelines. Last accessed August 6, 2019.

43. Samp RA. Letter to the CDC ATS DR. Available at https://s3.us-east-2.amazonaws.com/washlegal-uploads/upload/litigation/misc/CDCFOIARequest-Opioids.pdf. Last accessed August 6, 2019.

44. American Academy of Pain Medicine. Consensus Panel Report Addresses Challenges of Implementing the CDC Guideline for Prescribing Opioids for Chronic Pain. Available at https://painmed.org/aapm-news/consensus-panel-report-addresses-challenges-of-implementing-the-cdc-guideline-for-prescribing-opioids-for-chronic-pain. Last accessed August 6, 2019.

45. Alford DP. Opioid prescribing for chronic pain: achieving the right balance through education. N Engl J Med. 2016;374(4):301-303.

46. Wallwork RS, Chipidza FE, Stern TA. Obstacles to the prescription and use of opioids. Prim Care Companion CNS Disord. 2016;18(1):10.

47. U.S. Department of Veterans Affairs. VA/DoD Clinical Practice Guidelines: Management of Opioid Therapy (OT) for Chronic Pain (2017). Available at https://www.healthquality.va.gov/guidelines/Pain/cot/. Last accessed August 6, 2019.

48. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130.

49. The Florida Senate. CS/CS/HB 21: Controlled Substances. Available at https://www.flsenate.gov/Session/Bill/2018/21. Last accessed August 6, 2019.

50. Argoff CE, Silvershein DI. A comparison of long- and short-acting opioids for the treatment of chronic noncancer pain: tailoring therapy to meet patient needs. Mayo Clin Proc. 2009;84(7):602-612.

51. McCarberg BH, Barkin RL. Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther. 2001;8(3):181-186.

52. National Comprehensive Cancer Network. Adult Cancer Pain, V.3.2019. Available at https://www.nccn.org/professionals/physician_gls/PDF/pain.pdf. Last accessed August 6, 2019.

53. Utah Department of Health, Utah Medical Association. Utah Clinical Guidelines on Prescribing Opioids for Treatment of Pain: 2018. Available at http://www.health.utah.gov/vipp/pdf/RxDrugs/UtahClinicalGuidelinesOnPrescribing.pdf. Last accessed August 6, 2019.

54. Sloan P. Update on extended-release opioids in pain management. Expert Opin Drug Deliv. 2014;11(2):155-158.

55. Federation of State Medical Boards. Model Policy for the Use of Opioid Analgesics in the Treatment of Chronic Pain. Washington, DC: Federation of State Medical Boards; 2013.

56. Cheatle MD, Barker C. Improving opioid prescription practices and reducing patient risk in the primary care setting. J Pain Res. 2014;7:301-311.

57. Nadeau SE. Opioids for chronic noncancer pain. To prescribe or not to prescribe: what is the question? Neurology. 2015;85(7):646-651.

58. U.S. Food and Drug Administration. Guidance: Medication Guides: Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS). Available at https://www.fda.gov/media/79776/download. Last accessed August 6, 2019.

59. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2—guidance. Pain Physician. 2012;15(3 Suppl):S67-S116.

60. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the opioid risk tool. Pain Med. 2005;6(6):432-442.

61. Butler SF, Budman SH, Fernandez KC, Fanciullo GJ, Jamison RN. Cross-validation of a Screener to Predict Opioid Misuse in Chronic Pain Patients (SOAPP-R). J Addict Med. 2009;3(2):66-73.

62. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004.

63. CAGE-AID Overview. Available at https://www.integration.samhsa.gov/images/res/CAGEAID.pdf. Last accessed August 3, 2019.

64. Fine PG, Finnegan T, Portenoy RK. Protect your patients, protect your practice: practical risk assessment in the structuring of opioid therapy in chronic pain. J Fam Pract. 2010;59(9 Suppl 2):S1-S16.

65. DIRE Score: Patient Selection for Chronic Opioid Analgesia. Available at http://www.emergingsolutionsinpain.com/content/tools/esp_9_instruments/pdf/DIRE_Score.pdf. Last accessed August 3, 2019.

66. Katz NP. Opioid Prescribing Toolkit: A Workbook for Clinicians. New York, NY: Oxford University Press; 2010.

67. Dalal S, Bruera E. Assessment and management of pain in the terminally ill. Prim Care Clin Office Pract. 2011;38(2):195-223.

68. Berger AM, Shuster JL, Von Roenn JH (eds). Principles & Practice of Palliative Care & Supportive Oncology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013.

69. Strickland JM, Huskey A, Brushwood DB. Pharmacist-physician collaboration in pain management practice. J Opioid Manag. 2007;3(6):295-301.

70. Crespi-Lofton J. VIGIL: answer the question "Is it legitimate?" Pharm Today. 2006;12(1):1.

71. Tanzi MG. VIGIL helps pharmacists screen controlled substances: goal is controlling diversion. Pharm Today. 2012:58.

72. Passik SD, Kirsh KL, Whitcomb L, et al. A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther. 2004;26(4):552-561.

73. Pain Assessment and Documentation Tool. Available at https://www.drugabuse.gov/sites/default/files/files/PainAssessmentDocumentationTool.pdf. Last accessed August 3, 2019.

74. Atluri SL, Akbik H, Sudarshan G. Prevention of opioid abuse in chronic non-cancer pain: an algorithmic, evidence-based approach. Pain Physician. 2012;15(3 Suppl):ES177-ES189.

75. Baxter J. Minimizing the Misuse of Prescription Opioids in Patients with Chronic Nonmalignant Pain. Available at https://www.drugabuse.gov/nidamed/centers-excellence/resources/minimizing-misuse-prescription-opioids-in-patients-chronic-nonmalignant-pain. Last accessed August 6, 2019.

76. American College of Preventive Medicine. Use, Abuse, Misuse and Disposal of Prescription Pain Medication Time Tool. Available at https://c.ymcdn.com/sites/www.acpm.org/resource/resmgr/timetools-files/painmedsclinicalreference.pdf. Last accessed August 6, 2019.

77. Office of National Drug Control Policy. Proper Disposal of Prescription Drugs. Available at https://www.ncjrs.gov/ondcppubs/publications/pdf/prescrip_disposal.pdf. Last accessed August 6, 2019.

78. Campbell G, Hall WD, Peacock A, et al. Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: findings from a 4-year prospective cohort study. Lancet Public Health. 2018;3(7):e341-e350.

79. Merlin JS, Long D, Becker WC, et al. Marijuana use is not associated with changes in opioid prescriptions or pain severity among people living with HIV and chronic pain. J Acquir Immune Defic Syndr. 2019;81(2):231-237.

80. Mucke M, Phillips T, Radbruch L, Petzke F, Hauser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;3:CD012182.

81. Wheeler E, Davidson PJ, Jones TS, Irwin KS. Community-based opioid overdose prevention programs providing naloxone—United States, 2010. MMWR. 2012;61(6):101-105.

82. Florida Legislature. 381.887 Emergency Treatment for Suspected Opioid Overdose. Available at http://www.leg.state.fl.us/statutes/index.cfm?App_mode=Display_Statute&Search_String=&URL=0300-0399/0381/Sections/0381.887.html. Last accessed August 6, 2019.

83. Gutstein HB, Akil H. Opioid analgesics. In: Brunton L, Parker K, Lazo J, Buxton I, Blumenthal D (eds). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011: 547-590.

84. van den Brink W, Haasen C. Evidence-based treatment of opioid-dependent patients. Can J Psychiatry. 2006;51(10):635-646.

85. Lexicomp Online. Available at https://online.lexi.com/lco/action/login. Last accessed August 6, 2019.

86. Centers for Disease Control and Prevention. Risk for overdose from methadone used for pain relief—United States, 1999–2010. MMWR. 2012;61(26):493-497.

87. Hannon K. Prescription Drug Abuse Crisis in New York State: Comprehensive Approach - New. Available at https://www.scribd.com/doc/82474334/Prescription-Drug-Abuse-Crisis-in-NYS-Comprehensive-Approach-New. Last accessed August 6, 2019.

88. U.S. Drug Enforcement Administration. Drug Scheduling. Available at https://www.dea.gov/drug-scheduling. Last accessed August 6, 2019.

89. Florida Legislature. Chapter 893: Drug Abuse Prevention and Control. Available at http://www.leg.state.fl.us/statutes/index.cfm?App_mode=Display_Statute&URL=0800-0899/0893/0893.html. Last accessed August 6, 2019.

90. Reifler LM, Droz D, Bailey JE, et al. Do prescription monitoring programs impact state trends in opioid abuse/misuse? Pain Med. 2012;13(3):434-442.

91. Florida Legislature. 893.055 Prescription Drug Monitoring Program. Available at http://www.leg.state.fl.us/statutes/index.cfm?App_mode=Display_Statute&URL=0800-0899/0893/Sections/0893.055.html. Last accessed August 6, 2019.

92. Data Submission Dispenser Guide. Florida Department of Health Prescription Drug Monitoring Program: E-FORCSE: 2018. Available at http://rxsentry.net/assets/files/flpdms/2018/FL_Dispenser_Guide_V1.pdf. Last accessed August 5, 2019.

93. Substance Abuse and Mental Health Services Administration. Key Substance Use and Mental Health Indicators in the United States: Results from the 2016 National Survey on Drug Use and Health. Available at https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR1-2016/NSDUH-FFR1-2016.pdf. Last accessed August 5, 2019.

94. Sekhon R, Aminjavahery N, Davis CN Jr, et al. Compliance with opioid treatment guidelines for chronic non-cancer pain (CNCP) in primary care at a Veterans Affairs Medical Center (VAMC). Pain Med. 2013;14(10):1548-1556.

95. Meier B. Increase in Urine Testing Raises Ethical Questions. Available at https://www.nytimes.com/2013/08/02/business/increase-in-urine-testing-raises-ethical-questions.html?_r=0. Last accessed August 6, 2019.

96. Passik SD. Issues in long-term opioid therapy: unmet needs, risks, and solutions. Mayo Clin Proc. 2009;84(7):593-601.

97. Holliday S, Hayes C, Dunlop A. Opioid use in chronic non-cancer pain. Part 2: prescribing issues and alternatives. Australian Fam Physician. 2013;42(3):104-111.

98. U.S. Department of Justice Diversion Control Division. Don't Be Scammed By A Drug Abuser. Available at https://www.deadiversion.usdoj.gov/pubs/brochures/drugabuser.htm. Last accessed August 6, 2019.

99. American Medical Association. Terminating a Patient-Physician Relationship. Code of Medical Ethics: Opinion 1.1.5. Available at https://www.ama-assn.org/delivering-care/terminating-patient-physician-relationship. Last accessed August 6, 2019.

100. Bolen J. Discharging Patients Who Abuse Controlled Substances. Available at https://www.painmedicinenews.com/Policy-Management/Article/04-06/Discharging-Patients-Who-Abuse-Controlled-Substances/4340. Last accessed August 6, 2019.

101. U.S. Department of Health and Human Services, Centers for Medicare and Medicaid Services. What is a Prescriber's Role in Preventing the Diversion of Prescription Drugs? Available at https://www.cms.gov/Medicare-Medicaid-Coordination/Fraud-Prevention/Medicaid-Integrity-Education/Provider-Education-Toolkits/Downloads/prescriber-role-drugdiversion.pdf. Last accessed August 6, 2019.

Evidence-Based Practice Recommendations Citations

1. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2—guidance. Pain Physician. 2012;15(3 Suppl):S67-S116. Available at https://painphysicianjournal.com/2012/july/2012;%2015;S67-S116.pdf. Last accessed August 14, 2019.

97110 • Recognizing and Reporting Human Trafficking in Florida

Alice Yick Flanagan, PhD, MSW

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Today, some label human trafficking as a form of "modern day slavery," and frequently, human trafficking has been linked to sex work and prostitution, although there are other forms of trafficking, such as forced labor and domestic work. Human trafficking can involve women, men, and children. Its victims experience a host of psychologic problems, including post-traumatic stress, helplessness, and depression, due to the physical, sexual, and psychologic abuse they have experienced. This course encompasses a basic overview of human trafficking. The course will attempt to provide practitioners with a glimpse of the realities of human trafficking victims' lives and the physical, psychologic, social, and sexual abuse they experience. Specific interventions and responses are covered, including mental health, social services, educational, prevention, and legal efforts. The course provides an array of resources for victims and practitioners, including organizations/agencies, books, and films/documentaries focusing on the issue of human trafficking.

Table of Contents

97110 • Recognizing and Reporting Human Trafficking in Florida

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. SCOPE OF HUMAN TRAFFICKING

3. DEFINITIONS OF HUMAN TRAFFICKING

4. FORMS OF TRAFFICKING

SEX TRAFFICKING

BONDED LABOR/FORCED LABOR

CHILD LABOR

CHILD CONSCRIPTION

5. FACTORS THAT CONTRIBUTE TO HUMAN TRAFFICKING

GLOBALIZATION

POVERTY

SOCIAL AND FAMILIAL DISORGANIZATION

CORRUPTION

DIGITAL TECHNOLOGY

RACIALIZED SEXUAL STEREOTYPES

CULTURE

6. THE TRAFFICKING EXPERIENCE

TRAFFICKERS: AN OVERVIEW

7. CONSEQUENCES OF HUMAN TRAFFICKING: IMPACT ON VICTIMS

PSYCHOLOGIC AND MENTAL HEALTH CONSEQUENCES

SOCIAL CONSEQUENCES

HEALTH CONSEQUENCES

8. IDENTIFICATION AND ASSESSMENT

POTENTIAL RED FLAGS

SCREENING QUESTIONS

INTERVIEWING TRAFFICKED VICTIMS: BEST PRACTICE GUIDELINES

9. REPORTING

10. INTERVENTIONS AND RESOURCES

EDUCATION AND PREVENTION

MENTAL HEALTH AND SOCIAL SERVICES

ADVOCACY

LAWS AND POLICIES

RESOURCES

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

97110 • Recognizing and Reporting Human Trafficking in Florida

Education Category. Ethics - Human Rights

Release Date. 09/01/2019

Expiration Date. 08/31/2022

Course Overview

Today, some label human trafficking as a form of "modern day slavery," and frequently, human trafficking has been linked to sex work and prostitution, although there are other forms of trafficking, such as forced labor and domestic work. Human trafficking can involve women, men, and children. Its victims experience a host of psychologic problems, including post-traumatic stress, helplessness, and depression, due to the physical, sexual, and psychologic abuse they have experienced. This course encompasses a basic overview of human trafficking. The course will attempt to provide practitioners with a glimpse of the realities of human trafficking victims' lives and the physical, psychologic, social, and sexual abuse they experience. Specific interventions and responses are covered, including mental health, social services, educational, prevention, and legal efforts. The course provides an array of resources for victims and practitioners, including organizations/agencies, books, and films/documentaries focusing on the issue of human trafficking.

Audience

This course is designed for all health and mental health professionals in Florida who may identify and intervene in cases of human trafficking and exploitation.

Course Objective

The purpose of this course is to provide physicians, nurses, and other healthcare professionals an in-depth, practical review of human trafficking, including the definition and scope of the problem, the means of identification and assessment of individuals who may be victims, guidance on reporting of cases, and interventions and resources available to victims.

Learning Objectives

Upon completion of this course, you should be able to:

1. Define human trafficking.

2. Identify the forms of human trafficking.

3. Identify economic, political, social, and cultural factors that contribute to human trafficking.

4. Analyze the trafficking experience, including how traffickers recruit and the financial implications of trafficking.

5. Explain the psychologic, health, and social consequences of human trafficking.

6. Utilize interviewing strategies to assess and identify victims and promote the ethical treatment of trafficking victims

7. Describe the appropriate steps for reporting suspected cases of trafficking.

8. Describe various interventions and resources for human trafficking victims.

Faculty

Alice Yick Flanagan, PhD, MSW, received her Master’s in Social Work from Columbia University, School of Social Work. She has clinical experience in mental health in correctional settings, psychiatric hospitals, and community health centers. In 1997, she received her PhD from UCLA, School of Public Policy and Social Research. Dr. Yick Flanagan completed a year-long post-doctoral fellowship at Hunter College, School of Social Work in 1999. In that year she taught the course Research Methods and Violence Against Women to Masters degree students, as well as conducting qualitative research studies on death and dying in Chinese American families.

Previously acting as a faculty member at Capella University and Northcentral University, Dr. Yick Flanagan is currently a contributing faculty member at Walden University, School of Social Work, and a dissertation chair at Grand Canyon University, College of Doctoral Studies, working with Industrial Organizational Psychology doctoral students. She also serves as a consultant/subject matter expert for the New York City Board of Education and publishing companies for online curriculum development, developing practice MCAT questions in the area of psychology and sociology. Her research focus is on the area of culture and mental health in ethnic minority communities.

Faculty Disclosure

Contributing faculty, Alice Yick Flanagan, PhD, MSW, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Abimbola Farinde, PharmD, PhD

James Trent, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Although human trafficking has always existed, it has begun to receive increased attention as a result of awareness and outreach efforts. All social problems compete for attention, and various groups will make compelling claims about social problems using persuasive rhetoric and dramatic statistics [1]. More than just a human rights issue, it has garnered attention from feminists, religious conservatives, labor activists, immigration specialists, and the mental health professions [2]. Furthermore, attention will be drawn from the media, politicians, organizations, and public, all of whom will respond to the gravity of the condition. It is through this process of claims-making and counter claims-making that "conditions" that may not necessarily have initially attracted attention can develop into a recognized social problem [1]. How the problem is described or constructed will influence public opinion, which will then ultimately facilitate action from governmental agencies, social service organizations, and international agencies [3,4,5].

This course will provide a basic overview of human trafficking (e.g., the scope, definitions and frameworks, contributing factors, different forms). The course will attempt to provide practitioners a glimpse of the lives of human trafficking victims, including physical, psychologic, social, and sexual abuse that human trafficking victims experience and the types of control tactics perpetrators use. Specific interventions and responses will be covered, including mental health, social services, educational, prevention, and legal efforts. Finally, for practitioners who do work with human trafficking victims, the emotional toil that it takes upon practitioners as well as the importance of self-care will be discussed. The course will end by offering an array of resources. Practitioners will be encouraged to view films and documentaries about human trafficking, as this is one way to "enter the lives" of human trafficking victims and better understand the dynamics of the complex world of human trafficking.

2. SCOPE OF HUMAN TRAFFICKING

As the issue of human trafficking is so complex, it is difficult to determine the scope of the problem. Many scholars and researchers believe that published estimates are just educated guesses. On a global level, the International Labour Organization has estimated that there are 40.3 million human trafficking victims [6]. The estimates for the United States are not totally clear, but there were approximately 78,000 human trafficking victims reported to the U.S. State Department in 2016; only an estimated 0.2% are rescued [7]. According to Polaris, which founded and runs the National Human Trafficking Hotline, there have been a total of 40,200 cases of human trafficking reported since 2007 [7].

Weitzer's content analysis of websites and publications about human trafficking found that human trafficking is portrayed as an epidemic, growing at alarming rates, with some government reports estimating 40,000 to 50,000 individuals trafficked in the United States each year [8]. Weitzer argues that many of the reports have overestimated the scope of the problem and points out that the estimates fluctuate drastically year to year [9]. Sex trafficking tends to be portrayed more frequently due to its sensationalism. In a study of 50 human trafficking campaigns in Spain between 2004 and 2017, 40 (80%) depicted sex trafficking and exploitation involving women [10]. The U.S. Department of Justice reported 1,045 convictions for human trafficking-related crimes in 2017, including forced labor and sex trafficking of adults and minors. This was an increase of more than 78% over the number reported in 2015 [6]. In 2016, the International Labour Organization stated that there were 4.8 million victims of sex trafficking, and 15.4 million in forced marriages. The majority (62%) of those trafficked are in Asia and Pacific regions [11]. In 2017, it is estimated that there are 24.9 million people around the world who are in forced labor [11].

Florida ranks third in the United States in terms of destinations for trafficked persons [12]. In 2018, the National Human Trafficking Hotline received 1,885 contacts (e.g., phone calls, texts, e-mails) and 767 human trafficking cases reported in Florida. The most common type was sex trafficking (68%), followed by labor trafficking (16.5%) and combined sex/labor trafficking (7.5%) [12]. The majority of victims were female (69%) and adult (55.8%).

3. DEFINITIONS OF HUMAN TRAFFICKING

The United Nations defines human trafficking as [13]:

The recruitment, transportation, transfer, harbouring or receipt of persons, by means of threat or use of force or other forms of coercion, of abduction, of fraud, of deception, of the abuse of power or of a position of vulnerability, or of the giving or receiving of payments or benefits to achieve the consent of a person having control over another person, for the purpose of exploitation. Exploitation shall include, at a minimum, the exploitation or the prostitution or other forms of sexual exploitation, forced labour or services, slavery or practices similar to slavery, servitude, or the removal of organs.

In essence, this definition involves three elements: the transport of the person, the force or coercion of the victim, and the abuse and exploitation [14]. The United Nations Office on Drugs and Crime divides the definition of human trafficking into three sections: the act, means, and purpose [15]. The act, or what is done, generally refers to activities such as recruitment, transportation, transfer, harboring, or receipt of persons. The means of trafficking consists of threats or use of force, coercion, abduction, fraud, deception, abuse of power or vulnerability, or giving payments or benefits to a person in control of the victim. Finally, these acts are carried out for the purpose of exploitation, which includes prostitution, sexual exploitation, forced labor, slavery or forced servitude, and the removal of organs [15]. It is important to remember that human trafficking is not human smuggling. Human smuggling involves an individual being brought into a country through illegal means and is voluntary. The individual has provided some remuneration to another individual or party to accomplish this goal [16].

The following video, produced by Free the Slaves, provides a snapshot of modern slavery, including the economics of slavery and the various types of slavery worldwide.

To see this media go to http://www.NetCE.com/activities/ using a browser that supports Adobe Flash.

For more information, visit Free the Slaves at https://www.freetheslaves.net.

The Trafficking Victims Protection Act (TVPA) defines human trafficking to include both sex trafficking and labor trafficking [17]. Sex trafficking is the recruitment, harboring, transportation, provision, obtaining, patronizing, or soliciting of a person for the purposes of a commercial sex act, in which the commercial sex act is induced by force, fraud, or coercion, or in which the person induced to perform such an act has not attained 18 years of age. Labor trafficking is the recruitment, harboring, transportation, provision, or obtaining of a person for labor or services, through the use of force, fraud, or coercion for the purposes of subjection to involuntary servitude, peonage, debt bondage, or slavery. A victim need not be physically transported from one location to another for the crime to fall within this definition.

In many cases, women and children are considered the typical victims of human trafficking. Hart posits that women are more vulnerable to trafficking due to the lack of social safety nets in many developing countries [18]. Coupled with women's subordinate social statuses in many cultures, this leads to the "feminization of poverty." Although the social conditions may make women and children more vulnerable to human trafficking, the reality is that men are also victims of human trafficking.

Overall, the definition of human trafficking is ambiguous because of the many intersections with other issues (e.g., sexual abuse, domestic violence, forced marriage, forced labor) [19]. It occurs both domestically and internationally, but is primarily a hidden problem. This makes research efforts, the prosecution of perpetrators, and policy and community efforts to protect victims even more challenging [19].

4. FORMS OF TRAFFICKING

SEX TRAFFICKING

The TVPA of 2000 is a U.S. federal statute passed by Congress to address the issue of human trafficking and offers protection for human trafficking victims [17]. This statute defines sex trafficking as, "the recruitment, harboring, transportation, provision, or obtaining of a person for the purpose of a commercial sex act" [17]. A commercial sex act is, "any sex act on account of which anything of value is given to or received by any person" [17]. In other words, it usually involves the illegal transport of humans into another country to be exploited in a sexual manner for financial gains [20]. However, it does not always involve the transport of victims from one region to another; such cases are referred to as "internal trafficking" [21]. Victims of sex trafficking could be forced into prostitution, stripping, pornography, escort services, and other sexual services [22]. Victims may be adult women or men or children, although there is a higher prevalence of women and girls. The term "domestic minor sex trafficking" has become a popular term used to connote the buying, selling, and/or trading of children younger than 18 years of age for sexual services within the country, not internationally [22,23]. An element of force, fraud, or coercion is not necessary, as the victims are children and inherently vulnerable [23]. In the United States, the children most vulnerable to domestic minor sex trafficking are those who are homeless, abused, runaways, and/or in child protective services [22].

Although highly controversial, it is said that sex trafficking victims differ from prostitutes in that sex trafficking victims are forced to involuntarily perform sexual services and are often not paid for their "work." Sex trafficking involves the use of force and coercion and can encompass other forms of criminal sexual activities, including forced erotic dancing, "mail-order brides," and pornography [21]. On the other hand, individuals involved in prostitution make a decision to provide sex services for a fee. The decision to enter prostitution does not eliminate the possibility of being a victim of trafficking if one is held against his/her will through physical and/or psychologic abuse [24]. It is also important to remember that this does not necessarily mean prostitution is a choice these individuals would have made if other options were available or that they have a choice in selecting their sexual partners and/or sexual activities [25].

Visit the PBS Frontline website (https://www.pbs.org/wgbh/pages/frontline/slaves/map/indexflash.html) and read the transcripts of interviews with a sex trafficker and five Eastern European female victims who were deceived into sexual slavery.

BONDED LABOR/FORCED LABOR

The United Nations has defined debt bondage as [26]:

The status or condition arising from a pledge by a debtor of his personal services or of those of a person under his control as security for a debt, if the value of those services as reasonably assessed is not applied towards the liquidation of the debt or the length and nature of those services are not respectively limited and defined.

Essentially, because the individual does not have money as collateral for the debt owed, the individual pledges his/her labor or, in some cases, the labor of a child or another individual for an unspecified amount of time [27]. These individuals may be transported or trafficked into another country for the purpose of forced labor.

In many cases of bonded labor, the initial loan may be welcomed by the individual. However, the victims do not realize that with the low wages, unspoken high interest rates and other continually accruing fees, and the perpetrator's manipulation of the "accounts," laborers can never repay the loans. Some estimate that half of all persons in forced labor are bonded laborers. The majority of bonded labor cases occur in India, Bangladesh, and Pakistan [28]. Some families find themselves in a cycle of poverty as the debt cannot be paid off and is passed down from generation to generation [27]. Bonded labor can involve laborers in brick kilns, mines, stone quarries, looming factories, agricultural farms, and other manufacturing factories [27]. In the United States, individuals may be trafficked to work long hours in garment factories, restaurants, and other manufacturing sectors. Frequently, the employer/captor will take away victims' identifications, monitor their movements, socially isolate them, and/or threaten deportation if they do not comply [29]. Migrant workers are at high risk of forced labor [24].

In the United States, forced labor is predominantly found in five sectors [29]:

- Prostitution and sex industry (46%)

- Domestic servitude (27%)

- Agriculture (10%)

- Sweatshops and factories (5%)

- Restaurant and hotel work (4%)

It is speculated that most of the forced labor occurs in California, Florida, New York, and Texas, all major routes for international travel [29].

Domestic servitude refers to a category of domestic workers (usually female) who work as servants, housekeepers, maids, and/or caregivers, often in private homes. In some cases, young women are lured with the promise of a good education and work, and when they arrive in the United States, they are exploited economically, physically, and/or sexually. Their passports or identification papers are taken away, and they are told they have to pay off the debt incurred for their travel, processing fees, and any other bogus expenses. Because they do not speak English, they find they have no other recourse but to endure exploitive working conditions [30]. Unfortunately, as in many sectors of forced labor, there are no regulations to monitor the conditions under which domestic servants operate [29].

The following documentary, A Global Alliance Against Forced Labour, was produced by the International Labour Organization in order to tell the stories of men and women forced to labor and show what is being done globally to combat modern day slavery.

To see this media go to http://www.NetCE.com/activities/ using a browser that supports Adobe Flash.

For more information, visit the International Labour Organization at https://www.ilo.org.

CHILD LABOR

Child labor can be viewed as a specific form of bonded labor or forced labor. However, not all child laborers have been trafficked. Child labor is defined by International Labour Organization (ILO) as economic labor performed by a child younger than 15 years of age or hazardous labor done by a child 18 years of age or younger. Child labor is deeply rooted in poverty and the infrastructure and political stability of the country as well as market forces [31]. The ILO estimates that there are 152 million child laborers in the world [32]. Between 2000 and 2016 there was a nearly 38% decrease in the number of children in child labor. The reduction was greater for girls (43%) than for boys (34%). The largest numbers of child laborers are found in Asia and the Pacific region; however, there is evidence that the number of child laborers in Africa is increasing [32].

The definition of child labor is controversial because the definitions for "work" and "childhood" are ambiguous and often culturally defined [33]. On a conceptual level, work may be beneficial for the socialization and educational processes of children [33,34]. So, it is important to differentiate between child work and child labor. Child work has been defined as activities that are supervised by an adult and that promote the development and growth of the child, while child labor does not benefit the child [31]. Many definitions of child labor create a dichotomy whereby child work is considered not harmful while child labor has negative emotional, intellectual, and social consequences [35]. Work that is exploitive for children has been defined as working long hours at a young age, work that is poorly compensated, and work that produces physical, social, and psychologic stress that will hamper development, access to education, and self-esteem [36]. The ILO adds that child labor is work that interferes, deprives, and interrupts schooling and places children in the position of trying to balance school and long work hours [34].

It is important to remember that child labor occurs in the United States. Runaway and homeless youths are at greatest risk, often lured by promises of work and housing [37]. The Polaris Project found that the top three forms of child labor trafficking in the United States were begging, peddling, and traveling sales crews [37].

CHILD CONSCRIPTION

In some cases of trafficking, children are kidnapped and trafficked to serve as soldiers. Other times, children are coerced by a narrative indicating they will be serving a higher purpose and avenge the deaths of family and friends; this is known as comradeship [38]. Some children are actively recruited and may be promised a small salary to "voluntarily" join. In a study of 132 cases of child conscription in Columbia, 18% of the children were motivated by perceived economic rewards [39]. Many children lack educational opportunities or hope for a better future, perceiving soldiering as the only option [38]. Conscripted girls often cite educational opportunities as a motive [38]. In Nepal, former female soldiers also indicated they were driven to volunteer in the armed groups by a fear that if they stayed with their families they would be married away as children or raped [38].

It is estimated that at any one time 250,000 to 300,000 children younger than 18 years of age are currently serving as child soldiers [40,41]. Traffickers prefer to recruit children to serve as soldiers because they are inexpensive and more easily molded and shaped to comply and obey without question [42]. They are also more likely to kill fearlessly and recklessly. Child soldiers are treated as adults, without any regard to how the physical and psychologic rigors of war will affect them psychologically and developmentally. In Uganda, where children are kidnapped or recruited as child soldiers relatively often, the Lord's Resistance Army has been known to initiate new child soldiers in brutal ritualized killings of others so as to terrorize them into submission and annihilate any moral conscience they may have about killing [42]. In Afghanistan, children have been recruited by the Taliban and have served as suicide bombers [28].

It can be difficult to comprehend the atrocities that these children witness and experience. Bayer, Klasen, and Adam conducted a study involving 169 former Ugandan and Congolese child soldiers who were an average of 15.3 years of age [43]. Almost all (92.9%) reported having witnessed a shooting, 89% witnessed someone wounded, and 84% witnessed someone seriously beaten. A total of 54.4% reported having killed someone, and 27.8% reported that they were forced to engage in sexual activity [43]. In another study, the researchers found that the experience of conscription among children produced significant emotional and psychologic traumas and a host of cognitive and behavioral problems [24]. In this study of 19 child soldiers, 18 had volunteered to join the army and one had been abducted. Although most of the children volunteered into the army, their participation became involuntary. Some tried to run away or disobey, which resulted in beatings and imprisonment. If captured, they were told to commit suicide [24]. The reintegration of child soldiers is not easy. Many are stigmatized when they return to their home villages, as their families and friends fear that these former child soldiers may be violent [41,44].

Listen to a National Public Radio interview with Ishmael Beah, a former child soldier, at https://www.npr.org/templates/story/story.php?storyId=7519542.

5. FACTORS THAT CONTRIBUTE TO HUMAN TRAFFICKING

GLOBALIZATION

Human trafficking has been called one of the "darkest sides of globalization" [45]. Globalization is the term used to describe the interconnectedness of countries and nations, which facilitates easy communication, exchange of ideas, and flow of goods, capital, and services [45]. Crimes such as human trafficking are affected by globalization just as legitimate businesses are [46]. Furthermore, the ideals of Western capitalism may reinforce human trafficking as a business or industry, with its emphasis on the free market and the flow of goods and services across international borders [46].

Globalization has also created the need for cheaper labor [28,47]. A study involving 160 countries examined the effects of globalization and human trafficking trends [48]. Researchers found a positive relationship between globalization and trafficking for forced labor, prostitution, and debt bondage.

POVERTY

Poverty and incessant economic stressors caused by civil wars, natural disasters, and collapses of government systems all contribute to human trafficking [18,23,49]. Families entrenched in deep poverty may feel they have no other recourse but to sell a child or may be more easily lured with promises of money and a better future [49,50,51]. In one study, the odds of being trafficked were nine times greater for those who felt extremely hopeless about upward mobility compared with those with lower levels of hopelessness [49].

SOCIAL AND FAMILIAL DISORGANIZATION

Community factors (such as high social disorganization characterized by violence, unemployment, and high crime) contribute to higher risk of trafficking [23]. In addition, families marked by instability (e.g., domestic violence, child abuse, continual unemployment) are also at higher risk of having a member trafficked [23].

CORRUPTION

Human trafficking cannot occur without the existence of corruption within existing infrastructures. Public officials, police officers, and local leaders in many developing countries have been known to take bribes to provide protection to parties involved in various aspects of human trafficking [45,48,52].

DIGITAL TECHNOLOGY

The rampant use of digital technology, such as the Internet, greatly facilitates sex trafficking. The relative anonymity of online contact can empower traffickers to recruit or sell victims. Graphic images of women and children engaged in sexual acts can be easily disseminated over the Internet [53]. Traffickers may employ the Internet for advertising, marketing to those interested in making pornography [53]. In addition, social media sites such as Facebook, Craigslist, and Instagram have been used as a means of facilitating trafficking (e.g., by connecting and grooming potential victims) [54,55,56]. Newsgroups offer opportunities for those interested in locating women and children for sexual exploitation.

In a qualitative study, smartphones were found to be integral in the business of trafficking [54]. Researchers indicated the phones were used "to maintain contact with each other, in order to facilitate the business 'transactions' and stay in touch with transnational 'partners' and other traffickers who remained in the country of origin" [54,55].

RACIALIZED SEXUAL STEREOTYPES

Race and ethnicity have been inextricably linked to sexual violence and victimization. Myths regarding sexuality in certain cultures or racial fetishization may affect trafficking patterns. For example, there is an over-representation of Asian women on American Internet pornography sites in part due to popular myths sexualizing, eroticizing, and exoticizing Asian women. This has translated into trafficking, as traffickers respond to the demand for young Asian women and girls in part fueled by these stereotypes of exotic, docile, submissive, and eager-to-please Asian women [30]. These stereotypes devalue and dehumanize people, which is the underlying core of human trafficking. This contributes to the acceptability of the exploitation of individuals, particularly members of marginalized groups [57].

These racial stereotypes go beyond simply framing the victims in a particular manner [58]. They raise implicit questions regarding how the powers of state are depicted. In other words, the patriarchal attitudes of certain countries lead to "bad" or "backward" cultural practices or ways of being that then cause trafficking—setting up is a dichotomy of the "West" and "others" [58].

CULTURE

Although many are careful in linking cultural factors to the etiology of human trafficking for fear of imposing judgment on a particular culture, many maintain that cultural ideologies that tolerate sexual trafficking, bonded labor, and child labor may be a stronger factor than poverty in predicting trafficking rates [30,36]. For example, some cultures emphasize collectivism and prioritizing the needs of the family and group first before the needs of the individual. Some children may feel they have to sacrifice themselves for their family when traffickers promise money [30]. Traffickers also know that they can threaten to hurt victims' families to keep them from escaping [30].

Furthermore, in many cultures, boys are more highly valued than girls, and as a result, girls are considered more dispensable [30]. Sons are considered the family's social security, staying with the family while daughters marry into other families. Therefore, girls may be more likely to be sold into slavery than boys.

Child labor is also inextricably tied to cultural factors. In India, for example, child labor is common because it is believed that children in the lower levels of caste system (i.e., the "untouchables") should be socialized early to understand their positions in society [36]. It has been observed that when traditional cultural and societal norms about women's roles were relaxed in some European countries and more women entered the labor force, child labor decreased [36]. Ultimately, it is difficult to unravel the effects of poverty and culture because the pressures of poverty can lead families to use tradition as a justification to sacrifice young men, women, and children [36].

Ultimately, the conversation about human trafficking is complex, and to attempt to isolate the causes is beyond challenging. Multiple factors have been suggested as possibly predicting human trafficking, including macroeconomic factors (e.g., gross domestic product per capita), unemployment rates, female inequality, cultural oppression, and lack of protection of women's rights [59,60]. In one study, ease of land access to the destination country appeared to be a powerful predictor in terms of the number of individuals trafficked [59].

6. THE TRAFFICKING EXPERIENCE

Five stages of the trafficking experience have been identified [61,62,63]:

- Pre-departure stage: The period before the victim becomes involved in the trafficking situation. This may include recruitment and preparing for travel.

- Travel and transit stage: The time after recruitment during which the victim "agrees" or is coerced into the trafficked situation. This phase also includes the journey whereby the trafficker(s) brings the victim(s) to their work destination. It is important to remember that this stage can be very dangerous and can involve numerous transit points.

- Destination stage: This is the period during which the victim arrives at the intended destination. This stage is marked by exploitation, abuse, victimization, and coercion. One way to control the victims is to continually inflate their debt so they have to constantly work to pay it off. Another is to confine and isolate victims.

- Detention, deportation, and criminal evidence stage: If a victim is arrested by the police or immigration authorities, victims are held in legal proceedings and they often fear deportation, and/or retaliation from the trafficker(s).

- Integration and re-integration stage: During this stage, government and nongovernment agencies provide services to victims that involve a long process of attempting to reintegrate the victim back into his/her community.

TRAFFICKERS: AN OVERVIEW

Much attention has been focusing on victims of trafficking; however, it is important to also understand the perpetrators.

Methods of Recruitment

It has been suggested human traffickers employ five general strategies to recruit and traffic victims [64,65,66,67]:

- Kidnapping: Traffickers may kidnap their victims. They may lure them with food or treats or take them by force. Victims with few if any social ties are highly vulnerable, as no one will miss them or report their disappearance.

- Targeting poor families: Traffickers may convince families to sell their children (often daughters). Because many families in developing countries live in abject poverty, traffickers will stress to victims' families how the money will help them to survive. Other traffickers may tell families that selling their daughter will provide her with more promising opportunities.

- Developing a false romantic relationship with victim: A tactic often used with young girls, perpetrators pose as boyfriends by romancing victims, buying gifts, and proclaiming their love. Victims have a difficult time believing that their boyfriends would hurt or deceive them, making them easy targets for trafficking.

- Fake storefronts: Some employment, modeling, or marriage agencies are fronts for illegal trafficking operations. A potential victim might be lured with the promise of employment, a lucrative modeling contract, or an arranged marriage in the United States. After victims have been lured in, traffickers come to assess their "product." Perpetrators may be family members or friends.

- Legal storefronts: Some legal businesses in the tourism, entertainment, and leisure industries integrate trafficking activities into their business structure.

- Recruiting local prostitutes: Traffickers might purchase prostitutes working in local night clubs from brothel owners or simply lure prostitutes by promising them a more affluent future. Women working as prostitutes may later recruit younger victims.

The Financial Profits

Unfortunately, human trafficking can be a lucrative business. According to the ILO, profits from forced labor, trafficking, and modern slavery are estimated to be $150 billion annually [68]. The majority of this total is attributable to commercial sexual exploitation ($99 billion) followed by construction/manufacturing/mining ($34 billion), agriculture ($9 billion), and domestic work ($8 billion) [68].

The receiving country and location of trafficking will affect the profits. For example, if a girl is kidnapped from a village in Nepal and taken to India, she can be sold in India for $1,000 [64]. If she is then trafficked to the United States, she could be sold for $20,000.

Interestingly, the "cost" of a slave has not risen over time. According to Bales, the cost of obtaining a slave to work in the agriculture sector in 2007 was about $100; in 1850, this same slave would cost the equivalent of $40,000 in 2007 currency [69]. In one study, it was approximated that in the United States, a trafficker can make an average of about $300,000 per victim lifetime, which would total $32 billion annually [70]. Income in larger cities (e.g., Atlanta, San Diego, Washington, DC) may be even greater.

7. CONSEQUENCES OF HUMAN TRAFFICKING: IMPACT ON VICTIMS

The social realities of victims of human trafficking are difficult to comprehend, and some may wonder why victims remained silent and complied with their traffickers. The Silence Compliance Model was created to explore the factors that promote victims' seeming willingness to comply to their traffickers' demands [71]. This model has three categories: coercion, collusion, and contrition. Victims are coerced, brutalized, and threatened, and basic necessities of life are withheld from them. Methods of psychologic coercion include isolation, induced exhaustion, threats, degradation, and monopolizing perception [72]. This serves to silence victims and create a sense of helplessness. By isolating and controlling victims' movements and limiting their exposure to the outside world, traffickers have complete monopoly of their attention and perception of reality [72]. Victims are then forced to collude with the traffickers as a result of their relative isolation, fear, false sense of belonging, and complete dependence on the trafficker. Finally, victims feel contrite, ashamed, stigmatized, and remorseful of the things they have been made to do [71].

PSYCHOLOGIC AND MENTAL HEALTH CONSEQUENCES

Victims of trafficking experience a host of psychologic, mental health, and emotional distress. Depression, suicidal ideation, substance use, and anxiety are typically cited mental health problems [23]. Post-traumatic stress disorder (PTSD) is also common given the trauma many victims experience, including physical and/or sexual violence and abuse; victims forced into prostitution experience continual, daily sexual assault [73]. In a study of 192 European women who were trafficked but who managed to escape, the overwhelming majority (95%) disclosed that they experienced physical and sexual violence during the time of their trafficked experience [74]. More than 90% reported sexual abuse, and 76% reported physical abuse.

Trafficked victims experience fear from the start of their capture through the transit phase and after they arrive at their destination. During the transit stage, many victims experience dangerous border crossings, risky types of transports, injury, beatings, and sexual assault [61]. Upon arrival to their destination, many trafficking victims have been socially isolated, held in confinement, and deprived of food [75]. All sense of security is stripped from them—their personal possessions, identity papers, passports, visas, and other documents [61,75]. The continual fear for their personal safety and their families' safety and the perpetual threats of deportation ultimately breed a sense of loss of control and learned helplessness. It is not surprising that depression, anxiety, and PTSD are common symptoms experienced by trafficked victims.

In a study of 164 survivors of human trafficking who returned to Nepal, the authors examined the extent to which they experienced PTSD, depression, and anxiety [76]. All of the survivors experienced some level of these disorders, but the survivors who were trafficked for sex experienced higher levels of depression and PTSD compared to those who were not trafficked for sex. In a study with Moldovan survivors of human trafficking, researchers found that six months after their return, 54% had diagnosable mental health issue. Specifically, 35.8% met the diagnostic criteria for PTSD, 12.5% met the criteria for major depression, and 5.8% were diagnosed with an anxiety disorder [77].

There is also some evidence that trafficked victims may experience complex PTSD, a type of PTSD that involves an acute change of the victims' sense of self, their relationship with others, and their relationship with God or higher being [78]. These persons direct anger inwardly (toward themselves) in addition to toward their perpetrators, which results in a loss of faith in themselves and the world [63,75,78]. Perhaps due to self-directed anger and shame, some will engage in risky sexual behaviors, self-harm, and substance abuse. Some victims also have difficulty managing and expressing how they are feeling, while others experience dissociation [75].

Substance abuse is also common among victims. In interviews, trafficked women discussed how traffickers forced them to use substances like drugs and/or alcohol so they could work longer hours, take on more clients, and/or perform sexual acts that they could not normally [61]. Other victims used substances as a means to cope with their situations. Trafficked individuals who are gender and/or sexual minorities report shame, confusion, and sexual identity issues if forced into heterosexual relationships [63].

Children forced into labor experience grueling hours and are frequently beaten by their captors. According to Clawson and Goldblatt, underage victims of domestic sex trafficking fluctuate through a range of emotions from despair, shame, guilt, hopelessness, anxiety, and fear [79]. Depending upon the level of trauma, some engage in self-destructive behaviors like self-mutilation or suicide attempts. For some, their ambivalence toward the perpetrators may be confusing. On the one hand, they want to escape the abuse, yet simultaneously, they may have a sort of traumatic bond with the perpetrators [79].

Children forced into conscription will also experience a host of psychologic symptoms. In a study comparing former Nepalese child soldiers and children who were never conscripted, former child soldiers experienced higher levels of depression, anxiety, PTSD, psychologic difficulties, and functional impairments [80]. In another study of former children soldiers from the Congo and Uganda, one-third met the criteria for PTSD [43]. The researchers found there was a relationship between greater levels of PTSD symptoms and higher levels of feelings of revenge and lower levels of openness to reconciliation [43]. In-depth narrative interviews of former child soldiers from northern Uganda found that the children spoke of the violence and atrocities they witnessed without any emotion, as if they had removed themselves from their experiences [81]. This speaks to how the victims have to numb themselves psychologically in order to cope. The researchers also found that the children who lost their mothers were more traumatized by this experience than the violence they witnessed as soldiers.

Some have argued that the diagnostic criteria of PTSD may not be easily applied to those from different cultures. As a result, it is important to assess for other psychiatric disorders, such as depression. Japan, for example, never used the PTSD diagnosis prior to 1995, despite the fact that they have a large and intricate mental health system [82]. Ultimately, PTSD cannot be universally applied to every culture and for every humanitarian crisis; therefore, if a human trafficking victim does not necessarily fall within the Diagnostic and Statistical Manual of Mental Disorders criteria for PTSD, one cannot necessarily conclude that they have not experienced trauma or are not traumatized [82].

SOCIAL CONSEQUENCES

When rescued and attempting to reintegrate into their communities, victims of human trafficking often experience stigma, ostracism, and marginalization [80,83]. For example, in Nepal, community members perceived returning child soldiers who had performed acts such as carrying dead bodies or coed sleeping as in violation of Hindu cultural norms [80]. One documentary following former child soldiers living in a refugee camp in northern Uganda found that preconceived notions and myths about children soldiers often led to ridicule and ostracism after they were liberated from the army and returned home.

However, girls who were recruited as soldiers, who were forced to have sex, or who return with children appear to be the most marginalized group [84]. In a qualitative study of former girl soldiers in Sierra Leone, researchers found that, compared to returning boy soldiers, girls were perceived to have violated gender norms and values about sexuality. Although psychologically and developmentally they were still children, the community perceived and treated them as "damaged" or "unclean" women. Their communities were not able to integrate them back in despite the victimization they experienced. These girls lacked voice and experienced shame, marginalization, poverty, and powerlessness upon their return [84]. In a study of former child soldiers in Uganda, the children reported having difficulty finding jobs or getting married when they returned home. Girls who had been raped were stigmatized and made to feel unwelcome in their communities. Others stated that their community perceived them as murderers [44].

HEALTH CONSEQUENCES

In studies of trafficked women, headaches, fatigue, dizziness, back pain, pelvic pain, stomach pain, sexually transmitted infections (STIs), unwanted pregnancies, and gynecologic infections were common, generally the result of continual physical, psychologic, and sexual abuse [23,74]. Victims of labor trafficking also experience health issues related to the type of work, workplace conditions, malnutrition, and violence [85]. It is important to remember that some of these somatic complaints, such as headaches, fatigue, and gastrointestinal problems, may be underlying symptoms of anxiety, depression, and stress [74]. Some cultural groups might not use the terms "depression," "sad," or "anxious," but may use metaphors and somatic symptoms to describe their pain, all of which are embedded within cultural ideologies. The most common culture-based idioms of distress are somatic symptoms. Some groups tend not to psychologize emotional problems; instead, they experience psychologic conflicts as bodily sensations (e.g., headaches, bodily aches, gastrointestinal problems, and dizziness).

Using an in-depth, direct interview survey designed to explore each stage of the trafficking experience, a multi-country European study identified a range of aversive health, sexual, and reproductive consequences common among women and adolescent victims of human trafficking [61]:

- Pre-departure stage: All victims reported having had limited knowledge of the health implications of having sex with strangers, and only 1 in 25 felt well-informed regarding the risks of acquiring HIV or other STIs.

- Travel and transit stage: Half of those interviewed reported having been confined, beaten, and/or raped during the journey.

- Destination stage: A large majority reported having been "intentionally hurt" (as evidenced by contusions, lacerations, loss of consciousness, and signs of head trauma); subjected to solitary confinement and deprived of human contact and adequate food and nutrition; subject to a variety of physical ailments, including headache, fever, undiagnosed pelvic pain, urinary tract infection, STIs, rash/scabies, and oral/dental health issues. All had experienced repeated sexual abuse or coercion, and 1 in 4 reported at least one unintended pregnancy (often involving negative outcomes of abortions performed in unsafe and unhealthy conditions).

Evidence Based Practice Recommendation

The British Association for Sexual Health and HIV has identified trafficked women/commercial sex workers as a group vulnerable to sexual violence. Inquiries about such vulnerabilities will help to identify those in need of additional support and help to facilitate appropriate referrals to mental health services, general practitioners, and support agencies. Access to interpreter and advocacy services may be helpful.

https://www.bashhguidelines.org/media/1079/4450.pdf

Last Accessed: August 15, 2019

Level of Evidence: Expert Opinion/Consensus Statement

In the context of forced prostitution among trafficked victims, safeguards against infection (e.g., regular condom use), early diagnosis, and adequate antimicrobial treatment are inconsistently employed or absent entirely [61]. Consequently, in addition to unwanted pregnancy, the risk for pelvic inflammatory disease and subsequent infertility is relatively high. Moreover, the relationship between forced prostitution and HIV infection is stronger when sexual violence is involved. Women who are forced into prostitution are 11 times more likely to become HIV-infected than women who entered prostitution voluntarily [86]. Sexual violence may increase the transmission risk as a result of open abrasions and injuries to the vagina. Furthermore, sexual violence can negatively impact self-esteem, which could then deter victims from advocating more strongly for condom use [86].

Among child victims of human trafficking, healthy growth and development is especially problematic. Malnourishment and poor hygiene often lead to delayed bone growth, poorly formed teeth, and early dental caries [87]. The intense nature of child labor also has severe negative physical and health consequences. Children working in unsafe conditions without protection, such as in mines or mills, can lead to respiratory problems such as asthma and bronchitis [88]. A study of adult and child laborers on tobacco farms in Kazakhstan found that the workers were unaware that exposure to tobacco and pesticides could affect their health. Protective garments were also rare, with many children not even having gloves [89].

Under normal circumstances, young children are still developing physically; however, such adverse conditions can halt their development. The lungs of adolescent boys typically experience the most rapid growth around 13 to 17 years of age; working in conditions characterized by excessive toxic dust or unclean air makes them more vulnerable to developing silicosis and fibrosis [88]. In the United States, young children participating in agricultural work are at risk of the major traumas associated with farm work, such as injuries caused by tractors or falling from heights, in addition to those injuries associated with repetitive stress and exposure to toxins. Children have thinner layers of epidermis, which make them more vulnerable to the toxicity of pesticides, and this can ultimately increase their risks for certain cancers [88]. Children working in gold mines do intensive digging, lifting, and transporting and mix mercury with the crushed ore, often with their bare hands. Mercury toxicity can lead to neurologic symptoms such as loss of vision, tremors, and memory loss [89].

8. IDENTIFICATION AND ASSESSMENT

Healthcare providers are often the most likely to encounter a victim of human trafficking under circumstances that provide an opportunity to intervene. Yet, many providers lack the training and confidence to identify and assist victims. In a survey of 110 emergency department physicians, nurses, and physician assistants, the majority (76%) reported having a knowledge of human trafficking, but only 13% felt equipped to identify a trafficking victim and only 22% were confident in their ability to provide satisfactory care for such patients [90]. Less than 3% had ever received any training on this topic. In a separate survey of healthcare and social service providers, only 37% had ever received training on identification of trafficking victims [91].

Because human trafficking and exploitation are, by nature, covert processes, the identification and rescue of the victim can be difficult. Traffickers move victims from one area to another to reduce the risk of identification, and one of the main problems with the assessment of such individuals is that practitioners may only have a one-time encounter with the victim [92].

POTENTIAL RED FLAGS

Bruises, scars, and other signs of physical abuse may be missed on examination, as victims are often beaten in areas hidden by clothing (e.g., the lower back) so as not to affect the victim's outer appearance. Physical trauma symptoms may be present, commonly on the torso, breast, and/or genital areas [70]. Burns, broken bones, pelvic pain, and/or STIs (particularly in children) may also be red flags [93]. However, more common physical injuries are also typical with other circumstances, making physical exam of limited value. The entire clinical picture should be considered.

It may also be helpful to assess for tattoos and/or other modifications (e.g., branding, piercings). Some perpetrators use tattoos to identify victims or to signify "ownership" [56].

With regard to episodic clinical encounters, recommendations for providing safe assessments in a culturally sensitive manner are lacking. The Department of Health and Human Services Administration for Children and Families maintains a useful website that addresses practical issues of human trafficking for allied professional groups, known as the Rescue and Restore Campaign [87]. Included are diagnostic and interviewing tips to help healthcare providers recognize, intervene, and refer trafficking victims. Emergency and primary care providers should be cognizant of clues that a patient may be the victim of trafficking and prepared to engage in greater depth of inquiry with special attention to the following indicators [87,93,94,95]:

- Does someone, other than family, who behaves in a controlling manner, accompany the patient? Traffickers attempt to guard and control most every aspect of the victim's life, while maintaining isolation from family, friends, and other common forms of human interaction.

- Are there inconsistencies in answers to basic questions (e.g., name, age, address)?

- Does the patient speak English? If not, has he or she recently been brought to this country, and from where? Many victims of human trafficking have recently been trafficked from other countries. As discussed, common sending countries/regions include Eastern Europe, Asia, Latin America, Africa, India, and Russia.

- If the patient is accompanied by someone other than a family member, who does the talking, and why? Attempt to interview and examine the patient separately and alone, using an interpreter if necessary. Probe in a sensitive manner for detailed information on the situation and relationship.

- Does the patient show signs of psychosocial stress (e.g., appears withdrawn, submissive, fearful, anxious, depressed)? Can the individual account for this?

- Are there visible signs of physical abuse (e.g., bruises, lacerations, scars)? How does the individual explain these?

- Does the patient lack a passport or other immigration and identification documentation (e.g., driver's license, social security number, visa)? If so, what explanation is given? To control victims' movements, traffickers often take away passports and any legal identification documents.

- What is the patient's home and work situation? Basic questions about what they eat, where they live and sleep, who else lives with them, and what work they do can be revealing. For example, "Can you leave your work or job situation if you wish?" or "When you are not working, can you come and go as you please?"

- Is the explanation given for the clinical visit consistent with the patient's presentation and clinical findings?

- Does the victim appear fearful when asked questions about citizenship, country of origin, immigration status, or residence? This may indicate a fear of deportation.

- If the victim is a minor, is s/he in school? Living with parents or relatives? If not, what reasons are given for these circumstances?

SCREENING QUESTIONS

Examples of questions to screen for human trafficking include [96,97,98]:

- Can you tell me about your living situation?

- Has anyone ever threatened you with violence if you attempted to leave?

- Does anyone force/require you to have sexual intercourse for your work?

- Has anyone ever threatened your family if you attempted to leave?

- Does anyone make you feel scared at work?

- Are you free to come and go as you wish?

- Does your home have bars on windows, blocked windows/doors, or security cameras?

- How many hours do you work?

- Have you ever worked without receiving payment you thought you would get?

- Do you owe your employer money?

- Do you have to ask permission to eat, sleep, use the bathroom, or go to the doctor?

The Polaris Project has developed a flow chart for the assessment of potential trafficking victims, available at https://www.traffickingresourcecenter.org/sites/default/files/Assessment%20Tool%20-%20Medical%20Professionals.pdf. If a person is thought to be a victim, one should follow workplace protocols and/or contact the National Human Trafficking Resource Center at (888) 373-7888 for next steps.

INTERVIEWING TRAFFICKED VICTIMS: BEST PRACTICE GUIDELINES

Service providers should repeatedly weigh the risks and benefits of various actions when interviewing human trafficking victims [65,99,100]. The following interviewing recommendations were published by the World Health Organization to encourage service providers to continually and ethically promote human trafficking victims' safety during every phase of the interviewing process [93,101]:

- Each victim and trafficking situation should be treated as unique; there are no standard templates of experiences. Listen carefully to the victim's story. Each story told is unique, and each patient will voice distinctive concerns. Believe each story, no matter how incredible it may seem. As rapport and trust build (perhaps very slowly), accounts may become more extensive.

- Always be safe and assume the victim is at risk of physical, psychologic, social, and legal harm.

- Evaluate the risks and benefits of interviewing before starting the interviewing process. The interviewing process should not invoke more distress. In other words, the interviewing process should not end up re-traumatizing the victim.

- Provide referrals for services where necessary; however, it is necessary to be realistic and not make promises that cannot be kept. Trust is vital because it has been severed on so many levels for trafficking victims.

- Victims' readiness to change will not be based on what societal defines as "ready" or social expectations. Some victims will eagerly grasp new opportunities, while others may be fearful of potential traffickers' threat and be less receptive to help.

- Determine the need for interpreters and if other service providers should be present during the interviewing phase. Ensure that everyone involved is adequately prepared in their knowledge about human trafficking, how perpetrators control their victims, and how to ask questions in a culturally sensitive manner. Keep in mind that often times, traffickers will offer to help with the interpreting. Using interpreters from the same community of the victim should be avoided to prevent breaches in confidentiality.

- All involved should be prepared for an emergency plan. For example, is there a set plan for a victim who indicates he/she is suicidal or in danger of being hurt?

- Always be sure to obtain informed consent. Remember the informed consent process is going to be unfamiliar to many victims. In addition, self-determination and autonomy have been compromised by continual threats and being forced to commit dehumanizing acts. Avoid using legal and technical jargon.

It is important to use a trauma-informed approach when assessing and caring for potential victims, which requires that practitioners understand the impact of trauma on all areas of an individual's life [102]. Physical, emotional, and psychologic safety is at the heart of trauma-informed care. Providers should assume that human trafficking victims are describing their reality to the best of their ability, given the trauma they have experienced. Responses and behaviors (e.g., being guarded, defensive, belligerent) may be coping mechanisms [102].

9. REPORTING

If screening and assessment findings indicate that an individual may be a victim of human trafficking, one should contact the National Human Trafficking Hotline at 1-888-373-7888. A text telephone (TTY) option for people who are deaf, hard of hearing, or speech impaired can be accessed by dialing 711. Reporting by text is available by texting the National Human Trafficking Hotline at 233733. Online chat is also accessible at https://humantraffickinghotline.org.

The National Human Trafficking Hotline collects information about the location of the trafficking case and the name of the suspected trafficker. The hotline will also request non-personally identifying information, such as the city and state of the reporter and how he or she learned of the hotline; reporting can be done anonymously. Reporters and/or victims are only asked to provide information they feel comfortable sharing, and the hotline does not share information with external agencies unless permission is given or when required by law. Hotline calls are managed by anti-trafficking hotline advocates, who are specifically trained. After receiving a report of suspected human trafficking, the National Human Trafficking Hotline will assess each case individually to determine if a case should be reported to a local, state, or federal investigative and/or service agency equipped to investigate the tip and/or respond to the needs of the potential victim.

Under the child abuse laws, practitioners who are mandated reporters and who are suspicious that a minor is being abused should immediately report the abuse. Persons in Florida who know, or have reasonable cause to suspect, that a child is abused, neglected, or abandoned must immediately report such knowledge or suspicion to the Florida Abuse Hotline of the Department of Children and Families at 1-800-96-ABUSE.

10. INTERVENTIONS AND RESOURCES

EDUCATION AND PREVENTION

Education is believed to be a key ingredient in the prevention of human trafficking. Raising awareness through advertisements, campaigns, and other creative vehicles regarding recruitment threats, the various deception techniques employed, the different forms of human trafficking, and the consequences of human trafficking can decrease the incidence [64,103]. Because the general public often believes human trafficking is a problem that only occurs in developing countries, there is a clear need for public education about trafficking and safety for young children and women in and outside the United States [22]. The Campaign to Rescue and Restore Victims of Human Trafficking provides brochures and posters about human trafficking, which are available to be ordered (at no cost) from https://www.acf.hhs.gov/archive/otip/resource/about-rescue-restore [87]. Posting these brochures or posters increases the possibility that a trafficked victim will self-report [100].

Education about human trafficking has become a higher international priority. Innovative and creative approaches are being implemented to disseminate information about human trafficking, particularly how perpetrators recruit high-risk groups (e.g., youths with disabilities, runaways) [67]. For example, groups have used street plays to educate communities about child labor dangers in India [104].

India: Fighting Child Labour with Street Plays was produced by the International Labour Organization to explore the use of street plays to educate communities about child labor in India.

To see this media go to http://www.NetCE.com/activities/ using a browser that supports Adobe Flash.

For more information, visit the International Labour Organization at http://www.ilo.org.

Although the topic of human trafficking has become more common in public discourse, service providers and law enforcement authorities remain under-educated about human trafficking. They are not sure what to look for, what to ask, and what to do if they do identify individuals who are victims of human trafficking [103]. Law enforcement officials require training to identify and assess potential victims at various borders and ports of entry. If a minor is accompanied by an adult who is not the child's parent or legal guardian, this should raise a red flag [103]. Furthermore, to work effectively to identify human trafficking victims, there is a need for service providers to navigate and collaborate with a complex host of government, social service, mental health, and nongovernment legal entities [103].

MENTAL HEALTH AND SOCIAL SERVICES

Care and services provided to victims can be organized into three distinct categories: immediate and concrete services at the time of rescue; services related to recovery; and long-term services pertaining to reintegration [105]. When trafficking victims are rescued, a great deal of counseling services and practical, day-to-day assistance will be required. Housing, transportation, food, clothing, medical care, dental care, financial assistance, educational training, reunification (for those who wish to return to their homeland), and legal aid are some of the concrete services needed [71]. Practitioners should connect, coordinate, and case manage these services as much as possible. During this stage, it is also important to understand victims' needs, their strengths, and their risks and vulnerabilities [75].

Safety planning is also crucial in the immediate rescue stage. Traffickers may be continuing to try to locate some victims; placing victims in safe houses may be necessary [63]. The National Human Trafficking Hotline encourages that safety planning be based on the unique needs and circumstances of the individual.

During the recovery and reintegration stages, as discussed, human trafficking victims experience an array of mental health and psychologic issues. Mental health counseling is vital, but it is important to remember that the concept of counseling or talk therapy may be foreign to victims from non-Western cultures [65]. The expression of emotions may be in opposition to cultural values of emotional restraint, which can be intensified by feelings of shame and guilt resulting from experiences with sexual and physical assault. Beyond the paramount importance of the practitioner gaining the patient's trust, practitioners may educate patients about the counseling process and explore their patients' expectations about counseling, healing, and recovery [106]. As noted, victims' symptoms may not only be a manifestation of the trauma but also coping mechanisms to cope with self-blame, shame, and trauma [56].

Given differing cultural beliefs about healing, it is crucial that practitioners be open to alternative treatment and explore with patients the use of traditional healing methods [65]. There are many indigenous healing interventions victims may be using, including cultural rituals, faith healing, therapeutic touch, herbal remedies, and spiritual practices [107]. These interventions are multi-layered, taking into account the physical, psychologic, communal, and spiritual [107]. These healing methods are historically rooted in specific cultures, and therefore, practitioners should become familiar with traditional healing methods and how they can be integrated with Western counseling techniques [106]. For example, given many cultural groups' beliefs that unmarried girls are defiled if raped, a cultural cleansing ritual may be needed as a first step to help a community accept a returning victim who was sexually assaulted during her trafficking experience [30]. After this ritual is performed, it is possible that both the patient and her family may be more open to counseling and other services.

Other trauma interventions that might be beneficial include cognitive-behavioral therapies, eye movement and desensitization reprocessing therapies, mindfulness techniques, and expressive therapies [56,63].

Physicians, social workers, nurses, therapists, and counselors must be familiar with legal, case management, educational, job and life skills training, and housing services in the community. Human trafficking victims are not only unfamiliar with navigating the social service system, but many are also not proficient in English. Therefore, practitioners will serve as coordinators and advocates, linking necessary services. In one study, the majority of agencies had to rely on collaboration in order to refer clients [108]. Social workers and practitioners relied on word-of-mouth and community meetings to learn about services in order to better meet the needs of human trafficking victims. Furthermore, because many community organizations and agencies are not familiar with human trafficking, practitioners must take a primary role in educating colleagues about the complex dynamics of human trafficking.

It is important to remember that the evidence supporting interventions and therapies for victims of human trafficking is in its infancy [105]. Most efficacy studies of therapies and interventions do not involve experimental designs, which makes it difficult to draw definitive conclusions regarding efficacy. Future work is needed to develop and evaluate interventions that address the multilayered and complex needs of human trafficking survivors.

This informational video on human trafficking and how to identify and assist victims is part of the Rescue & Restore Victims of Human Trafficking public awareness campaign, an initiative of the U.S. Department of Health and Human Services.

To see this media go to http://www.NetCE.com/activities/ using a browser that supports Adobe Flash.

For more information, visit the Office on Trafficking in Persons website at https://www.acf.hhs.gov/otip/partnerships/look-beneath-the-surface.

ADVOCACY

Physicians, social workers, nurses, allied health professionals, counselors, and psychologists will find themselves in multiple roles when working with victims of human trafficking. Advocacy is one of these roles and involves the practitioner being an agent for change. This consists of engaging in activities that alter the social conditions at the individual, family, community, and institutional levels [109]. One way to advocate on behalf of human trafficking victims is by signing petitions or joining credible organizations concerned with changing the circumstances that lead to human trafficking. Many organizations have petitions established on their websites for individuals to persuade policymakers, legislators, and government officials to advocate for the protection of human trafficking victims, create greater awareness of the problem, and prosecute traffickers, including:

- https://www.freetheslaves.net

- https://polarisproject.org

- https://www.stopthetraffik.org

LAWS AND POLICIES

Justice for Victims of Trafficking Act

In 2015, the Justice for Victims of Trafficking Act (JVTA) became law, allowing survivors formal input in federal anti-trafficking policy and providing incentives for states to enact laws to prevent the prosecution of child victims for crimes committed as a direct result of being subjected to trafficking. The JVTA provides additional bases of criminal liability for those who patronize or solicit trafficking victims for commercial sex and creates a new offense prohibiting the advertising of sex trafficking activity. It also clarifies that traffickers in child sex trafficking cases who had a reasonable opportunity to observe the victim can no longer claim ignorance about a victim's age as a defense [24]. Some provisions of this law are scheduled to expire in 2019 and 2020 [110].

Victims of Trafficking and Violence Protection Act

A wide range of laws have been established to protect human trafficking victims and to prosecute perpetrators. A general knowledge of these laws is helpful when caring for victims and seeking appropriate social services. The TVPA was enacted in 2000 and reauthorized in 2003, 2005, 2008, 2013, and 2018 by the Trafficking Victims Protection Reauthorization Acts [24]. It emphasizes the three Ps: prevention, protection, and prosecution [111]. The prevention component consists of training and awareness; the protection dimension gives trafficked victims the ability to receive services using federal funds like other refugees; and the prosecution component focuses on laws and policies for the prosecution of traffickers.

Because victims of trafficking are often viewed as criminals, this law states that victims of severe trafficking should not be penalized for any illegal behaviors or acts they engaged in as a result of being trafficked, including entering the United States with false documents or no documentation or working without appropriate paperwork [64]. This law also allows T Nonimmigrant Status (T visas) to be granted to victims of trafficking so they may remain in the United States with the purpose of collaborating with the federal authorities to prosecute the perpetrators. During this time, victims are offered a range of benefits and services, including access to the Witness Protection Program [64]. After three years, victims can apply for permanent resident status [16].

One of the criticisms of the Act is that it places the burden of demonstrating innocence and coercion on the victim [112]. The Act also fails to recognize the complex dynamics of human trafficking. For example, it focuses more on sex trafficking versus other forms [113]. Many victims have been abused and terrorized by the perpetrators, who they must now provide information and evidence against to stay in the country. Victims are continually fearful that they will be deported [112].

Victims who are of minor age are eligible for Unaccompanied Refugee Minors programs, the Children's Health Insurance program, and Temporary Assistance to Needy Families [103]. Furthermore, victims between 16 and 24 years of age are eligible for work permits and can apply for the Job Corps program [103]. However, it is important to remember that the key to this law is that the victim must have experienced a "severe form" of trafficking and the victim must be willing to assist in the apprehension and prosecution of the perpetrator to receive services [114].

Preventing Sex Trafficking and Strengthening Families Act

The Preventing Sex Trafficking and Strengthening Families Act was signed into law in 2014. In accordance with this law, child welfare agencies are required to monitor and report the number of child sex trafficking victims. Cases of suspected or known child sex trafficking must also be reported to law enforcement [37].

Trafficking Victims Protection Reauthorization Act

The Trafficking Victims Protection Reauthorization Act was introduced and signed into law in 2013. It allocated $5 million in 2009, $7 million in 2010, $7 million in 2011, and $8 million annually through 2017 to provide services to victims and to prevent human trafficking [22,115,116]. It amends the TVPA and assists foreign governments to implement programs to prevent human trafficking. Victims of human trafficking in other countries are also eligible for assistance through organizations that have grants from the U.S. government [115]. Greater monitoring of trafficking trends through databases will also be implemented. The Act also declares that it is not a defense that a defendant is not criminally liable or is subject to reduced criminal liability due to acceptance of the illicit conduct in the foreign jurisdiction.

The Prosecutorial Remedies and Other Tools to End the Exploitation of Children Today Act

The Prosecutorial Remedies and Other Tools to End the Exploitation of Children Today Act was enacted in 2003. This law maintains that all sexual activity with minors, within or outside the United States, is illegal. American citizens who engage in sex with minors in any country and who are caught will be prosecuted in the United States [64].

As of 2017, all 50 states have enacted criminal anti-trafficking laws. In addition, every state has a law on labor trafficking, and all have passed criminal statutes for sex trafficking [117].

SOAR to Health and Wellness Act

The SOAR (Stop, Observe, Ask, and Respond) to Health and Wellness Act was signed into law in 2018. It directs the Department of Health and Human Services to develop a program to train healthcare providers and practitioners to identify possible human trafficking victims, to work with law enforcement agencies, and to refer victims to services [7].

Florida House Bill 369

In 2015, The Florida Legislature passed House Bill 369, which mandates the display of a human trafficking public awareness sign in a wide range of locations, including [118]:

- Every public rest area, turnpike service plaza, weigh station, primary airport, passenger rail station, and welcome center in the state

- Emergency rooms at general acute care hospitals

- Strip clubs or other adult entertainment establishments

- A business or establishment that offers massage or bodywork services for compensation that is not owned by a healthcare professional

The sign must contain text, in both English and Spanish, regarding the steps to take if you or someone you know is the victim of trafficking, exploitation, and/or forced labor.

RESOURCES

For more information and to become involved in advocacy movements, please utilize the following resources. In some cases, the tools provided may be valuable for patient and/or peer training. In particular, the National Human Trafficking Hotline provides free, downloadable awareness materials for victims, first responders, and healthcare and mental health professionals, including a flyer available in 20 languages.

Alliance for Children in Trafficking

https://www.napnappartners.org/provider-public-resources

Coalition to Abolish Slavery & Trafficking

https://castla.org

Coalition Against Trafficking in Women

http://www.catwinternational.org

Futures Without Violence

https://www.futureswithoutviolence.org

HEAL Trafficking

https://healtrafficking.org

Human Rights Watch

https://www.hrw.org

International Justice Mission

https://www.ijm.org

International Labour Organization

https://www.ilo.org

Office of Refugee Resettlement

https://www.acf.hhs.gov/orr

National Human Trafficking Hotline

https://humantraffickinghotline.org

Polaris Project

https://polarisproject.org

Salvation Army

https://www.salvationarmyusa.org

Sex Workers Project

http://sexworkersproject.org

United Nations Office on Drugs and Crime

Human Trafficking Knowledge Portal

https://sherloc.unodc.org/cld/en/v3/htms/index.html

U.S. Department of Health and Human Services

Administration for Children and Families

https://www.acf.hhs.gov

U.S. Department of Health and Human Services

Administration for Children and Families

SOAR to Health and Wellness Training

https://www.acf.hhs.gov/otip/training/soar-to-health-and-wellness-training

Services Available to Victims of Human Trafficking: A Resource Guide for Social Service Providers

https://www.acf.hhs.gov/otip/resource/services-available-to-victims-of-human-trafficking

U.S. Department of Justice

Bureau of Justice Assistance

https://www.bja.gov

U.S. Department of Justice

Office for Victims of Crime

https://ojp.gov/ovc

U.S. Department of Labor

Bureau of International Labor Affairs

https://www.dol.gov/agencies/ilab

U.S. Department of State, Office to Monitor and Combat Trafficking in Persons

https://www.state.gov/bureaus-offices/under-secretary-for-civilian-security-democracy-and-human-rights/office-to-monitor-and-combat-trafficking-in-persons

11. CONCLUSION

Human trafficking is a severe human rights violation. Because the roots of human trafficking are multifaceted, no one solution exists to eliminate this problem. Unfortunately, as the problem grows, practitioners will be confronted with the issue in their patient populations. Practitioners should be committed to the collaboration amongst disciplines to address poverty, racism, discrimination, and oppression in order to reduce the vulnerable positions of human trafficking victims and their families. Because of the social justice component in the codes of ethics of professionals such as physicians, nurses, social workers, psychologists, and counselors, all practitioners can play a key role in the individual, community, and systemic levels to help address this gross abuse of power. One way to begin is to educate oneself and one's respective disciplines about the global nature of human trafficking and the complex dynamics of the problem.

The following video is an excerpt of California Senator Kamala Harris’s keynote address at Examining the Roots of Human Trafficking and Exploitation, the 2014–2015 UCLA School of Law Symposium.

To see this media go to http://www.NetCE.com/activities/ using a browser that supports Adobe Flash.

This recording from the January 2015 University of California Los Angeles Law Review Symposium is provided with permission from the University of California, Los Angeles, School of Law.

Works Cited

1. Best J. Promoting bad statistics. Society. 2001;38(3):10-15.

2. Gulati G. News frames and story triggers in the media's coverage of human trafficking. Human Rights Review. 2011;12(3):363-379.

3. Burr V. Social Constructionism. 3rd ed. London: Routledge; 2015.

4. de Moura SL. Social construction of street children: configuration and implications. Br J Soc Work. 2002;32(3):353-367.

5. Limoncelli SA. The global development of contemporary anti-human trafficking advocacy. Int Sociol. 2017;32(6):814-834.

6. International Labour Organization. What is Forced Labour, Modern Slavery, and Human Trafficking? Available at https://www.ilo.org/global/topics/forced-labour/definition/lang-en/index.htm. Last accessed August 13, 2019.

7. Mason S. Human trafficking: a primer for LNCs. Journal of Legal Nurse Consulting. 2018;29(4):28-33.

8. Weitzer R. The Social Construction of Sex Trafficking: A New Moral Crusade. Paper presented at the Annual Meeting of the American Sociological Association; Montreal, Canada; August 10, 2006.

9. Weitzer R. The social construction of sex trafficking: ideology and institutionalization of a moral crusade. Polit Soc. 2007;35(3):447-475.

10. Saiz-Echezarreta V, Alvarado M-C, Gómez-Lorenzini P. Advocacy of trafficking campaigns: a controversy story. Comunicar. 2018;26(55):29-38.

11. International Labour Organization. Global Estimates of Modern Slavery: Forced Labour and Forced Marriage. Available at http://www.ilo.org/global/publications/books/WCMS_575479/lang–en/index.htm. Last accessed August 13, 2019.

12. National Human Trafficking Hotline. Florida Statistics. Available at https://humantraffickinghotline.org/state/florida. Last accessed August 14, 2019.

13. United Nations. Protocol To Prevent, Suppress And Punish Trafficking In Persons, Especially Women And Children, Supplementing The United Nations Convention Against Transnational Organized Crime. Available at https://www.ohchr.org/EN/ProfessionalInterest/Pages/ProtocolTraffickingInPersons.aspx. Last accessed August 13, 2019.

14. Parreñas RS, Hwang MC, Lee HR. What is human trafficking? A review essay. Signs: Journal of Women in Culture & Society. 2012;37(4):1015-1029.

15. United Nations Office on Drugs and Crime. Human Trafficking. Available at http://www.unodc.org/unodc/en/human-trafficking/what-is-human-trafficking.html. Last accessed August 13, 2019.

16. Lusk M, Lucas F. The challenge of human trafficking and contemporary slavery. Journal of Comparative Social Welfare. 2009;25(1):49-57.

17. U.S. Congress. Victims of Trafficking and Violence Protection Act of 2000. Public Law 106-386. Available at https://www.govinfo.gov/content/pkg/PLAW-106publ386/pdf/PLAW-106publ386.pdf. Last accessed August 13, 2019.

18. Hart A. Power, Gender and Human Trafficking. Paper presented at the Annual Meeting of the American Sociological Association; New York, NY; August 11, 2007.

19. Hume DL, Sidun NM. Human trafficking of women and girls: characteristics, commonalities, and complexities. Women Ther. 2017;40(1-2):7-11.

20. Bertone AM. Sexual trafficking in women: international political economy and the politics of sex. Gender Issues. 2000;18(1):2-22.

21. Reap VJ. Sex trafficking: a concept analysis for health care providers. Adv Emerg Nurs J. 2019;41(2):183-188.

22. Kotrla K. Domestic minor sex trafficking in the United States. Soc Work. 2010;55(2):181-187.

23. Greenbaum J. Child sex trafficking and commercial sexual exploitation. Adv Pediatr. 2018;65(1):55-70.

24. U.S. Department of State. Trafficking in Persons Report: 2018. Available at https://www.state.gov/reports/2018-trafficking-in-persons-report. Last accessed August 13, 2019.

25. Batsyukova S. Prostitution and human trafficking for sexual exploitation. Gender Issues. 2007;24:46-50.

26. United Nations. Supplementary Convention on the Abolition of Slavery, the Slave Trade and Institutions and Practices Similar to Slavery, 1956. Available at https://www.ohchr.org/EN/ProfessionalInterest/Pages/SupplementaryConventionAbolitionOfSlavery.aspx. Last accessed August 13, 2019.

27. U.S. Department of Labor. International Child Labor and Forced Labor Reports. Available at https://www.dol.gov/agencies/ilab/resources/reports/child-labor. Last accessed August 13, 2019.

28. Patterson O, Zhuo X. Modern trafficking, slavery, and other forms of servitude. Annu Rev Sociol. 2018;44:407-439.

29. Free the Slaves and Human Rights Center of the University of California, Berkeley. Hidden slaves forced labor in the United States. Berkeley Journal of International Law. 2005;23(1):47-109.

30. Chung R. Cultural perspectives on child trafficking, human rights and social justice: a model for psychologists. Couns Psychol Q. 2009;22(1):85-96.

31. Otis J, Pasztor EM, McFadden EJ. Child labor: a forgotten focus on child welfare. Child Welfare. 2001;80(5):611-622.

32. International Labour Organization. Global Estimates of Child Labour: Results and Trends, 2012–2016. Available at http://www.ilo.org/wcmsp5/groups/public/---dgreports/---dcomm/documents/publication/wcms_575499.pdf. Last accessed August 13, 2019.

33. Bhukuth A. Defining child labour: a controversial debate. Dev Pract. 2008;18(3):385-394.

34. International Labour Organization. What is Child Labour? Available at http://www.ilo.org/ipec/facts/lang--en/index.htm. Last accessed August 13, 2019.

35. Bourdillon M. Children and work: a review of current literature and debates. Dev Change. 2006;37(6):1201-1226.

36. Murshed M. Unraveling child labor and labor legislation. Journal of International Affairs. 2001;55(1):169-189.

37. Walts KK. Child labor trafficking in the United States: a hidden crime. Social Inclusion. 2017;5(2):59-68.

38. Kohrt BA, Yang M, Rai S, Bhardwaj A, Tol WA, Jordans MJD. Recruitment of child soldiers in Nepal: mental health status and risk factors for voluntary participation of youth in armed groups. Peace Confl. 2016;22(3):208-216.

39. Hurtado M, Iranzo Dosdad Á, Gómez Hernández S. The relationship between human trafficking and child recruitment in the Colombian armed conflict. Third World Q. 2018;39(5):941-958.

40. UNICEF. Press Release: UNICEF Urges Demobilization and Reintegration of Child Soldiers. Available at https://www.unicef.org/newsline/02pr58soldiers.htm. Last accessed August 13, 2019.

41. Johannessen S, Holgersen H. Former child soldiers' problems and needs: Congolese experiences. Qual Health Res. 2014;24(1):55-66.

42. Breen C. When is a child not a child? Child soldiers in international law. Human Rights Rev. 2007;8(2):71-103.

43. Bayer CP, Klasen F, Adam H. Association of trauma and PTSD symptoms with openness to reconciliation and feelings of revenge among former Ugandan and Congolese child soldiers. JAMA. 2007;298(5):555-559.

44. Van Leeuwen JM, Miller L, Zamir M, et al. Community reintegrating former child soldiers in Northern Uganda: a qualitative study on the road to recovery. J Psychol Afr. 2018;28(2):105-109.

45. Jones L, Engstrom DW, Hilliard T, Diaz M. Globalization and human trafficking. J Sociol Soc Welfare. 2007;34(2):107-122.

46. Aguilar-Millan S, Foltz JE, Jackson J, Oberg A. The globalization of crime. Futurist. 2008;42(6):41-50.

47. Huang L. The trafficking of women and girls in Taiwan: characteristics of victims, perpetrators, and forms of exploitation.BMC Womens Health. 2017;17(1):104.

48. Majeed MT, Malik A. Selling souls: an empirical analysis of human trafficking and globalization. Pakistan Journal of Commerce and Social Sciences. 2018;11(1):452-487.

49. Gezie LD, Yalew AW, Gete YK. Human trafficking among Ethiopian returnees: its magnitude and risk factors. BMC Public Health. 2019;19(1):104.

50. Rao S, Presenti C. Understanding human trafficking origin: a cross-country empirical analysis. Fem Econ. 2012;18(2):231-263.

51. Bettio F, Nandi TK. Evidence on women trafficked for sexual exploitation: a rights-based analysis. European Journal of Law and Economics. 2010;29(1):15-42.

52. Contreras PM. Human trafficking of women and girls in the United States: toward an evolving psychosocial-historical definition. In: Travis CB, White JW, Rutherford A, Williams WS, Cook SL, Wyche KF (eds). APA Handbook of the Psychology of Women: Perspectives on Women's Private and Public Lives. Vol. 2. Washington, DC: American Psychological Association; 2018: 175-193.

53. Hughes DM. The use of new communications and information technologies for sexual exploitation of women and children. Hastings Womens Law J. 2002;13:129-148.

54. Elliott J, McCartan K. The reality of trafficked people's access to technology. J Crim Law. 2013;77(3):255-273.

55. Barney D. Trafficking technology: a look at different approaches to ending technology-facilitated human trafficking. Pepperdine Law Rev. 2018;45(4):747-784.

56. Litam SDA. Human sex trafficking in America: what counselors need to know. Professional Counselor. 2017;7(1):45-61.

57. Bryant-Davis T, Tummala-Narra P. Cultural oppression and human trafficking: exploring the role of racism and ethnic bias.Women Ther. 2017;40(1-2):152-169.

58. Hua J, Nigorizawa H. U.S. sex trafficking, women's human rights and the politics of representation. International Feminist Journal of Politics. 2010;12(3/4):401-423.

59. Jac-Kucharski A. The determinants of human trafficking: a U.S. case study. Int Migr. 2012;50(6):150-165.

60. Bonaventure NN. Perception of demographic and cultural factors associated with the crime of human trafficking in Nigeria.Etude Popul Afr. 2018;32(2):4239-4251.

61. Zimmerman C, Yun K, Shvab I, et al. The Health Risks and Consequences of Trafficking in Women and Adolescents: Findings from a European Study. London: London School of Hygiene and Tropical Medicine; 2003.

62. Jones L, Engstrom D, Hilliard P, Sungakawan D. Human trafficking between Thailand and Japan: lessons in recruitment, transit and control. Int J Soc Welf. 2011;20(2):203-211.

63. Pascual-Leone A, Kim J, Morrison O-P. Working with victims of human trafficking. J Contemp Psychother. 2017;47(1):51-59.

64. Hodge D. Sexual trafficking in the United States: a domestic problem with transnational dimensions. Soc Work. 2008;53(2):143-152.

65. Hodge DR. Assisting victims of human trafficking: strategies to facilitate identification, exit from trafficking, and the restoration of wellness. Soc Work. 2014;59(2):111-118.

66. Reed SM, Kennedy MA, Decker MR, Cimino AN. Friends, family, and boyfriends: an analysis of relationship pathways into commercial sexual exploitation. Child Abuse Negl. 2019;90:1-12.

67. Reid JA. Entrapment and enmeshment schemes used by sex traffickers. Sex Abuse. 2016;28(6):491-511.

68. International Labour Organization. Profits and Poverty: The Economics of Forced Labor. Geneva: International Labour Organization; 2014.

69. Bales K. Ending Slavery: How We Free Today's Slaves. Berkeley, CA: University of California Press; 2007.

70. Peck J. Guidance on spotting possible victims of human trafficking. Briefings on Hospital Safety. 2018;26(9):10-17.

71. Johnson BC. Aftercare for survivors of human trafficking. Soc Work Christianity. 2012;39(4):370-389.

72. Baldwin SB, Fehrenbacher AE, Eisenman DP. Psychological coercion in human trafficking. Qual Health Res. 2015;25(9):1171-1181.

73. Sigmon JN. Combatting modern-day slavery: issues in identifying and assisting victims of human trafficking worldwide. Vict Offender. 2008;3(2/3):245-257.

74. Zimmerman C, Hossain M, Yun K, et al. The health of trafficked women: a survey of women entering posttrafficking services in Europe. Am J Public Health. 2008;98(1):55-59.

75. Oram S, Domoney J. Responding to the mental health needs of trafficked women. Healthcare Counselling and Psychotherapy Journal. 2018;18(2):10-15.

76. Tsutsumi A, Izutsu T, Poudyal AK, Kato S, Marui E. Mental health of female survivors of human trafficking in Nepal. Social Science & Medicine. 2008;66:1841-1847.

77. Abas M, Ostrovschi NV, Prince M, et al. Risk factors mental disorders in women survivors of human trafficking: a historical cohort study. BMC Psychiatry. 2013;13(1):1-11.

78. Blumhofer R, Shah N, Grodin M, Crosby S. Clinical issues in caring for former chattel slaves. J Immigr Minor Health. 2011;13(2):323-332.

79. Clawson HJ, Goldblatt GL. Finding a Path to Recovery: Residential Facilities for Minor Victims of Domestic Sex Trafficking. Available at https://aspe.hhs.gov/report/finding-path-recovery-residential-facilities-minor-victims-domestic-sex-trafficking. Last accessed August 13, 2019.

80. Kohrt BA, Jordans MJD, Tol WA, et al. Comparison of mental health between former child soldiers and children never conscripted by armed groups in Nepal. JAMA. 2008;300(6):691-702.

81. O'Callaghan P, Storey L, Rafferty H. Narrative analysis of former child soldiers' traumatic experiences. Educational & Child Psychology. 2012;29(2):87-97.

82. Breslau J. Cultures of trauma: anthropological views of posttraumatic stress disorder in international health. Cult Med Psychiatry. 2004;28(2):113-126.

83. Reda AH. An investigation into the experiences of female victims of trafficking in Ethiopia. African and Black Diaspora. 2018;11(1):87-102.

84. Burman M, McKay S. Marginalization of girl mothers during reintegration from armed groups in Sierra Leone. Int Nurs Rev. 2007;54(4):316-323.

85. Pocock NS, Tadee R, Tharawan K, et al. "Because if we talk about health issues first, it is easier to talk about human trafficking:" findings from a mixed methods study on health needs and service provision among migrant and trafficked fishermen in the Mekong. Global Health. 2018;14(1):45.

86. Wirth KE, Tchetgen EJ, Silverman JG, Murray MB. How does sex trafficking increase the risk of HIV infection? An observational study from Southern India. Am J Epidemiol. 2013;177(3):232-241.

87. U.S. Administration for Children and Families. Look Beneath the Surface. Available at https://www.acf.hhs.gov/otip/partnerships/look-beneath-the-surface. Last accessed August 13, 2019.

88. Narayan N. Stolen childhoods: tackling the health burdens of child labor. Harvard Int Rev. 1997;19(4):50-55.

89. Amon JJ, Buchanan J, Cohen J, Kippenberg J. Child labor and environmental health: government obligations and human rights. Int J Pediatr. 2012;2012:1-8.

90. Chisolm-Strike M, Richardson I. Assessment of emergency department provider knowledge about human trafficking victims in the ED. Acad Emerg Med. 2007;14(suppl 1):134.

91. Beck ME, Lincer MM, Melzer-Lange M, Simpson P, Nugent M, Rabbitt A. Medical providers' understanding of sex trafficking and their experience with at-risk patients. Pediatrics. 2015;135(4):e895-e902.

92. Macy RJ, Graham LM. Identifying domestic and international sex-trafficking victims during human service provision. Trauma Violence Abuse. 2012;13(2):59-76.

93. Hemmings S, Jakobowitz S, Abas M, et al. Responding to the health needs of survivors of human trafficking: a systematic review. BMC Health Serv Res. 2016;16:320.

94. Moynihan BA. The high cost of human trafficking. J Forensic Nurs. 2006;2(2):100-101.

95. Baldwin SB, Eisenman DP, Sayles JN, et al. Identification of human trafficking victims in health care settings. Health Hum Rights. 2011;13(1):1-14.

96. Byrne M, Parsh B, Ghilain C. Victims of human trafficking: hiding in plain sight. Nursing. 2017;47(3):48-52.

97. Hachey LM, Phillippi JC. Identification and management of human trafficking victims in the emergency department. Adv Emerg Nurs J. 2017;39:31-51.

98. Mumma BE, Scofield ME, Mendoza LP, Toofan Y, Youngyunpipatkul J, Hernandez B. Screening for victims of sex trafficking in the emergency department: a pilot program. West J Emerg Med. 2017;18(4):616-620.

99. DeBoise C. Human trafficking and sex work: foundation social-work principles. Meridians. 2014;12(1):227-233.

100. Eastern Missouri, Southern Illinois Rescue and Restore Consortium. Developing policies and protocols to address human trafficking in health care settings. Migrant Health Newsline. 2012;29(4):6.

101. Zimmerman C, Watts C. WHO Ethical and Safety Recommendations for Interviewing Trafficked Women. Available at https://www.who.int/mip/2003/other_documents/en/Ethical_Safety-GWH.pdf. Last accessed August 13, 2019.

102. Greenbaum VJ. Child sex trafficking in the United States: challenges for the healthcare provider. Plos Med. 2017;14(11):e1002439.

103. Gozdziak EM, MacDonnell M. Closing the gaps: the need to improve identification and services to child victims of trafficking. Human Organization. 2007;66(2):171-184.

104. International Labour Organization. India: Fighting Child Labour with Street Plays. Available at http://www.ilo.org/global/about-the-ilo/multimedia/video/video-news-releases/WCMS_114207/lang--en/index.htm. Last accessed August 13, 2019.

105. Dell NA, Maynard BR, Born KR, Wagner E, Atkins B, House W. Helping survivors of human trafficking: a systematic review of exit and postexit interventions. Trauma Violence Abuse. 2019;20(2):183-196.

106. Chung R, Bemak F, Ortiz D, Sandoval-Perez P. Promoting the mental health of immigrants: a multicultural/social justice perspective. J Couns Dev. 2008;86(3):310-317.

107. Marks L. Global health crisis: can indigenous healing practices offer a valuable resource? International Journal of Disability, Development and Education. 2006;53(4):471-478.

108. Baker DA, Grover EA. Responding to victims of human trafficking: Interagency awareness, housing services, and spiritual care.Soc Work Christianity. 2013;40(3):308-321.

109. Patrick PKS. Counselors advocates for practice and the profession. In: Patrick PKS (ed). Contemporary Issues in Counseling. Boston, MA: Pearson; 2007: 187-209.

110. Public Law 114-22: May 29, 2015.Available at https://www.congress.gov/114/plaws/publ22/PLAW-114publ22.pdf. Last accessed August 13, 2019.

111. Hounmenou C. Human service professionals' awareness of human trafficking. J Policy Pract. 2012;11(3):192-206.

112. Desyllas M. A critique of the global trafficking discourse and U.S. policy. J Sociol Soc Welfare. 2007;34(4):57-79.

113. Potocky M. Effectiveness of services for victims of international human trafficking: an exploratory evaluation. J Immigr Refug Stud. 2010;8(4):359-385.

114. Roby JL, Turley J, Cloward JG. U.S. response to human trafficking: is it enough? J Immigr Refug Stud. 2008;6(4):508-525.

115. Congressional Research Service. H.R. 7311: William Wilberforce Trafficking Victims Protection Reauthorization Act of 2008. Available at https://www.govtrack.us/congress/bills/110/hr7311. Last accessed August 13, 2019.

116. U.S. Congress. H.R.898: Trafficking Victims Protection Reauthorization Act of 2013. Available at https://www.congress.gov/bill/113th-congress/house-bill/898. Last accessed August 13, 2019.

117. Ren X. Legal protection and assistance for victims of human trafficking: a harm reduction approach. Int Perspect Vict. 2013;7(2):65-76.

118. Florida House of Representatives. House Bill 369 (2015). Available at https://www.flsenate.gov/Session/Bill/2015/369/BillText/er/PDF. Last accessed August 14, 2019.

Evidence-Based Practice Recommendations Citations

1. Clinical Effectiveness Group. UK National Guidelines on the Management of Adult and Adolescent Complainants of Sexual Assault, 2011. London: British Association for Sexual Health and HIV; 2012. Available at https://www.bashhguidelines.org/media/1079/4450.pdf. Last accessed August 15, 2019.

91783 • Smoking and Secondhand Smoke

Mark S. Gold, MD, DFASAM, DLFAPA

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

This course provides comprehensive clinical education on tobacco smoke in primary care and public health. It addresses core competencies as well as knowledge, assessment, and treatment-based competencies of healthcare providers. It covers the history of tobacco, epidemiology of tobacco use, tobacco smoke metabolism, dependence, treatment and relapse. It also addresses complications associated with direct and indirect exposure to tobacco smoke, effects of prenatal exposure, methods of screening for exposure, and brief intervention training. This course includes a review of available screening tools, predisposing genetic factors, associated risk and protective factors, withdrawal symptoms and treatment, lab testing procedures, diagnostic tools, and age and gender issues.

Table of Contents

91783 • Smoking and Secondhand Smoke

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. DEFINITIONS

3. HISTORY OF TOBACCO USE AND RESTRICTION

4. PREVALENCE AND ECONOMIC IMPACT OF SMOKING

5. TOBACCO AND NICOTINE PRODUCTS

6. TOBACCO-RELATED CONCEPTS

7. CIGARETTE SMOKE

POTENTIALLY THERAPEUTIC COMPONENTS OF TOBACCO

8. ANATOMY AND PHYSIOLOGY OF SMOKE INHALATION

9. LEARNING OF BEHAVIOR

RITUALISM

MEDIA INFLUENCE

GENETICS

10. SMOKING DEPENDENCE

PSYCHOLOGIC DEPENDENCE

11. HEALTH COMPLICATIONS RELATED TO SMOKING

PULMONARY COMPLICATIONS

CARDIOVASCULAR COMPLICATIONS

NEUROLOGIC COMPLICATIONS

CANCER

OSTEOPOROSIS

PROBLEMS WITH CONCEPTION AND EMBRYONIC HEALTH

12. COMORBID CONDITIONS

ALCOHOL ABUSE

DRUG ABUSE

PSYCHIATRIC DISORDERS

13. FETAL EXPOSURE

PHARMACOKINETICS AND DYNAMICS

NEUROLOGIC COMPLICATIONS

PULMONARY COMPLICATIONS

CARDIOVASCULAR COMPLICATIONS

LOW BIRTH WEIGHT AND SMALL FOR GESTATIONAL AGE

MIDDLE EAR DISEASE

CANCER

OSTEOPOROSIS

PSYCHIATRIC DISORDERS

14. PASSIVE SMOKING EFFECTS ON CHILDREN

NEUROLOGIC EFFECTS

CARDIAC COMPLICATIONS

SIDS

PULMONARY COMPLICATIONS

DENTAL CARIES

VITAMIN DEFICIENCY

RESULTANT SYMPTOMS IN ADULTHOOD

15. PASSIVE SMOKING EFFECTS ON ADULTS

OCCUPATIONAL EXPOSURE

HEART DISEASE

STROKE

LUNG DISEASE

CANCER

GLUCOSE INTOLERANCE/DIABETES

SKIN DISORDERS

WOUND REPAIR

AGE-RELATED MACULAR DEGENERATION

CERVICAL INTRAEPITHELIAL NEOPLASM (CIN)

NONALCOHOLIC FATTY LIVER DISEASE

16. MEASURING SECONDHAND SMOKE EXPOSURE

17. THIRDHAND SMOKE

18. INTERVENTIONS FOR SMOKING CESSATION

PRIMARY CARE INTERVENTION

BRIEF INTERVENTION

MOTIVATIONAL INTERVIEWING

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT INDIVIDUALS

TREATING NICOTINE DEPENDENCE

19. REDUCING TOBACCO SMOKE EXPOSURE

20. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

91783 • Smoking and Secondhand Smoke

Education Category. Community Health

Release Date. 06/01/2019

Expiration Date. 05/31/2022

Course Overview

This course provides comprehensive clinical education on tobacco smoke in primary care and public health. It addresses core competencies as well as knowledge, assessment, and treatment-based competencies of healthcare providers. It covers the history of tobacco, epidemiology of tobacco use, tobacco smoke metabolism, dependence, treatment and relapse. It also addresses complications associated with direct and indirect exposure to tobacco smoke, effects of prenatal exposure, methods of screening for exposure, and brief intervention training. This course includes a review of available screening tools, predisposing genetic factors, associated risk and protective factors, withdrawal symptoms and treatment, lab testing procedures, diagnostic tools, and age and gender issues.

Audience

This course is designed for physicians, nurses, and other healthcare professionals who may intervene to stop patients from smoking.

Course Objective

The purpose of this course is to provide physicians, nurses, behavioral health professionals, and other members of the interdisciplinary team with a formal educational opportunity that will address the impact of tobacco smoking and secondhand exposure in public health and disease as well as interventions to promote smoking cessation among their patients.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the history of tobacco and its impact on society.

2. Define the prevalence and economic impact of tobacco smoke exposure on public health.

3. Differentiate between available tobacco products.

4. Describe the neurophysiologic effects and addictive components of tobacco smoke.

5. Describe the anatomy and physiology of smoke inhalation, and outline key points in learning of behavior.

6. Define the psychologic and physiologic aspects of smoking dependence.

7. List the common health complications related to smoke exposure.

8. Identify the common comorbid conditions of tobacco users.

9. Describe the developmental complications related to prenatal exposure to smoke.

10. Define the effects of exposure to secondhand smoke for children and adults.

11. Identify the methods of detecting and measuring tobacco smoke exposure.

12. Define thirdhand smoke.

13. Outline the methods of tobacco cessation interventions, including necessary considerations for non-English-proficient patients.

14. Define the treatment modalities for tobacco addiction, including pharmacologic options.

15. Identify strategies to reduce exposure to tobacco smoke.

Faculty

Mark S. Gold, MD, DFASAM, DLFAPA, is a teacher of the year, translational researcher, author, mentor, and inventor best known for his work on the brain systems underlying the effects of opiate drugs, cocaine, and food. Dr. Gold was a Professor, Eminent Scholar, Distinguished Professor, Distinguished Alumni Professor, Chairman, and Emeritus Eminent Scholar during his 25 years at the University of Florida. He was a Founding Director of the McKnight Brain Institute and a pioneering neuroscience-addiction researcher funded by the NIH-NIDA-Pharma, whose work helped to de-stigmatize addictions and mainstream addiction education and treatment. He also developed and taught courses and training programs at the University of Florida for undergraduates and medical students.

He is an author and inventor who has published more than 1,000 peer-reviewed scientific articles, 20 text books, popular-general audience books, and physician practice guidelines. Dr. Gold was co-inventor of the use of clonidine in opioid withdrawal and the dopamine hypothesis for cocaine addiction and anhedonia. Both revolutionized how neuroscientists and physicians thought about drugs of abuse, addiction, and the brain. He pioneered the use of clonidine and lofexidine, which became the first non-opioid medication-assisted therapies. His first academic appointment was at Yale University School of Medicine in 1978. Working with Dr. Herb Kleber, he advanced his noradrenergic hyperactivity theory of opioid withdrawal and the use of clonidine and lofexidine to ameliorate these signs and symptoms. During this time, Dr. Gold and Dr. Kleber also worked on rapid detoxification with naloxone and induction on to naltrexone.

Dr. Gold has been awarded many state and national awards for research and service over his long career. He has been awarded major national awards for his neuroscience research including the annual Foundations Fund Prize for the most important research in Psychiatry, the DEA 30 Years of Service Pin (2014), the American Foundation for Addiction Research’s Lifetime Achievement Award (2014), the McGovern Award for Lifetime Achievement (2015) for the most important contributions to the understanding and treatment of addiction, the National Leadership Award (NAATP) from addiction treatment providers for helping understand that addiction is a disease of the brain, the DARE Lifetime Achievement Award for volunteer and prevention efforts, the Silver Anvil from the PR Society of America for anti-drug prevention ads, the PRIDE and DARE awards for his career in research and prevention (2015), and the PATH Foundation’s Lifetime Achievement Award (2016) as one of the “fathers” of addiction medicine and MAT presented to him by President Obama’s White House Drug Czar Michael Botticelli. He was awarded Distinguished Alumni Awards at Yale University, the University of Florida, and Washington University and the Wall of Fame at the University of Florida College of Medicine. Gold was appointed by the University President to two terms as the University’s overall Distinguished Professor, allowing him to mentor students and faculty from every college and institute. The University of Florida College of Medicine’s White Coat Ceremony for new medical students is named in his honor.

Since his retirement as a full-time academic in 2014, Dr. Gold has continued his teaching, mentoring, research, and writing as an Adjunct Professor in the Department of Psychiatry at Washington University and an active member of the Clinical Council at the Washington University School of Medicine’s Public Health Institute. He regularly lectures at medical schools and grand rounds around the country and at international and national scientific meetings on his career and on bench-to-bedside science in eating disorders, psychiatry, obesity, and addictions. He continues on the Faculty at the University of Florida College of Medicine, Department of Psychiatry as an Emeritus Distinguished Professor. He has traveled extensively to help many states develop prevention, education, and treatment approaches to the opioid crisis.

Faculty Disclosure

Contributing faculty, Mark S. Gold, MD, DFASAM, DLFAPA, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

Abimbola Farinde, PharmD, PhD

James Trent, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Tobacco smoke exposure is a major cause of the nation's most serious and preventable health problems. This course provides comprehensive clinical education on tobacco smoke in primary care and public health. It addresses core competencies as well as knowledge, assessment, and treatment-based competencies of healthcare providers. It covers the history of tobacco, epidemiology of tobacco use, tobacco smoke metabolism, dependence, treatment, and relapse. It also addresses complications associated with direct and indirect exposure to tobacco smoke, effects of prenatal exposure, methods of screening for exposure, and brief intervention training. This course includes a review of available screening tools, predisposing genetic factors, associated risk and protective factors, withdrawal symptoms and treatment, lab testing procedures, diagnostic tools, and age and gender issues.

2. DEFINITIONS

A clear understanding of tobacco use and smoking is dependent on a knowledge of the basic underlying concepts associated with addiction [1].

Tolerance: The need for greatly increased amounts of the substance to achieve intoxication (or the desired effect) or a markedly diminished effect with continued use of the same amount of the substance.

Withdrawal: Maladaptive behavioral change, with physiologic and cognitive concomitants, that occurs when blood or tissue concentrations of a substance decline in an individual who had maintained prolonged heavy use of the substance. After developing unpleasant withdrawal symptoms, the person is likely to take the substance to relieve or to avoid those symptoms, typically using the substance throughout the day, beginning soon after awakening.

Substance use disorder: A cluster of cognitive, behavioral, and physiologic symptoms indicating that the individual continues using the substance despite significant substance-related problems. There is also an underlying change in brain circuits that may persist beyond detoxification.

3. HISTORY OF TOBACCO USE AND RESTRICTION

Tobacco was the first export of the New World and was marketed in Europe as a remedy for stress, ulcers, headaches, asthma, and even rheumatism. Tobacco's botanical name, Nicotiana tabacum, is derived from Jean Nicot, a French ambassador to Portugal who, convinced of tobacco's medicinal value, sent the plant's seeds to the royal family in France [2].

Tobacco product use has been discouraged in the United States and abroad for centuries. In 1586 the first recorded tobacco prohibition was issued by Pope Sixtus V, who declared it a sin "for any priest to use tobacco before celebrating or administering communion." In 1604, King James I published A Counterblaste to Tobacco, describing smoking tobacco as, "a custome lothsome to the eye, hatefull to the Nose, harmefull to the braine, [and] dangerous to the Lungs" [3]. Tobacco use and distribution saw further restrictions across the globe in the early 1600s. King James I levied heavy taxes on tobacco, the czar of Russia exiled tobacco users, and the Chinese executed persons caught selling tobacco [4].

However, in contrast to strict regulations found elsewhere in the world, tobacco was brought to the United States as a cash crop. The 1880s saw the invention of an automated cigarette-making machine, which paved the way for cigarettes to become the predominant form of tobacco with the start of World War I. The twentieth century also experienced the first major outcry against tobacco in the United States. Though medical concerns were suggested, the first tobacco prohibition movements in the United States were primarily driven by religious and moral motivations. Groups including religious leaders, the Women's Christian Temperance Union, and the Non-smokers Protective supported efforts for prohibition of tobacco. However, strong public resistance against alcohol prohibition also led to the repeal of tobacco restrictions, and by the 1930s these restrictions had all but vanished [5].

One of the lesser known consequences of World War II was that German smoking research and corresponding social change were not acknowledged by the rest of the world. In the 1930s and early 1940s, Germany conducted an aggressive anti-smoking campaign based on medical research from the 1920s and 1930s, which elucidated the carcinogenic effects of smoking. As part of the German movement aimed to preserve a racial "utopia" of pure, healthy Germans, they banned smoking in the workplace, imposed cigarette taxes, restricted advertising and farming, and implemented programs to eliminate smoking [6,7].

Associations between smoking and cancer were not published in the United States until the 1950s and 1960s. The 1964 publication Smoking and Health: Report of the Advisory Committee to the Surgeon General led to immediate political notice of the tobacco issue and the advent of programs and policies to reduce smoking [8]. Anti-tobacco policies have included taxation on tobacco products, increased insurance premiums, warning labels, public health campaigns, and restrictions on tobacco sales to minors, smoking in public areas, and tobacco marketing. Prior to 1964 there were few if any laws regulating involuntary secondhand smoke (SHS) exposure. Studies revealing the detrimental effects of SHS to nonsmokers led to new anti-smoking legislation. As of June 2009, the General Services Administration (GSA) has established smoke-free environments for federal facilities. Interior areas previously designated for smoking have been closed and smoking is prohibited in courtyards and within 25 feet of doorways and air intake ducts in outdoor spaces [9]. Further, nearly all 50 states have laws restricting smoking in places such as schools, public transportation, government buildings, elevators, and restaurants. In accordance with federal law, smoking is prohibited on buses, trains, and domestic airline flights. Such laws have decreased cigarette consumption by making smoking less socially acceptable and more inconvenient [5].

On June 22, 2009, President Barack Obama signed HR1256: The Family Smoking Prevention and Tobacco Control Act. This was enacted as a result of several findings made by Congress, specifically that almost all new users of tobacco products are younger than the minimum legal age to purchase such products. Under this law, the U.S. Food and Drug Administration (FDA) now has the authority to regulate tobacco products [10]. The FDA had previously attempted to assert jurisdiction under the Food, Drug, and Cosmetic Act in 1996 to regulate tobacco advertising, labeling, and purchasing restrictions (e.g., federal minimum age of 18 years and requiring retailers to check identification). However, the tobacco industry retaliated by suing the federal government, as there was no set legislation to give the FDA this authority. As a result, all FDA regulations were dropped [11]. Due to the 2009 law, the FDA can now establish a minimum age of sale of tobacco products, test and report on tobacco product ingredients/additives, prohibit cigarettes from containing any flavors other than tobacco or menthol, and apply the same restrictions on labeling and advertising of cigarettes to smokeless tobacco products. Of note, this law states that the FDA cannot ban existing products or require nicotine be eliminated from any product.

In 2017, the FDA unveiled a comprehensive plan on tobacco and nicotine regulation to reduce the number of preventable deaths caused by smoking and tobacco use. The two key areas of focus of this plan are reducing the nicotine levels in combustible cigarettes to render them minimally or nonaddictive and harnessing new forms of nicotine delivery that could allow currently addicted adult smokers to get access to nicotine without many of the risks associated with using combustible tobacco products. Similar to the 2009 policy, this plan will also explore the extent of tobacco flavoring in attracting youth and new smokers; menthol flavoring will be included in this plan. Of note, this policy only affects newly regulated tobacco products and will not affect any current requirements for cigarettes and smokeless tobacco. As of 2019, the plan was still in development and the FDA was continuing to seek public comment and expert opinion [472,474].

4. PREVALENCE AND ECONOMIC IMPACT OF SMOKING

Approximately 480,000 Americans die each year as a result of active and/or passive smoking-related health consequences [12]. Despite the seemingly well-known and highly publicized health consequences of smoking, 13.9% of the U.S. population 18 years of age or older are current cigarette smokers [460]. Former U.S. Assistant Secretary for Health Howard Koh asserted that although evidence-based tools were successful in substantially reducing smoking prevalence between 1997 and 2004, efforts were not applied to their full potential nationwide, limiting the efficacy of anti-smoking campaigns [14]. Other experts have attributed declines in cigarette smoking to anti-smoking advertisements, stigma, smoking bans, and increased taxation [460]. Evidence-based tools remain valuable, indicated by slow, steady downward prevalence trends since 1997. However, they are only useful if they reach an audience. These tools seem not to be preventing the initiation of new smokers, despite the overall reductions in use [14,15].

Nearly 1.8 million Americans initiated cigarette smoking in 2016, continuing a downward trend noted between 2002 and 2013 (ranging from 1.9 to 2.2 million); 40.6% of these were younger than 18 years of age [13]. About one-third of new smokers will ultimately die from a smoking-related illness [16]. Higher levels of education are correlated with a lower likelihood of having smoked cigarettes in the past month [13]. The number of first-time cigar users is slowly declining, from 2.8 million in 2011 to 2.4 million in 2016 [13]. In 2016, current use of any tobacco product was highest among American Indians/Alaska Natives (42.6%) followed by persons of two or more races (40.2%), whites (31.3%), blacks (27.8%), Hispanics (22%), and Asians (11.9%) [13].

Approximately 41,000 adult nonsmokers die each year from exposure to SHS, and this continues to be a significant environmental risk in the United States [19]. According to a 2009 study by Ellis and colleagues, the prevalence of smoking in New York City was lower than the national average (23.3% vs. 29.7%), but the proportion of nonsmoking adults with elevated cotinine levels was higher (56.7% vs. 44.9%), especially among Asians, even after close to two years after implementation of smoke-free workplace legislation [20]. They attribute this finding to the large amounts of people in such small proximity (26,000 people and 10,000 housing units per square mile vs. the national average of 80 people and 33 housing units per square mile) [20]. In a 2017 study, Perlman and colleagues reviewed cotinine levels in New York City nonsmokers, and found that 37.1% had elevated levels [17]. It is thought that this reduction is a result of smoke-free air policies enforced within the previous 10 to 15 years. The researchers also agreed that greater population density and pedestrian exposure continued to contribute to the high number of nonsmokers with elevated cotinine levels [17].

Tobacco use is one of the most expensive addictive behaviors in the United States. In 2015, an estimated 299.9 billion cigarette stick equivalents (based on the weight of 0.0325 ounces of tobacco per cigarette) were consumed in the United States, of which 262.7 billion were cigarettes; the rest were other combustible tobacco products [21]. This accounted for $93.9 billion in national expenditures on cigarettes alone in the 2017 fiscal year [23].

Smoking-related costs in the United States are staggering. The total annual public and private healthcare expenditures caused by smoking are estimated to be greater than $300 billion, including nearly $170 billion in direct medical costs and more than $156 billion in lost productivity related to premature death and exposure to SHS [12].

5. TOBACCO AND NICOTINE PRODUCTS

Cigarette smoking is on the decline in the United States, but use of other tobacco products is not [21]. In addition to a rise in use of smokeless tobacco, people across the United States (especially youth) are using e-cigarettes, cigars, cigarillos (small cigars), hookahs, kreteks, pipes, and bidis (or beedis) [18,25]. Unfortunately, each of these products is just as dangerous (if not more so) as use of cigarettes. Cigarettes are defined by the U.S. Department of the Treasury as "any roll of tobacco wrapped in paper or in any substance not containing tobacco," while cigars are defined as "any roll of tobacco wrapped in leaf tobacco or in any substance containing tobacco" [26]. Cigars also differ from cigarettes in processing; they consist of filler, a binder, and a wrapper, all made of air-cured and fermented tobaccos [27]. Cigars show significant variability in physical and chemical characteristics, with total nicotine content ranging from 10.1 mg to 444 mg per cigar, length ranging from 68.0 mm to 213.5 mm, and diameter ranging from 8.0 mm to 20.5 mm [28]. Due to their size and makeup, smokers can spend up to an hour smoking a single cigar; therefore, its ensuing effects (e.g., rates of cancer, chronic obstructive pulmonary disease [COPD]) are more pronounced. Cigarillos, or "little cigars," are generally about half the size of a normal cigar, weighing 1.5 to 3 g on average [29]. Many types are made to look like cigarettes and are sold in packs of 20 with filter tips. Cigarillos are perceived as a less addictive, less harmful, and less expensive alternative to cigarette use [30; 31].

Due to increased federal taxation on cigarettes, cigarette tobacco, and small cigars, many consumers apparently switched to smoking products virtually identical to cigarettes or small cigars, but classified as large cigars, or from smoking roll-your-own tobacco to smoking pipe tobacco [22]. Subsequent to the 2009 tax increase and intensified FDA regulation, many companies simply relabeled cigarette rolling tobaccos as pipe tobaccos (not subject to increased taxation) [21]. Sales of "pipe tobacco" increased from 5.2 million pounds in 2009 to 43.7 million pounds in 2013 (a 740% change) while roll-your-own tobacco sales dropped from 21.3 million pounds to 3.8 million pounds [22]. Following a similar relabeling and marketing effort for small cigars, sales of large cigars jumped from 5.8 billion sticks in 2009 to more than 12.4 billion sticks in 2013, while small cigars decreased from 5.7 billion sticks to 0.7 billion sticks in the same years. In 2016, the FDA extended its limitations for tobacco products to include e-cigarettes, vaporizers, and other electronic nicotine delivery systems [458]. As a result, these products must include warnings and manufacturers must submit documentation to the FDA for review and limit sales to persons 18 years of age or older. The goals of these regulations are to increase public health awareness and, especially, reduce marketing and sales to adolescents, who are commonly targeted by providing tobacco flavors including apple, cherry, cream, grape, "jazz," strawberry, and wine. Before this ruling, there were no federal laws restricting sales of these types of products, but an alarming increase in unregulated tobacco products, especially among high school students, prompted the FDA to enforce regulations.

The rise of e-cigarettes in the past decade has introduced new variables in the prevention and treatment of nicotine addiction. Originally marketed as a smoking cessation tool, e-cigarettes are electronic products that typically deliver nicotine in the form of an aerosol [456]. Most e-cigarettes consist of a cartridge (which holds a liquid solution containing varying amounts of nicotine, flavorings, and other chemicals), a heating device (vaporizer), and a power source (usually a battery) [457]. In many e-cigarettes, puffing activates the battery-powered heating device, which vaporizes the liquid in the cartridge. The resulting aerosol or vapor is then inhaled (called "vaping") [457]. It is unclear if this delivery method decreases the risks seen with conventional tobacco smoking; however, it does introduce the risks of toxicity associated with consumption of the potent e-liquid.

In 2017, 2.8% of adults were current e-cigarette users. Adults 25 to 44 years of age have the highest rate of e-cigarette use (22.5%), followed by those 45 to 64 years of age (21.3%), 18 to 24 years of age (18.3%), and older than 65 (11%) [456]. Use is much higher among men (24.8%) than women (14.2%).

Adolescent use of e-cigarettes has skyrocketed from 1.5% in 2011 to 20.8% in 2018, making it the number one form of tobacco used among youth [459,465]. In 2018, the FDA issued more than 1,300 warnings and fines to retailers who illegally sold e-cigarette products to minors [464].

According to the Centers for Disease Control and Prevention (CDC), large cigar consumption increased 116% from 2000 to 2017, with cigar smoking being the third most common form of tobacco use among youth [32,33]. However, it has been shown that adolescent (and likely adult) cigar use is significantly underestimated due to systematic misreporting on statewide surveys, which is mainly attributed to the language and definitions used in questions that assume knowledge of all types of cigars [34]. For example, it was found that more than half of Black & Mild (brand of cigars and cigarillos) users did not report any cigar/cigarillo use on a 2009 Virginia survey, largely because the usage of the terms "cigar" or "cigarillo" for this (and other similar products) is not common in the youth- or culture-specific lexicon.

Bidis consist of sun-dried tobacco, finely ground and rolled into a leaf of the Diospyros melanoxylon plant native to India. They contain concentrated tobacco, with an average 21.2 mg/g of nicotine compared with 16.3 mg/g of nicotine in filtered and 13.5 mg/g in unfiltered cigarettes, but have less total nicotine because they are shorter [35]. Nonetheless, an unfiltered bidi can release three to five times more tar and nicotine and contain more ammonia and carbon monoxide (CO) than a regular cigarette. Bidis look similar to small cigars or marijuana cigarettes and are available filtered or unfiltered in many flavors, including vanilla, chocolate, strawberry, cherry, and menthol [36]. Bidis are not commonly used in the United States, and sale and distribution is banned in some states (e.g., Illinois, Vermont, West Virginia). However, these products are available on the Internet [37].

Kreteks, or clove cigarettes, are composed of a mixture of tobacco (60% to 80%) and ground clove buds (20% to 40%), available with or without filters [38]. A popular, representative kretek brand contains less nicotine than popular cigarettes (7.39 mg), but smokers extract equal amounts of nicotine by altering smoking behavior [39]. For example, clove cigarettes can be smoked slower, using more puffs. Overall, smokers will do whatever is necessary to achieve plasma levels of nicotine comparable to their usual brand of cigarette.

A hookah is a type of waterpipe comprised of a head or bowl, plate, body, jar, hose, and mouthpiece (Figure 1). The body of the hookah fits down into the jar, which is partially filled with water, although any liquid (e.g., alcohol, juice) can be used. Tobacco is placed in the bowl at the head of the body and covered with a filter, such as perforated tin foil, and then burning embers or charcoal is placed above it (and sometimes covered by a cap). The hot air from the charcoal roasts the tobacco and the ensuing smoke is passed down into the liquid in the jar where it is partially filtered, diluted, and cooled. The smoke then bubbles up and passes through the hose and mouthpiece for inhalation. Repeated inhalation is required to keep the tobacco burning. The plate stores dead coals/embers. The types of tobacco used for hookah are ajami or tumbak, which is a pure, dark tobacco paste; "honeyed" or tobamel or maassel, containing 70% honey or molasses and featuring flavors (e.g., apple, mango, banana); or jurak, which may be sweetened or contain fruits or oils. It is commonplace to use 10–20 g at a time, and these tobaccos may be mixed with other drugs [40]. Smoking sessions last up to an hour or longer, and it has been reported that the nicotine content of the tobacco used for hookah is higher than that in cigarettes [41]. Thus, the smoker is exposed to a higher volume of smoke for longer periods (not to mention those in the vicinity). A report from the World Health Organization states that a hookah user may inhale as much smoke in one session as a cigarette smoker would after consuming at least 100 cigarettes [42]. Contrary to popular belief, waterpipe smoking is not safer or less addictive than cigarette smoking [43]. The FDA began regulating the manufacture, import, packaging, labeling, advertising, promotion, sale, and distribution of tobacco mixtures used for hookah in 2016 [24]. Hookah smoke contains higher concentrations of CO, nicotine, tar, heavy metals, and carcinogens, likely because of its method of use (i.e., tobacco mixtures heated by quick-burning charcoal or wood embers and inhalation through use of a plastic hose for an hour or longer) [44,45]. It is also common to share a hookah, so users are also at risk of exposure to infections (e.g., herpes due to sharing of the mouthpiece) [46]. Hookah pipe smoking may be a gateway to cigarette smoking and other drug use. Although policies are in place to ban smoking in many public places, many times, hookah use is exempt because it is done in places which identify themselves as "tobacco bars," waterpipe smoking areas are set up outside, or the smoking is done in places where tobacco is sold.

Figure 1: SCHEMATIC OF A WATERPIPE

Source: [46]

6. TOBACCO-RELATED CONCEPTS

For many years, efforts to make cigarettes "safer" have been pursued as a compromise solution [48]. Filtering devices have been used to selectively reduce cigarette smoke constituents for almost 60 years [49]. Studies from the 1970s concluded that charcoal filters can remove up to 66% of ciliotoxic agents from mainstream smoke, and cellulose acetate filter tips can eliminate up to 75% of N-nitrosamines, which are known volatile carcinogenic compounds [50,51]. However more recent studies have shown that neither type of filter is effective for reducing the free radical and reactive oxygen species content in the particulate or gas phase of cigarette smoke [52]. Additionally, remnant (i.e., post-filter) aqueous tar can cause the formation of DNA adducts, particularly the mutagenic 8-Oxo-2'-deoxyguanosine (8-oxo-dG).

The FTC performs tar, nicotine, and CO content measurements in all domestic cigarette varieties sold in the United States, which numbered almost 1,300 in 1998, the last year the report was conducted. The FTC defines tar as the particulates of cigarette smoke minus water and alkaloids, such as nicotine, detected using a method developed in 1966 [53]. In 2016, 99.7% of cigarettes sold in the United States had filters, and the FTC reported that 87.9% of the market share of cigarettes had less than 15 mg of tar, compared with only 2% in 1967 [53,54]. Nevertheless, epidemiologic evidence does not indicate that modern cigarettes are any safer. Smokers participating in the Cancer Prevention Study II (CPS-II) from 1982 to 1988 manifested an almost sixfold increase in lung cancer death compared to Cancer Prevention Study I (CPS-I) participants during 1959 to 1965, even though filter tips were introduced in the 1950s and only the latter group benefited from their implementation [55]. Smoking pattern compensation and use of stronger tobacco strains may be at least partially responsible for this paradoxical trend.

Filter vents, usually shaped in rings of small perforations along the filter, allow air to mix with smoke, diluting the amount of tar, nicotine, and CO detected by the FTC method [53]. Interestingly, as many as 58% of smokers of cigarettes with tar less than approximately 7% (formerly labeled "ultralight") and 53% of smokers of cigarettes with tar levels of 8–14 mg of tar (formerly labeled "light") cover these vents to some extent [56,57]. Blocking half of the vents of a 4.4 mg tar cigarette, as is done when smokers pinch the cigarette with their fingers or hold the cigarette in their lips, increases yields of tar by 60%, nicotine by 62%, and CO by 73% [58]. Poor reliability of the FTC method is further made evident in the work of Byrd and Robinson, who concluded that the "FTC yield cannot precisely predict nicotine uptake for an individual smoker" and "nicotine uptake by smokers is influenced by…many possible smoker-controlled parameters" [59]. Interestingly, this publication originates from the R.J. Reynolds Tobacco Company. Another contributing factor to the increase in mortality related to smoking may be the concentration of nitrate in tobacco leaves, one of the most important precursors for the endogenous formation of N-nitrosamines during smoke inhalation [60]. Cigarette nitrate content has increased from 0.5% in the 1950s to 1.2% to 1.5% in the late 1980s, possibly due to the increased use of chemical fertilizers and the introduction of plant ribs and stems into U.S. tobacco blends [61]. The carcinogenic potential of nitrosamines has been well documented.

All in all, efforts to reduce the health hazards of smoking leave much to desire, and in spite of filter tip implementation and reportedly lower tar values, cigarettes remain a serious health hazard, affecting smokers and those around them.

7. CIGARETTE SMOKE

Cigarette smoke is a complex mixture of more than 7,000 components, including nicotine, aromatic hydrocarbons, sterols and oxygenated isoprenoid compounds, aldehydes, nitriles, cyclic ethers, and sulfur compounds [62,63,134]. At least 70 of these components are known to cause cancer [134]. Firsthand smoke is defined as the smoke that the smoker inhales. Smoking tobacco products also generates environmental tobacco smoke, also known as SHS and passive smoke, which consists of both exhaled mainstream and sidestream smoke. These two forms of smoke differ in chemical composition and have different temperatures and oxygen levels during generation. The burning end of a cigarette produces sidestream smoke, which in turn is the main component of SHS. Some known toxins of the thousands of chemical constituents in tobacco smoke are also present in SHS, including benzene, cadmium, ethylbenzene, formaldehyde, hydrazine, lead, limonene, methylamine, methylene chloride, nicotine, pyridine, toluene, and radioactive polonium-210 [64,65,66]. One study identified indoor air pollution from SHS as 10 times greater than diesel car exhaust [67].

Many of the diseases once thought only to be caused by active smoking have now been authoritatively linked to environmental tobacco smoke [62,68]. This finding is not surprising considering that many of the harmful components found in both firsthand smoke and SHS are more concentrated in SHS. Nicotine, tar, nitric oxide, and CO levels have been shown to be nearly twice as concentrated in SHS. Other harmful chemicals preferentially formed in SHS include carcinogenic aromatic amines (e.g., o-toluidine, 2-naphthylamine, and 4-aminobiphenyl) [62,65,69].

POTENTIALLY THERAPEUTIC COMPONENTS OF TOBACCO

According to Lans et al., the crushed leaves of Nicotiana tabacum are applied to wounds in Guatemala, and tobacco steam vapor is considered a cure-all in Latin America and the Caribbean. In addition to its most addictive component, nicotine, the tobacco plant contains many enzymes, flavonoids, and coumarins and malic, citric, and phenolic acids [70]. In a case-control study by Sandler et al., tobacco use and secondhand exposure (e.g., parents had smoked) reduced the risk of developing ulcerative colitis [71]. Plants of the genus Nicotiana have been manipulated in various experiments to express proteins that may be used medicinally. Indeed, transgenic tobacco plants have been used in the development of vaccines for measles, lymphoma, and diabetes [72,73,74].

8. ANATOMY AND PHYSIOLOGY OF SMOKE INHALATION

Administration of any drug via smoking is a highly efficient route, allowing rapid delivery to the brain. This act involves inhalation of a small volume of smoke (an average of about 35 ml for cigarettes) into the mouth from which it is drawn into the lungs [75]. The breathing pattern employed is different from normal tidal breathing in that a smoker's inhalation is deeper and more rapid, drawing the smoke in as a bolus at the beginning of inhalation [76]. However, this pattern varies greatly between smokers and during the course of consuming a single cigarette [77]. Uptake of smoke ingredients is determined by many factors, including chemical composition, smoker's inhalation behavior, lung morphology, and physiologic parameters such as tidal volume, vital capacity, rate of breathing, and rate of lung clearance [78]. Individual differences in size, metabolism, and genetics may also play a role. One hypothesis suggests that stimulation of nicotine-sensitive receptors in the upper airway by various elements of smoke governs the amount inhaled. Indeed, application of a topical anesthetic to the upper airway reduces the quantity of smoke inhaled [79].

Tobacco smoke consists of gaseous and particulate phases, with the particulate phase comprising about 8% of the total volume [76]. Particulate deposition depends on the size, shape, and hygroscopicity (ability to absorb water vapor) of the particles as well as the duration and depth of inhalation [77]. Smoke particles range from 0.1–1.0 mm in diameter as they exit a cigarette, doubling in size within half a second due to aggregation, cooling, and condensation [80]. Larger particles (1–5 mm) are likely to deposit in the trachea and bronchi, whereas smaller particles (0.01–1 mm) reach bronchioles, alveolar ducts, and alveoli. Irregularly shaped or fibrous particles tend to get trapped at branching points, although some of these particles can travel on to the alveoli [81]. Interestingly, smoking seems to result in a greater apical and central distribution of particles than normal tidal breathing. This finding may help to explain the pathogenesis of centrilobular emphysema [76].

Cigarettes deliver nicotine in a pulsatile manner, with plasma concentrations reaching their peak within 1.5 to 3 minutes of the commencement of smoking and gradually returning toward baseline within two to three hours [82]. Thus, nicotine levels rise and fall throughout the day with each cigarette smoked, declining to minimum amounts found in nonsmokers in the morning after the extended abstinence period of sleep. Such continuous flux in blood nicotine levels locks the user into an endless cycle of ups and downs and is thought to lead to the commonly held notion that smoking has a positive effect on mood. Considering smokers begin to experience withdrawal symptoms within hours of their last cigarette, and because these unpleasant effects are almost completely alleviated by smoking, this perception is hardly surprising. Daily repetition of this process links these perceived positive health benefits to the act of smoking in the smoker's mind and often results in the false identification of cigarettes as an effective form of self-medication [83].

9. LEARNING OF BEHAVIOR

What is it about smoking that makes it so addictive? On one hand, this form of drug delivery is very efficient; inhaled nicotine is absorbed through pulmonary rather than systemic circulation and can reach the brain within 10 to 20 seconds [84]. Once inside the central nervous system (CNS), nicotine stimulates release of dopamine from the nucleus accumbens, much like the use of cocaine and amphetamines, leading to the feeling of satisfaction and well-being. Given such rapid central reinforcement, it is not surprising that tobacco can become highly addictive. On the other hand, familial and social influences often play a crucial role in determining who might start smoking, quit, or become dependent [83]. For example, one study managed to train a small percentage of rhesus monkeys to smoke, but with such difficulty that it concluded that "environmental factors play the primary role in developing smoking behavior" [85].

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends that primary care clinicians provide interventions, including education or brief counseling, to prevent initiation of tobacco use in school-aged children and adolescents.

http://annals.org/aim/fullarticle/1748857

Last Accessed: May 13, 2019

Level of Evidence: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

Experimenting with smoking usually occurs in the early teen years and is predominantly driven by psychosocial motives [83]. For a first-time user, lighting a cigarette is a symbolic expression of autonomy and independence; acquisition of the desired image is often a sufficient incentive for a novice smoker to tolerate the body's rejection of the first few cigarettes. Despite an admitted awareness of at least some of the deleterious effects of smoking, in 2018, 1 in 4 high school students and 1 in 14 middle school students admitted to using a tobacco product in the past 30 days [135]. Almost all people (90%) who will smoke as adults have started doing so by 18 years of age, and the earlier a person begins, the more likely they are to continue [135]. Within a year, adolescents inhale the same amount of nicotine per cigarette as adults, and they too experience the craving and withdrawal symptoms associated with nicotine addiction [83]. By 20 years of age, 80% of smokers regret ever having started.

Much research has been dedicated to uncovering reasons for the development of a smoking habit. Risk factors include [86]:

- Presence of a smoker in the household

- Single parent home and/or strained relationship with parent

- Comorbid psychiatric disorders

- Low level of expressed self-esteem and self-worth

- Poor academic performance

- In boys, high levels of aggression and rebelliousness

- In girls, preoccupation with weight and body image

- Increased adolescent perception of parental approval of smoking

- Affiliation with smoking peers

- Availability of cigarettes

In addition, twin studies revealed a significant genetic contribution to both smoking initiation and dependence [87,88].

RITUALISM

In practice, many find the very act of smoking a cigarette ritualistic and calming. The process of "packing" cigarettes by tapping the box on the palm of a hand, removing a cigarette, lighting it, inhaling, and watching the smoke as it is exhaled all contribute to the perceived need to smoke. Some go so far as to claim that they "would not know what to do with their hands" if they were to stop smoking [83]. An investigation using denicotinized cigarettes illustrated that the sensorimotor experience of smoking makes a significant contribution to the perceived satisfaction [89].

MEDIA INFLUENCE

Mass media is another factor that contributes to the learning of smoking behavior. Historically, the tobacco industry recruited new smokers by associating its products with fun, excitement, sex, wealth, power, and a means of expressing rebellion and independence [90]. Such promotional efforts have proven to be especially effective on teenagers, a particularly lucrative market with a lifetime of cigarette consumption ahead of them [91]. Although at present tobacco companies can no longer directly advertise to teenagers, they retain the most potent form of marketing: movies. Smoking in film is a "more powerful force than overt advertising," perhaps because the audience is generally unaware of any sponsor involvement [92]. Philip Morris, one of the world's leading tobacco companies, stated in their 1989 marketing plan, "We believe that most of the strong, positive images for cigarettes and smoking are created by cinema and television" [90]. Although television is taking a more socially responsible stance on the subject of on-air tobacco use, movies continue to model smoking as a socially acceptable behavior, portraying it as a social behavior or a way to relieve tension [93,94]. A study exploring the connection between a child's professed favorite movie star and that actor's on-screen smoking history revealed "a clear relation between on-screen use and the initiation of smoking in the adolescents who admire them" [95]. Tobacco use in movies, albeit falling through the 1970s and 1980s, increased significantly after 1990 [90]. Furthermore, despite declining tobacco use and increasing public understanding of the dangers of nicotine, smoking in movies returned to the levels observed in the 1950s, when it was nearly twice as prevalent in society as in 2002 [96]. A study analyzing the content of the top 25 grossing films each year from 1988 to 1997 found that 87% of movies depicted tobacco use, with an average of 5 occurrences per film. The vast majority of tobacco use was portrayed as experienced use (91.5%) and rarely did it represent a character's first use (0.3%) or a relapse from a previous quit attempt (0.5%). Despite the fact that R-rated movies contained most tobacco exposure and were more likely to feature a major character using tobacco, about 60% of the total coverage of smoking occurred in youth-rated films (G, PG, and PG-13). Negative reactions to tobacco use, including comments about health effects or gestures such as coughing, were depicted in only 5.9% of the occurrences. Unrealistic portrayal of cigarette smoking on the big screen may help to explain the somewhat surprising finding that children of nonsmoking parents are especially susceptible to the effects of movie smoking exposure [93]. Between 2002 and 2017, 6 out of every 10 movies rated PG-13 contained smoking or tobacco use, with historically high average of occurrences per film in 2016 (34 per film) and 2017 (29 per film), prompting many health groups to advocate for the requirement of an R rating (i.e., younger than 17 years of age require accompanying adult) for any films containing tobacco use. Researchers estimate that requiring a R rating would reduce the number of teen smokers by 18%, preventing up to 1 million deaths from smoking in the future [184]. Since May 2007, the Motion Picture Association of America (MPAA) has made smoking a factor in assigning ratings to films. The pervasiveness of tobacco use, context in which smoking appears, and whether or not the act is glamorized are all taken into account by film raters [97].

GENETICS

It has been suggested that high genetic vulnerability to cigarette smoking may explain why some people begin and continue to smoke despite associated risks [98]. Twin studies found significant heritability for persistence of smoking versus quitting. Heritability estimates for smoking persistence ranged from 27% to 70% and were greater for older than younger cohorts [99,100,101]. Madden et al. examined cross-cultural differences in the genetic risk of becoming a regular smoker and of persistence in smoking in men and women. They found strong genetic influences on smoking behavior, 46% for women and 57% for men, consistent across country and age group [102]. In a U.S. study, estimates of the genetic contribution to risk of becoming a smoker were 60% in men and 51% in women [103].

10. SMOKING DEPENDENCE

Of the numerous ingredients in tobacco smoke, nicotine is believed to be the primary cause of cigarette addiction [104]. Commercially available forms of nicotine-replacement therapy (NRT) increase cessation rates approximately 1.5- to 2-fold [105,106,107]. Yet, the fact that only a fraction of those who use such products succeed suggests that cigarette addiction depends on specific characteristics of cigarette smoking. It appears that the rapid delivery of nicotine via inhalation is a primary contributor to cigarette dependence [108]. Indeed, a district court judge found that major U.S. cigarette companies have designed their cigarettes to precisely control nicotine delivery levels and provide doses of nicotine sufficient to create and sustain addiction [109].

Active components of cigarette smoke affect many organ systems, but the effects on the CNS may be of most clinical importance due to its mediating role in dependence. Central effects of nicotine include electroencephalogram (EEG) desynchronization, with a shift toward higher frequency [110]. Studies have demonstrated that nicotine from cigarette smoke reduces global cerebral blood flow (gCBF), most markedly in the right hemisphere, and increases regional cerebral blood flow (rCBF) by more than 10% in the cerebellum, occipital cortex, and insula. Decreases in rCBF have been observed in such subcortical structures as the hippocampus, anterior cingulate, amygdala, and nucleus accumbens [111]. Positron emission tomography (PET) studies show that nasal nicotine administration increases cerebral glucose metabolism in the left inferior frontal gyrus, left posterior cingulate gyrus, left lateral occipitotemporal gyrus, left and right cuneus, and right thalamus, while it decreases glucose metabolism in the left insula and the right inferior occipital gyrus [112].

Further, the physiology of nicotine dependence has been characterized as biphasic; it stimulates the pleasure response in the brain and creates a relaxed state. As with cocaine, amphetamines, and morphine, addiction to nicotine is believed to result from increased release of dopamine in the nucleus accumbens. Nicotinic acetylcholine receptors are located throughout the CNS. Neurons located in the ventral tegmental area become more active with nicotine administration, leading to an increase in dopamine release into the nucleus accumbens [113]. Indeed, lesions to these pathways reduce rates of self-administered nicotine [114].

PSYCHOLOGIC DEPENDENCE

Many smokers believe that smoking increases concentration, treats stress, and gives pleasure. These beliefs are false. The light-headed feeling that may accompany the act of smoking gives the smoker a false sense of pleasure or release. However, smoking actually causes a decline in physical and cognitive functioning. Additionally, a study by Ota et al. showed that nurses in Japan indulged in smoking as a result of the psychologic demands of their jobs, and this psychologic job demand was positively correlated with their Tobacco Dependence Screener score. The nurses associated stressful tasks with dysphoria, insomnia, anxiety, and other symptoms similar to that of nicotine withdrawal. To alleviate these symptoms, the nurses would smoke and become increasingly psychologically dependent on nicotine with each demanding occupational event [115].

11. HEALTH COMPLICATIONS RELATED TO SMOKING

PULMONARY COMPLICATIONS

Smoking severely compromises pulmonary function in a variety of ways, including causing infiltration of the airways with leukocytes. An imbalance among proteases, their endogenous inhibitors, and local cytokine secretion in the lung leads to airway inflammation and alveolar destruction. Smokers also experience more acute lower respiratory illnesses. Smoking has been implicated in the development of malignant and nonmalignant lung disease, including COPD, bronchitis, influenza, emphysema, pneumonia, and lung cancer. Smokers are also shown to be at increased risk of intraoperative pulmonary complications and a wide range of postoperative complications. For example, a study of postoperative care revealed smoking, being older than 65 years of age, and a history of chronic lung disease increased the risk of unplanned intensive care admittance [116].

Chronic Obstructive Pulmonary Disease

Smoking is the main cause of COPD, which encompasses both chronic bronchitis and emphysema. Between 20% and 30% of smokers (or about 1 in 4) will develop COPD, and risk is determined largely based on genetic susceptibility coupled with age at smoking initiation [117,118]. It is very rare in nonsmokers; at least 80% of deaths from this disease can be attributed to cigarette smoking. The risk of death from COPD rises concurrently with the number of cigarettes smoked. If smokers with COPD quit smoking while they are still young, an improvement in lung function can be expected. However, such improvement is not possible in older people, although after cessation further deterioration will run parallel to that of nonsmokers.

The age at which one begins smoking is important. Wiencke and colleagues discovered that smoking as an adolescent causes permanent genetic changes in the lungs and forever increases the risk of lung cancer, even if the smoker subsequently stops [119]. A Canadian community health survey conducted between 2000 and 2001 found that the risks for heart disease, COPD, and rheumatoid arthritis were far higher among people who began smoking as teenagers than among their nonsmoking peers. For COPD alone, teen smokers were three times more likely to develop the condition later in life than nonsmokers. Similarly, a retrospective cohort study of adult smokers suggests that women are particularly at risk of COPD if they start to smoke before 16 years of age [120].

Influenza

Upper respiratory tract infections are common, and tobacco smoke is a proven risk factor for bacterial infection. The link between influenza and smoking has been demonstrated both for adult smokers and children exposed to smoke-filled environments. According to Arcavi and Benowitz, influenza risk is higher and infections are more severe (e.g., more cough, phlegm production, breathlessness, and wheezing) in smokers versus nonsmokers. Apparently, the antibody response is depressed in cigarette smokers. Nonsmokers should also avoid SHS exposure to decrease the risk of contracting influenza [121]. In a study of Israeli military men, presence and severity of influenza was stronger in smokers than in nonsmokers. Of all smokers, 68.5% contracted influenza compared with 47.2% of nonsmokers, and 50.6% of smokers required bed rest or lost workdays compared with 30.1% of nonsmokers [122]. A 2018 study of patients older than 65 years of age showed that smokers had a higher rate of hospitalization due to influenza (47.4%) compared with nonsmokers (42.1%). In addition, the effectiveness of the influenza vaccine in preventing hospitalization was 21% among current and ex-smokers and 39% in nonsmokers [376].

Pneumonia

Smoking is associated with a significant increase in the relative risk of pneumonia and pneumonia-related hospitalization [123,124]. Pneumonia is not only more common among smokers, it is much more likely to be fatal. Longitudinal studies have identified an increase in the mortality rate from pneumonia in smokers associated with dose-response [125]. In general, cessation of smoking is not associated with a decrease in hospitalization for pneumonia; however, patients without COPD and a greater than 10-year history of not smoking are at a decreased risk [124]. A 2013 study found that children exposed to SHS were four times more likely to develop lower respiratory illnesses, including pneumonia [126]. Proposed explanations of the increased risk for infection in active, passive, and former smokers include increased bacterial adherence, decrease of lung and nasal clearance, and changes in the immune response.

CARDIOVASCULAR COMPLICATIONS

Cardiovascular disease, defined as acute myocardial infarction (MI) and stroke, is strongly related to smoking and comprises 34% of smoking-related mortality; conversely, smoking yields 16% of cardiovascular-related mortality [62]. The relative risk of MI for smokers has been estimated at 2.88 for men and 3.85 for women, and the relative risk of stroke for smokers is estimated at 2.80. These estimates do not include the effects of passive smoking. Low-tar cigarettes and smokeless tobacco have similarly been shown to increase the risk of cardiovascular events among users in comparison to nonsmokers [127]. Cigarette smoking impacts all phases of atherosclerosis, from endothelial dysfunction to acute clinical events. Both active and passive cigarette smoke exposure predispose to cardiovascular events. The exact toxic components of cigarette smoke and the mechanisms involved in smoking that are related to cardiovascular dysfunction are largely unknown, but smoking increases inflammation, thrombosis, and oxidation of low-density lipoprotein cholesterol (LDL-C). Experimental and clinical data support the hypothesis that increased oxidative exposure may be a potential mechanism for initiating cardiovascular dysfunction. Research also suggests that small doses of toxic materials from tobacco smoke cause a nonlinear dose-response effect on cardiovascular function [128]. The risk for cardiovascular disease declines rapidly after smoking is ceased [129].

NEUROLOGIC COMPLICATIONS

Tobacco smoking is strongly related to atherosclerosis and chronic vascular disease. Atherothrombotic ischemic stroke, transient ischemic attack, and atherothrombotic origin symptomatic or asymptomatic peripheral arterial disease are all associated with a high risk of vascular death, MI, and stroke. Exposure to tobacco smoke is a noted risk factor of all these events. A positive association was found between cigarette smoking and subarachnoid hemorrhage (SAH), especially for aneurysmal SAH in women [130].

Evidence is emerging that suggests an association between the development of other neurologic diseases and smoking. A study by Riise et al. identified the risk of multiple sclerosis as higher among smokers than among those who never smoked [131].

Studies have shown that the amount of monoamine oxidase (MAO) is reduced by 30% to 40% in the brains of smokers, compared to nonsmokers or former smokers [132]. This reduction in brain MAO levels may result in an increase in levels of dopamine. It has been suggested that nicotine may have short-term protective actions against mechanisms that cause Alzheimer disease; however, the numerous toxins in cigarette smoke negate any benefit [133]. Though the risk for dementia is slightly higher in smokers, the relative risk for Alzheimer disease is unclear. A 2013 Alzheimer study using a mouse model found that smoking hastens disease onset, exacerbates amyloid pathology, and increases neuroinflammation and tau phosphorylation [133]. Further research is needed in order to better elucidate the risk.

CANCER

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends annual screening for lung cancer with low-dose computed tomography in adults 55 to 80 years of age who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.

http://annals.org/aim/fullarticle/1809422

Last Accessed: May 13, 2019

Level of Evidence: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

In the United States beginning in the early 1950s, a series of epidemiologic, biochemical, pathologic, and animal studies demonstrated a link between cigarette smoking and lung cancer. Tobacco smoking increases the risk of all histologic types of lung cancer. More than 80% to 90% of people who develop lung cancer are current or past smokers. However, not all smokers will develop lung cancer [134]. Cited reasons include the modification of lung cancer risk by previous respiratory disease. In comparison to nonsmokers, smokers are 23 times more likely to develop lung cancer if male and 13 times more likely if female. The risk of lung cancer increases directly with the number of cigarettes smoked and decreases when smoking is ceased. The most important parameter of smoking that affects lung cancer risk is the duration of smoking. Smoking low-tar cigarettes does not substantially reduce the risk of lung cancer [14].

Tobacco smoking is also causally linked to other types of cancer, including oral, oropharyngeal and nasal cavity, urinary tract, larynx, pancreas, esophageal, stomach, liver, cervix, colon, breast, endometrial, prostate, and leukemia. In most cases, the risk increases substantially with duration of smoking and amount of cigarettes/tobacco consumed. Similarly, alcohol in combination with tobacco greatly elevates the risk of many forms of cancer [14].

OSTEOPOROSIS

Smoking can lead to adverse long-term effects on bone health, rendering smokers prone to falls and fractures. Many smokers begin smoking during adolescence—a point in which bone mass is still being constructed; thus, smoking may hinder a person from reaching their maximum bone mass, leaving them fragile and prone to fractures with longer recuperation time [136]. Further, cigarette smoking has been shown to be a key risk factor for osteoporosis and unfortunately, menopausal women are at increased risk due to a loss of estrogen during this period of life. Giampietro and colleagues suggest that a genetic variation in interleukin 6 (IL6) and lipoprotein receptor-related protein 5 (LRP5) observed in smoking white women may confer risk for osteoporosis among smokers [137]. In a study of human-derived osteoblast-like cells and trabecular bone organ culture, Walker et al. demonstrated the presence of the α4 neuronal nicotinic acetylcholine receptor (nAChR) and found that nicotine modulates proliferation in a dose-dependent manner, upregulates c-fos transcription factor, and affects synthesis of osteopontin, a bone matrix protein [138].

PROBLEMS WITH CONCEPTION AND EMBRYONIC HEALTH

Women who smoke prior to pregnancy are more likely to experience a delay in conception and have about 30% higher odds of infertility [139]. Further, men who smoke are at increased risk of erectile dysfunction due to decreased bioavailability of nitric oxide and damage to peripheral nerves, the vascular epithelium, and structure of corporal tissue. Smoking may also affect the quality and mobility of spermatozoa [140,141]. Ramlau-Hansen et al. report a dose-dependent relationship between smoking and sperm concentration, testosterone, luteinizing hormone (LH), and the LH/free testosterone ratio [142].

Success of assisted reproduction therapy (ART) is reduced among smoking couples. In a meta-analysis, Waylen and colleagues found that smokers undergoing ART (e.g., in-vitro fertilization, intracytoplasmic sperm injection, gamete intrafallopian transfer, zygote intrafallopian transfer) had lower odds of live birth per cycle (i.e., birth of one or more infants that show signs of life). They also observed lower odds of clinical pregnancy per cycle (i.e., a sonographically visible gestational sac in the uterus) and higher odds of spontaneous miscarriage and ectopic pregnancy when compared to nonsmokers undergoing the same treatments [143]. A retrospective study published in 2018 found that smoking has a negative effect on endometrial thickness on the day of the embryo transfer, resulting in lower rates of implantation and pregnancy [466].

If conception is achieved (with or without ART), maternal smoking during pregnancy increases the risk for adverse conditions including low birth weight, spontaneous abortion, placenta previa, abruptio placentae, preterm premature rupture of the membrane (PPROM), and overall poor outcomes [144,145].

The miscarriage rate among mothers who smoke may be as high as 33% [146,147]. This may be due to an increased syncytial necrosis and increased thickness of syncytio/cytotrophoblast membrane, as smoking appears to induce dysfunction of villous and invasive trophoblasts early in pregnancy. Additionally, maternal levels of estriol, estradiol, human chorionic gonadotropin, and human placental lactogen are lower in smokers than in nonsmokers [148]. All of these are markers of prenatal health and well-being.

12. COMORBID CONDITIONS

ALCOHOL ABUSE

There is a strong comorbidity between alcohol consumption and tobacco use. Drinkers are more likely to smoke than nondrinkers, and smokers are more likely to drink than nonsmokers [149]. In fact, smokers are 30% more likely to consume alcohol and 10 times more likely to develop alcoholism than nonsmokers. Between 80% and 95% of all alcoholics also smoke cigarettes, and 70% are heavy smokers who consume more than one pack per day [150]. A study examining an association between alcohol and tobacco, using a combination of short-term (1-year) and long-term (15-year) follow-up intervals, found that past-year alcohol and tobacco use disorders were associated not only cross-sectionally, but also prospectively. These associations were present even after controlling for age, gender, and race. Year 1 tobacco dependence prospectively predicted diagnosis with an alcohol use disorder (AUD) at year 2, and a baseline diagnosis of AUD increased the likelihood of diagnosis with tobacco dependence 15 years later. Having been diagnosed with tobacco dependence at year 1 predicted AUD persistence, and vice versa. These findings demonstrate the complex association between tobacco dependence and AUDs [151]. Similarly, a study examining the natural course of AUDs from adolescence to early adulthood found that daily smoking predicted future AUD when adolescent AUD and other disorders were controlled. It is possible that chronic smoking may contribute to alcohol tolerance, increasing alcohol consumption and metabolism [152].

In the instance of nonsmokers, data from a study by Romberger and Grant suggests that patterns of alcohol abuse would be similar in workers exposed to SHS; however, the severity of the alcohol abuse may be less pronounced [153].

DRUG ABUSE

Smoking usually precedes illicit drug use. Among those who used both cigarettes and marijuana by the 12th grade, 65% smoked cigarettes before marijuana, and 98% of those who used both cigarettes and cocaine smoked cigarettes first. Apparently, the earlier a person uses tobacco, the more likely he or she will be to experiment with cocaine, heroin, and other drugs. More than half of those who start smoking before 15 years of age use an illegal drug in their lifetime, compared to only a quarter of those who do not start smoking until 17 years of age or later. Moreover, those who start smoking before 15 years of age are seven times more likely to use cocaine than those who never smoke. Also, heavy smokers are more likely to use marijuana or harder drugs. For example, young people who smoke more than 15 cigarettes a day are twice as likely to use an illicit drug and 16 times more likely to use cocaine than those who smoke less frequently. They are also 10 times more likely to use an illicit drug and 100 times more likely to use cocaine than those who never smoked. Even heavy users of smokeless tobacco are more likely to experiment with drugs. High school students who used smokeless tobacco 20 to 30 days per month were four times more likely to concomitantly use marijuana than nonusers, and almost three times more likely to ever use cocaine [150].

PSYCHIATRIC DISORDERS

Many smokers report a link between smoking and anxiety. Researchers at the National Institute on Drug Abuse hypothesized that impaired respiration and the detrimental effects of nicotine on blood vessels to the brain elucidate why those exposed to smoking are at an increased risk of developing anxiety disorders [154,467].

Smoking is shown to be highly comorbid with such psychiatric disorders as major depression, panic disorder, and schizophrenia. Cigarette smoke has other psychoactive properties apart from nicotinic receptor stimulation. For example, it inhibits MAO, which is the enzyme responsible for breaking down the biogenic amine neurotransmitters norepinephrine, serotonin, and dopamine in the brain [155,156]. Not surprisingly, the association between smoking and major depression is well established [157,158,159]. Reports of severe major depressive episodes after smoking cessation are also common, with the onset of depressive symptoms ranging from two days to six weeks after the initial abstinence from smoking [160,161]. In some cases, depression was alleviated with the use of NRT or antidepressants; in others, depressive symptoms went away after a relapse to smoking [160,162]. In a trial of smoking cessation using fluoxetine (30 mg), 7% of participants with a previous history of major depressive disorder (MDD) were diagnosed with major depressive episodes after a 10-week treatment, suggesting that a subset of smokers may be particularly at risk for developing MDD after smoking cessation [163].

In addition to relieving depressive symptoms or major depressive episodes associated with nicotine withdrawal, antidepressants may aid in long-term smoking cessation by substituting for the antidepressant effects of nicotine that help maintain smoking. They may also have a specific effect on neural pathways (e.g., MAO inhibition) or receptors (e.g., nicotinic-cholinergic receptor blockade) that underlie nicotine addiction. A 2013 Cochrane review assessed the efficacy of antidepressant medications to aid long-term smoking cessation. The majority (75) of the 90 randomized trials included in the review were of bupropion and nortriptyline. The reviewers found high-quality evidence that bupropion significantly increased long-term smoking cessation when used as the sole pharmacotherapy, and moderate-quality evidence (limited by the small number of trials and participants) that nortriptyline also significantly increased long-term cessation. The drugs' effectiveness for long-term smoking cessation was independent of their antidepressant effects, with efficacy similar to NRT [156].

Smoking could also be a risk factor for panic disorder [164,467]. A disproportionate number of persons with panic disorder smoke cigarettes compared to the general population [165]. Mild-to-moderate nicotine dependence was associated with an 11% lifetime prevalence of panic disorder, a rate approximately 2.5 times greater than in persons with no nicotine dependence. Pohl et al. found that female patients with panic disorder had significantly higher smoking prevalence at the onset of their illness than did control subjects (54% versus 35%) and that smoking prevalence for the female patients was also significantly higher than for the control subjects (40% versus 25%) [166]. Male smoking rates did not differ between patients and control subjects.

Although the cause of this comorbidity remains controversial, several explanations have been offered: smoking promotes panic by inducing respiratory abnormalities/lung disease; nicotine produces the physiologic effects characteristic of panic by releasing norepinephrine; cigarette smoking is a form of self-medication for panic disorder; and/or a shared vulnerability promotes both conditions [167]. One study examined the effect of smoking cessation on the reduction of panic symptoms by monitoring the post-cessation abstinence status of 185 smokers. Abstinence was biochemically verified at weeks 1 and 2 and month 1. The severity of panic-relevant symptoms was self-reported by the participants at month 1 and month 3, post-cessation. The 80 participants (43.2%) who remained abstinent for one month, relative to the 105 (56.8%) who did not, demonstrated significant reductions in self-reported panic symptoms [168].

Smoking is also more prevalent in persons with schizophrenia, although reasons for its pervasiveness remain debatable [169,170,171]. Investigators have suggested that nicotine might temper positive or negative symptoms, and cigarette smoking is used as self-medication (e.g., to treat cognitive impairment and anhedonia) [171,172,173,174]. Nicotine may also attenuate the adverse effects of neuroleptics, perhaps by reducing elevated blood levels after use of antipsychotic medications [128,175,176]. Weiser et al. examined the prevalence of cigarette smoking in apparently healthy adolescents later hospitalized for schizophrenia. The number of cigarettes smoked was significantly associated with the risk for schizophrenia. Compared to nonsmokers, adolescents who smoked 1 to 9 cigarettes per day were 1.38 times as likely to be hospitalized later for schizophrenia, and adolescents who smoked 10 cigarettes per day or more were 2.28 times as likely; the latter difference was statistically significant. The authors concluded that the higher prevalence of smoking in future schizophrenia patients might indicate that impaired nicotinic neurotransmission is involved in the pathophysiology of schizophrenia [177]. Bupropion has been found to increase smoking abstinence rates in smokers with schizophrenia [178]. Additionally, a number of medications that target nicotinic acetylcholine receptors have been tested or are in development, but further research is necessary to determine their clinical utility in the treatment of schizophrenia [174].

13. FETAL EXPOSURE

Maternal cigarette smoking before and during pregnancy adversely affects the health of both mother and fetus. However, analysis of data from the 2016 National Vital Statistics Systems (NVSS) indicated that 7.2% of pregnant women in the United States reported smoking during pregnancy [179]. In addition to the effects on fertility and embryonic health discussed, maternal smoking before conception increases the risk of sudden infant death syndrome (SIDS), and smoking at the time of conception increases the risk of infants being born with cleft lip, with or without cleft palate [14,179,180]. A 2010 study showed that as many as 8% of preterm deliveries, 7% of preterm-related deaths, 19% of term low-birth-weight deliveries, and 34% of SIDS cases in the United States were attributable to prenatal smoking [181]. Further, several studies indicate that the offspring of mothers who smoked during pregnancy are at elevated risk of developing nicotine dependence as adults [182,183].

According to 2016 NVSS data, the prevalence of smoking during pregnancy was highest among women who were between 20 and 24 years of age (10.7%), followed by women 15 to 19 years of age (8.5%) and 25 to 29 years of age (8.2%). Among racial groups, the highest rates were found in non-Hispanic American Indian/Alaska Native women (16.7%%), followed by white (10.5%), black (6.0%), Native Hawaiian/Pacific Islander (4.5%), Hispanic (1.8%), and Asian (0.6%) women. Smoking rates were highest among those with a high school diploma or equivalent (12.2%), followed by those with less than 12 years of school completed (11.7%), and women with some college or an associate's degree (7.9%). Less than 1% of women with a bachelor's degree or higher reported smoking during pregnancy [179]. Rates of maternal smoking during pregnancy differ greatly between individual states, with West Virginia (25.1%) and Kentucky (18.4%) reporting the highest percentages, and the District of Columbia (2.6%) and California (1.6%) reporting the lowest. SHS exposure in infancy greatly increases the odds of respiratory tract infections, ear infections, and death from SIDS [14].

Ohida and colleagues performed cross-sectional surveys in Japanese obstetric clinics to investigate the effects of passive smoking on sleep disturbance during pregnancy [185]. Pregnant women exposed to passive smoking were likely to have insufficient sleep, difficulty initiating sleep, short sleep duration, loud snoring, or uncomfortable breathing. These experiences also occurred in pregnant women who were smokers.

Nicotine has a low molecular weight and high lipid solubility, allowing it to cross the placenta freely and accumulate in amniotic fluid. In animal models, nicotine could be identified in fetal tissues as early as five minutes following maternal injection [186,187]. Because less than 5% of nicotine binds to human plasma proteins, the majority of the administered dose is available to equilibrate with fetal circulation [188]. Studies in humans showed that nicotine is readily transferred to the fetal compartment throughout pregnancy, with accumulation in placental tissue and amniotic fluid [189]. Apparently, a significant amount of nicotine is retained by the placenta and may later transfer to fetal and maternal circulation, thus prolonging the effect of nicotine on the fetus [188].

Acetylcholine causes dilation of blood vessels and maintains placental blood flow by the activation of endothelial muscarinic receptors. Nicotine blocks acetylcholine-facilitated amino-acid transport, depressing diffusion of amino acids and other nutrients from the trophoblast into placental circulation. Maternal smoking actually leads to trophoblast apoptosis and thickening of the trophoblast basement membrane [190,191]. Further, CO from tobacco smoke crosses the placenta by passive diffusion, leading to increased carboxyhemoglobin in umbilical cord blood and placental hypoxia. The resultant hypoxia causes fetal growth retardation and alteration in the physiologic development of organs and tissues [192].

PHARMACOKINETICS AND DYNAMICS

Among pregnant smokers, maternal levels of cotinine correlate better with outcome measures such as birth weight than the number of cigarettes smoked per day [193]. Cotinine can accumulate in fetal compartments as early as 7 weeks' gestation in both active and passive smokers [194]. Of note, the half-life of nicotine is three to four times longer in newborns than in adults, whereas the half-life of cotinine is similar in newborns and adults. The prolonged elimination of nicotine, but not of cotinine, in the newborn compared with that in the adult may be a result of different newborn cytochrome P450 2A6 (CYP2A6) enzymatic substrate specificity, low CYP2A6 activity with another enzyme that is primarily responsible for cotinine metabolism, or differences in tissue distribution [195]. Also, pregnancy is well known for affecting metabolism of some drugs and may contribute to higher or lower clearances compared with the nonpregnant state [196]. Indeed, metabolic clearance of both nicotine and cotinine are substantially increased during pregnancy, resulting in a marked decrease in the half-life of cotinine. The mechanism for such increase in metabolic clearance is not known. It is possible that nicotine and cotinine clearances are accelerated by faster oxidation via CYP2A6 and faster glucuronide formation. Although nicotine and cotinine share the same metabolizing enzymes, their increased clearances may occur by different physiologic mechanisms. Nicotine is a rapidly cleared drug with a high affinity for CYP2A6, and the rate of clearance is primarily controlled by liver blood flow. Cotinine is a slowly metabolized chemical, with a low affinity for CYP2A6 relative to nicotine. The level of CYP2A6 in the liver, which is markedly elevated during pregnancy, primarily determines the rate of cotinine metabolism. A substantial increase in the percentage of nicotine and cotinine excreted as their glucuronide conjugates is also observed in pregnancy, but there is no increase in the percentage of 3'-hydroxycotinine excreted as a glucuronide. This suggests an acceleration of nicotine and cotinine metabolism via the N-glucuronidation pathway, but no effect on hydroxycotinine metabolism by the O-glucuronidation pathway. Also, the profile of nicotine and its metabolites in urine is altered during pregnancy. The excretion of nicotine is substantially decreased, and despite large differences in plasma cotinine concentration during smoking, there is no difference between the daily dose of nicotine absorbed from cigarette smoking during and after pregnancy [197].

NEUROLOGIC COMPLICATIONS

Fetal nicotine exposure can result in permanent abnormalities of the dopaminergic regulation of the brain [198]. These effects can occur even at low nicotine doses and lead to a greater nicotine dependence [182]. Unlike in mature organisms, where stimulation of a target cell elicits only a short-term response, receptor stimulation in the developing systems interacts with the genes controlling cell differentiation, permanently altering the cells' responsiveness. Nicotine exposure to the prenatal brain may also prematurely stimulate the shift from proliferation to differentiation; thus, nicotine may act as a cholinergic signal, mimicking trophic effects of acetylcholine. Because of the close regulatory association of cholinergic and catecholaminergic systems, adverse effects of nicotine involve multiple transmitter pathways and influence not only the immediate developmental events in the fetal brain but also the eventual programming of synaptic competence. Therefore, defects may appear after a prolonged period of apparent normality, leading to cognitive and learning defects that appear in childhood or adolescence. Similar modifications occur in peripheral autonomic pathways, leading to increased susceptibility to hypoxia-induced brain damage and perinatal mortality [199]. These changes are especially prominent in tissues rich in nicotinic cholinergic receptors, such as the brainstem [200].

Prenatal exposure to nicotine produces alterations in tegmental nuclei related to the following [201]:

- Cardiopulmonary integration (nucleus tractus solitarii, parabrachial complex)

- Regulation of arousal, attention, and rapid eye movement (REM) sleep (mesencephalic and pontine reticular formation)

- Somatic motor control (paramedian pontine and medullary reticular formation)

- Tongue and upper airway regulation (hypoglossal nucleus)

Autonomic deregulation could explain the inhibition of some homeostatic reflexes seen in infants exposed to tobacco smoke, including a deficiency in arousal responsiveness to hypoxia or hypercapnia [202]. Roy et al. evaluated cellular morphology and regional architecture in the juvenile and adolescent hippocampus and the somatosensory cortex in rats prenatally exposed to nicotine. They found a substantial decrease in cell size in the hippocampal CA3 region and dentate gyrus, with corresponding decrements in cell layer thickness and increments in cell packing density. Smaller, transient changes were seen in CA1. There was a reduction in the proportion of medium-sized pyramidal neurons in layer five of the somatosensory cortex and an increase in the proportion of smaller, nonpyramidal cells. All regions showed elevated numbers of glia. These data demonstrate that prenatal nicotine exposure compromises neuronal maturation, leading to long-lasting alterations in the structure of key brain regions involved in cognition, learning, and memory [203].

PULMONARY COMPLICATIONS

Fetal growth and duration of gestation are the major factors affecting lung development [204]. Intrauterine influences that retard fetal weight gain may irrecoverably restrict the growth of the airways, with consequences persisting throughout the individual's life span. Fetal exposure to nicotine is associated with several abnormalities in lung growth. In animal studies, nicotine has been shown to directly interact with nicotinic acetylcholine receptors in pulmonary vessels, altering connective tissue expression and producing vascular structural alterations [205]. Furthermore, maternal nicotine exposure results in larger alveolar volumes and suppresses alveolarization in the lungs of the offspring of rats, reducing the surface potentially available for gas exchange [206,207]. Human smokers have a high rate of poor perfusion patterns, suggesting that smoking during pregnancy may compromise uteroplacental blood flow and contribute to poor fetal development [208,209].

CARDIOVASCULAR COMPLICATIONS

Maternal smoking during pregnancy poses severe risks to the developing fetal heart. Nicotine alters cardiac cell differentiation to increase the cellular injury caused by hypoxia [210]. Prenatal nicotine exposure interferes with the ability of neonatal adrenal glands to secrete catecholamines in response to hypoxia [200]. Given that the neonatal heart lacks functional sympathetic innervation, there is virtually a complete dependence on circulating catecholamines secreted by the adrenal medulla to maintain heart rate response to hypoxia. Nicotine exposure reduces the number of cardiac ß-adrenergic receptors, magnifying functional consequences of impaired catecholamine release [211]. The resultant impaired cardiac function can lead to cardiovascular collapse, subsequent brain damage, and/or death during delivery [212,213].

Adenosine diphosphate (ADP) is a major factor in determining electrical stability of myocytes, because the longer the action potential, the higher the likelihood of abnormal cardiac activity [214]. It is possible that a component in smoke temporarily disables electrical properties of ventricular myocytes, rendering the ventricular muscle more susceptible to developing arrhythmias [215].

Fetuses exposed to smoke also manifest an increase in cardiac volume growth between 23 and 27 weeks' gestation [216,217]. This could be attributed to either an exaggeration of normal cardiac growth patterns or a compensatory response to an increase in upper body growth at the time.

LOW BIRTH WEIGHT AND SMALL FOR GESTATIONAL AGE

Infants born to mothers who smoke weigh less than other infants (independent of maternal body mass index), and low birth weight (<2,500 grams) is a key predictor for infant mortality. Effects of maternal smoking during pregnancy on infant birth weight have been recognized since 1957; nevertheless, smoking remains the most hazardous factor affecting a newborn's weight, even at present [218,219,220]. Similar to earlier studies, Bernstein and colleagues report that maternal third-trimester cigarette smoking is one of the strongest predictors of low birth weight. This study is thought to be the first to accurately assess maternal smoking levels, and startlingly, they purport that there is an estimated 27 g reduction in birth weight per cigarette consumed each day during the third trimester, or roughly twice the amount previously shown [220]. Another study found that 11.5% of infants born to women smoking less than six cigarettes daily had low birth weight [221]. Taken together, these studies demonstrate that there is not a safe level of smoking during pregnancy [221,222]. Additionally, Aagaard-Tillery et al. reported that tobacco-exposed infants were small for gestational age regardless of maternal body mass index or pregnancies complicated by diabetes or hypertension [223].

A study examining the effect of prenatal smoke on a fetus in midgestation identified greater early gestational upper-body growth with preferential growth of head dimensions, upper limb length, and abdominal circumference with smoke exposure. This was followed by decreases in biparietal dimensions of the head, abdominal diameter, and distal limb length. Data from the late gestation period revealed cranial dolichocephaly, proportionally longer upper limbs, and legs with relatively reduced tibias, indicating that smoke exposure altered the growth rate of individual body segments [216]. It is possible that during hypoxia, blood supply to the lower limbs and internal organs is reduced in order to preserve brain metabolism [224]. Retardation of limb growth by 32 weeks could be due to diminished oxygen availability for distribution to distal tissues. The tibia, being one of the last consumers in the fetal nutrient distribution food chain, is therefore regarded as a good marker of available oxygen resources [216].

MIDDLE EAR DISEASE

Passive smoke exposure is independently associated with an increased risk of otitis media [222,225,226]. Though the immediate complications of otitis media are significant, one must also consider the lasting complications including an increased prevalence of speech and language difficulties, attention disorders, and learning difficulty [226]. The mechanism by which cigarette smoke causes otitis media is currently unknown. Histologic changes in fetal alveolar and bronchial epithelium lend support to a contemporary theory that purports that fetal cigarette smoke exposure may interfere with the development of the middle ear and eustachian tube epithelium. An alternative theory proposes that passive smoke-related immune system depression allows for opportunistic middle ear infections [226].

CANCER

One of the potentially negative effects of smoking during pregnancy is exposure of the fetus to carcinogens [227,228]. The potent tobacco-related carcinogen 4-aminobiphenyl has been shown to cross the human placenta and bind to fetal hemoglobin [229]. Two metabolites of the tobacco-specific transplacental carcinogen NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide (NNAL-Gluc), were detected in the urine from newborns of mothers who smoked cigarettes during pregnancy [144]. Studies relating childhood and in utero cigarette exposure to brain tumors and leukemia have been inconsistent in their findings [230]. A meta-analysis of the association between exposure to maternal tobacco smoke during pregnancy and cancer in childhood found a small increase in risk of all neoplasms (based on 12 studies) but not of specific neoplasms such as leukemia (based on 8 studies) and CNS tumors (based on 12 studies) [231].

OSTEOPOROSIS

Maternal smoking has been shown to modulate bone mineral acquisition for the fetus, which may lead to increased risk of osteoporosis later in life [232].

PSYCHIATRIC DISORDERS

Previous studies have reported an association between maternal smoking during pregnancy and behavioral problems such as hyperactivity and decreased attention span. The association with behavioral problems has been shown in investigations of hyperactive children and controls, sibling studies in which the mother smoked in one pregnancy but not in the other, and in neuropsychologic evaluations of children of smokers and nonsmokers using tests of sustained vigilance and attention [233,234,235,236]. Naeye and Peters found that hemoglobin levels in neonates increased with the number of cigarettes smoked by the mother during pregnancy and that children who were more active or had shorter attention spans had significantly higher hemoglobin levels [235]. Further, early secondhand exposure to nicotine as a child via maternal smoking during pregnancy shows an association with offspring attention deficit hyperactivity disorder (ADHD) symptoms [237,238]. Evidence also supports a statistical association between prenatal smoking and increased risk for antisocial outcomes in offspring. Maternal smoking during pregnancy has been shown to be associated with a significant increase in externalizing behavior (tendency to seek controversy, aggressive, hyperactive) but not internalizing behavior (withdrawn, depressed, anxious) problems [239]. Similarly, maternal smoking during pregnancy has been shown to have an adverse effect on the child's negativity [240]. In a sample of 99 children 2 years of age, maternal smoking was identified as a significant predictor of childhood negativity, independent of demographic factors, perinatal factors, maternal personality attributes, and the mother-child relationship. Behavior problems associated with in utero exposure to SHS seem to continue into childhood and young adolescence, demonstrated by increased risk for ADHD, conduct disorders, criminality, and substance abuse [241]. An 18-year epidemiologic study of 1,265 New Zealand children identified that maternal smoking during pregnancy contributed to risk of higher psychiatric symptom rates for conduct disorder(s), alcohol abuse, substance abuse, and depression [242,243].

14. PASSIVE SMOKING EFFECTS ON CHILDREN

It is possible that SHS exposure during childhood may be potentially more hazardous to neurodevelopment than in utero exposure to maternal smoking. Young children have higher ventilation rates, meaning they receive higher levels of SHS for the same duration and level of external exposure [244]. Passive smoking is believed to increase the prevalence of sudden infant death syndrome (SIDS); exacerbate asthma symptoms; interfere with cognition and behavior; increase cancer risk; and cause respiratory tract illness [226,245,246]. Breastfed infants with a smoking or snuff-taking mother are exposed to nicotine in breast milk, with a mean intake of nicotine of 7 mcg/kg per day [247]. Older children experience decreased physical fitness and are susceptible to tobacco-related illnesses just as adult smokers are.

Evidence Based Practice Recommendation

The National Heart, Lung, and Blood Institute recommends promoting a smoke-free home environment for all children and reinforcing this message at every encounter, including urgent visits for respiratory problems.

https://www.nhlbi.nih.gov/node/80308

Last Accessed: May 13, 2019

Level of Evidence: A (Well-designed randomized controlled trials or diagnostic studies performed on a population similar to the Guidelines' target population)

Aside from adverse health effects due to SHS exposure, parental smoking is also positively correlated to their offspring's smoking as adolescents and adults. Counseling parents on the adverse health effects of SHS on children has been shown to dramatically reduce their children's subsequent cigarette smoke exposure [6,246]. Smokers should be encouraged to smoke outside their homes and minimize SHS exposure to their children [248]. However, studies have shown that, though smoking outdoors decreases SHS exposure, children of parents who smoke outdoors still have higher prevalence of ear infections and respiratory symptoms than children of nonsmokers [249].

NEUROLOGIC EFFECTS

Prenatal and perinatal exposure to SHS adversely affects neurobehavioral development. Evidence now supports the notion that tobacco-exposed infants are more excitable and hypertonic, require more handling, and show more stress and abstinence signs than infants not exposed to tobacco. Symptoms are particularly noteworthy in the CNS, gastrointestinal system, and visual areas [250]. The presumed neurobiologic effect of SHS is altered brain development resulting from fetal hypoxia, due to either nicotine acting to reduce blood flow to the fetus, or possibly CO, which produces higher levels of carboxyhemoglobin. Nicotine may also target specific neurotransmitter receptors in the fetal brain to discoordinate the events of cell replication, differentiation, and synaptic development in the brain. Nicotine is thought to disrupt brain development via cholinergic mechanisms. In rats, exposure to nicotine alone has been shown to result in a significant increase in acetylcholinesterase (AChE) activity in the brainstem and midbrain. A significant increase in ligand binding to nAChR has been observed in the brainstem and cortex following exposure to nicotine. This suggests that exposure to nicotine may impair neurobehavioral performance and affect the cholinergic pathways [251].

In another study, postnatal SHS reduced hindbrain (comprising the pons and medulla oblongata) DNA concentration, increased the protein-to-DNA ratio, and reduced the body weight of exposed rats. These data suggest that postnatal exposure to SHS affects the hindbrain, a region that undergoes significant postnatal growth, by reducing the total number of cells and by increasing cell size. The authors concluded that, despite preserved hindbrain weight, the effects of postnatal exposure to SHS might result in neurologic dysfunction [252]. This study provided clear biologic evidence for an alteration of brain development due to postnatal, but not prenatal, SHS exposure. Interestingly, although gross dysmorphology is demonstrable in the animal brain by SHS exposure to nicotine, brain structures are not grossly abnormal when examined later in adolescence or adulthood [203]. However, longer-lasting changes in morphology are noted in the hippocampus and somatosensory cortex in the form of decreased cell size and elevated numbers of glia. In considering synaptic function, several neurochemical studies have identified multiple biochemical markers of cell injury that indicate prenatal nicotine exposure damages the developing brain [253,254].

CARDIAC COMPLICATIONS

Nicotine exposure causes myocyte cell damage in newborns, reduced platelet activation, increased resting sympathetic nerve activity, and hypertension. In rats, exposure to SHS during the neonatal period resulted in abnormal vasoconstrictor and vasodilator responses and smooth muscle dysfunction [255]. Abnormalities of endothelial cell function were found in rabbits exposed to SHS for 3 to 10 weeks [256]. Exposure to SHS also appears to directly affect endothelial function in children by means of a dose-dependent decrease in the bioavailability of nitric oxide [257]. Exposure to SHS also caused left ventricular hypertrophy in rabbits [258]. SHS exposure in childhood reduces high-density lipoprotein levels [259]. In addition, adolescents exposed to their parents' smoke show depressed levels of high-density lipoprotein cholesterol (HDL-C), suggesting that SHS exposure may accelerate atherosclerotic change and place children at increased risk for the premature development of coronary artery disease [260,261].

SIDS

SIDS occurs within the first year of life and is a significant cause of infant mortality, with an estimated 1,400 deaths in the United States annually [262]. SIDS is a diagnosis of exclusion, and etiology is presently unclear. Various risk factors have been suggested including prone sleeping position, sex, age, birth weight, parental cigarette smoking, maternal substance abuse, bed sharing, soft bedding, and overheating [262,263]. Matturi et al. found evidence supporting an association between maternal smoking and SIDS. Specifically, CO from cigarette smoke forms carboxyhemoglobin, leading to brain hypoxia. This lack of oxygen inhibits normal brain development of the arcuate nucleus and normal brain function in the locus coeruleus and arcuate nucleus. These abnormalities could potentially affect control of the respiratory and cardiovascular systems, resulting in sudden unexplained infant death. Matturi et al. concluded that the most preventable risk factor for SIDS is maternal smoking during pregnancy [264]. Zhang et al. concluded that the association between maternal smoking and elevated SIDS risk is dose-dependent and significantly increased in infants who co-sleep with smoking mothers [265]. Another study that sampled pericardial fluid in SIDS cases found that 70% had elevated levels of cotinine [266].

PULMONARY COMPLICATIONS

Children with smoking parents demonstrate higher frequencies of common respiratory symptoms including cough, phlegm, asthma, breathlessness, and wheeze. Parental smoking inhibits lung growth and function during childhood [267,268,269,270]. One study assessed the pulmonary function of 80 healthy infants soon after birth and found significantly reduced pulmonary function in infants whose mothers had higher urine cotinine concentrations [271]. Another study demonstrated an association between in utero nicotine exposure and variable DNA methylation in fetal lung and placental tissues, suggesting that this variation may have a role in the fetal origins of chronic diseases [272].

Cough/Wheeze

Both past and current SHS exposure has been shown by multiple studies to cause cough and wheeze in children. Joad et al. worked with guinea pigs to establish the mechanism by which air pollutants, particularly SHS, causes cough. Secondhand smoke modifies afferent sensory fibers (specifically C-fibers and rapidly activating receptors) in the lungs and airways, thereby activating a neurally controlled cough mechanism. The vagus nerve receives input from the afferent sensory fibers, which is modified by interneurons in the nucleus tractus solitarius (NTS). A few additional modifications of the efferent activity occur in the brain stem. Cough occurs when the efferent signal modifies input to the respiratory muscles involved in inspiration and expiration. Wheeze occurs with bronchoconstriction and mucus secretion, which can be caused by locally released neurokinins or parasympathetic fibers synapsing on airway ganglia [64].

Asthma

Asthma is a chronic inflammatory disease, often with an initial onset in childhood. An association has been established between exposure to passive tobacco smoke and pediatric asthma development, while a causal relationship has been shown between exacerbated pediatric asthma and environmental tobacco exposure [273,274]. Cigarette smoke causes an "exaggerated bronchoconstrictor response" in asthmatics, leading to an increase in severity and frequency of acute asthma attacks as well as asthma-related hospitalizations [275]. Studies have shown a decreased respiratory drive and hypoxic ventilatory response in infants of smoking mothers [247]. Exposure to nicotine for the full gestation produced an increased risk of depressed hypoxic ventilatory response in rats [18]. Parents of asthmatic children should be strongly cautioned that smoke exposure is likely to dramatically worsen their child's asthma [276,277].

DENTAL CARIES

Each year, several billion dollars are spent treating pediatric dental caries in the United States. Dental caries are an oral infectious disease caused by Streptococcus mutans colonization and subsequent lactic acid production leading to dental decay. In addition to poverty, passive smoking is a substantial risk factor for developing dental caries. The reason for an increased prevalence of dental caries in children of low socioeconomic status is unclear. However, as poor children are more likely to be exposed to SHS, it has been suggested that environmental tobacco smoke exposure may help explain the increased dental decay in this particular population. Environmental tobacco smoke is considered a causal factor for dental caries in primary but not in permanent teeth. Mechanisms for the role of cigarette smoke in the development of pediatric dental decay include nicotine promotion of bacterial growth; immunosuppression from environmental tobacco smoke; decreased levels of vitamin C leading to increased bacterial growth; passive smoking-related saliva reduction, which impairs the natural defense against bacteria-related acid production; and a general increase in inflammation [278].

VITAMIN DEFICIENCY

Vitamin C (ascorbic acid) deficiency is common among active smokers due to both increased metabolism and decreased dietary consumption [68]. Cigarette smoking-induced oxidant damage is caused by both the immune system's inflammatory response and free radicals in cigarette smoke. Vitamin C and other antioxidants play an important role in preventing oxidant-induced damage.

Studies have supported a dose-dependent inverse relationship between environmental tobacco smoke exposure and ascorbic acid and beta carotene concentrations [68,279]. A 2011 study found that children with no SHS exposure had higher levels of vitamin A, C, and E, beta carotene, and folate (controlling for dietary and supplement intake) than children with either moderate or high SHS exposure [279]. A lower concentration of these key nutrients was associated with higher cotinine levels. Vitamin B6, B12, and D levels were not found to be significantly affected.

RESULTANT SYMPTOMS IN ADULTHOOD

The relationship between childhood passive smoke exposure and resultant health consequences in childhood has been firmly established. There is less known about the long-term respiratory effects of childhood passive smoke exposure. David et al. studied Chinese adults from the Singapore Chinese Health study who were exposed to cigarette smoke as children but never actively smoked, thereby eliminating active smoking as confounding bias often found in similar studies. They found an association, independent of adult SHS exposure, between childhood environmental tobacco smoke exposure and chronic dry cough and phlegm production. Other findings included a lack of an association between childhood SHS exposure and asthma or chronic bronchitis. Also, they found low-fiber predisposed patients to respiratory maladies [280]. One study found a 50% increase in adult-onset cancer for children whose fathers smoked, and the risk of hematopoietic cancer increased when both parents smoked [281].

Peppone et al. reported that never-smoking women who grew up with a smoking parent may have more difficulty becoming pregnant. Those exposed to SHS regularly in childhood and adulthood were 39% more likely to have suffered a miscarriage or stillbirth and 68% more likely to have trouble conceiving when trying for more than one year [282]. Further, among women exposed to environmental tobacco smoke in youth undergoing ART between 1994 and 1998, there was decrease in implantation rate and increased odds of spontaneous abortion [65].

In a study by Strohsnitter et al., early menopause was more likely to occur in never-smoking women exposed to maternal cigarette smoke. They attribute this association to smoke's effects on follicle production in utero [283].

15. PASSIVE SMOKING EFFECTS ON ADULTS

The International Agency for Research on Cancer (IARC) Working Group concluded that secondhand tobacco smoke is carcinogenic to humans [284]. Complications of exposure to SHS include adverse effects on the pulmonary, cardiovascular, and neurologic systems as well as increased risk for cancer and fibroblast changes.

OCCUPATIONAL EXPOSURE

Occupational exposure to SHS affects the health of countless employees worldwide. Workplace exposure is highly influenced by the type of smoking policy in the workplace. Airborne nicotine is present, often in excessive concentrations, in various job settings due to variable public smoking laws [285,286]. Local and state regulation of smoking in public places was instituted in response to data published by the American Society of Heating, Refrigerating and Air Conditioning Engineers (ASHRAE). These standards assert that satisfactory indoor air quality cannot be maintained if smoking is allowed indoors, even with additional ventilation and air-cleaning devices [287]. Several studies have shown that smoke-free workplace policies decrease exposure of nonsmoking employees to SHS at work, while increasing rates of smoking cessation and decreasing the number of employees who smoke [14,288,289,290,291]. Policies that are less restrictive are associated with higher levels of sustained tobacco use among employees [290]. Policies that make indoor workplaces smoke-free result in improved worker health [290,292]. For example, smoke-free polices in the hospitality industry have been shown to improve health among bar workers, who are often heavily exposed to SHS in the absence of such policies [184,290,293].

Studies have shown that segregating smokers and nonsmokers within the same airspace reduces SHS exposure to nonsmokers but does not eradicate it. One such study, in smoking-segregated restaurants in Albuquerque, New Mexico, showed levels of nicotine in nonsmoking sections approximately equal to those found in smoking sections [294].

SHS remains an issue for those employed in some casinos, bowling alleys, restaurants, lounges, and bars [295]. These work environments can contain high concentrations of airborne nicotine in the air if there is a lenient smoking policy. One study found that male blue-collar workers are exposed to significantly more SHS than their counterparts in management/professional occupations [296]. Also, on average, blue-collar smokers smoke more heavily than white-collar smokers [296]. Interestingly, female blue-collar workers are far less likely to smoke than women in management/professional occupations [296]. However, women's SHS exposure is approximately equal regardless of occupation, and SHS exposure is lowest for female service industry workers.

In 1986, the National Academy of Sciences warned, "SHS (also called environmental tobacco smoke) is a hazardous substance and is the most frequent source of complaint about aircraft air quality. Because of the high concentration of SHS generated in the smoking zone, it cannot be compensated for by increased ventilation in that zone" [297]. The area, volume, and ventilation rate per smoker on an aircraft is the smallest of any workplace setting. However, essentially all airlines now prohibit smoking on their planes.

Overall, exposure to SHS in different microenvironments is based on the strength of the active source, the ventilation system, and the presence and effectiveness of air-cleaning devices. Personal SHS exposure is also affected by age, gender, and race. Constant exposure to SHS at workplaces leads to various complications to the exposed workers.

HEART DISEASE

SHS is estimated to cause 5% to 30% of premature deaths from heart disease each year in the United States among nonsmokers [14,298]. A key difference between the effects of smoking on the risk of cancer compared with the risk of heart disease is that the effects on cancer develop slowly, whereas the effects of smoking on the cardiovascular system occur rapidly. Passive smoking has been shown to cause atherosclerosis in both animal and human models, increase platelet aggregation, and increase myocardial oxygen demand. Multiple epidemiologic studies have consistently found an increased relative risk of cardiac events in nonsmokers with regular SHS exposure [299,300]. Investigators demonstrated through experimentation that 30 minutes of exposure to SHS compromised the endothelial function in coronary arteries of nonsmokers so that the endothelial response of nonsmokers was identical to that of routine smokers [301].

The CDC asserts that people at risk for heart disease should avoid SHS because it can increase one's risk of acute MI. A study was conducted to verify this assertion and concluded that smoking bans at public working places correlate with a reduced morbidity from heart disease [302]. Researchers have suggested that platelet activation, endothelial dysfunction, and broad inflammation may have some relevance [303]. Another theory states that even light exposure to smoke concomitantly restricts blood vessels and allows for blood clotting. This combination raises the risk for MI.

Atherosclerosis

Atherosclerosis, a chronic inflammatory atheromatous disease characterized by focal, noncircumferential, and (most often) proximal plaques, is a major underlying cause of cardiovascular disease, which continues to be the leading cause of death, accounting for 840,678 deaths in the United States in 2016 [304]. Monocytes play a key role in the pathogenesis of atherosclerosis. Monocytes migrate from the blood to the subendothelial space beneath injured endothelial cells, where they differentiate into macrophages. These subendothelial macrophages readily take up oxidized LDL, becoming "foam cells." Collections of "foam cells" are dubbed "fatty streaks" and may first appear in the aorta at 10 years of age. Fatty streaks are precursors to atherosclerotic plaques. Such plaques are advanced lesions characterized by the accumulation of lipid-rich necrotic debris and smooth muscle cells [63,305]. Triggers of endothelial cell injury include hyperlipidemia; bacterial or viral infection; oxidative stress through abnormal regulation of reactive oxygen species, hypoxia, turbulent blood flow, and shear stress; and environmental irritants, such as tobacco smoke [306].

Yuan et al. exposed transgenic human apoB-100 mice to sidestream whole smoke (SSW) (a major component of SHS) in order to study the effects of SHS on atherosclerosis. The transgenic mice received SHS exposure comparable to SHS exposure a nonsmoker would receive from a typical smoking housemate. They found a decrease in plasma HDL-C levels; a decrease in the ratio between HDL-C and triglyceride; and a decrease in ratio between HDL-C and total cholesterol. Yuan et al. noted increased lipid accretion in the aorta, heart vessels, and hepatocytes corresponding to the noted blood lipid profile alterations. Furthermore, they found increased levels of monocyte chemoattractant protein-1 (MCP-1) in blood, heart tissue, and aortic tissue. Increased numbers of macrophages were noted in arterial walls. This finding was significant as MCP-1 is a chemokine that attracts monocytes to the damaged subendothelial cells in the process of plaque formation. Decreased adiponectin monomer levels were noted in the smoke-exposed mice [63]. Adiponectin is an adipocyte-specific plasma protein with potential anti-atherogenic properties. In vitro, adiponectin suppresses the endothelial inflammatory response, the proliferation of vascular smooth muscle cells, and the transition of macrophages to foam cells [307]. Finally, based on examination of the cytokine profile, Yuan et al. determined that cigarette exposure caused a permanent pro-inflammatory state; the normal adaptive response (i.e., initial pro-inflammatory Th1 type cell-mediated response to a Th2 mediated immune response) did not occur [63].

Coronary Heart Disease

A strong association between active smoking and coronary heart disease has been well established, and one study found a 50% to 60% increase in risk for coronary heart disease development in passive smokers [308,309]. Active and passive smoking are known to [310]:

- Increase the incidence and frequency to cardiac arrhythmias

- Decrease the oxygen-carrying capacity of blood

- Increase the incidence of coronary artery spasm

- Promote atherosclerosis, thereby increasing the risk of cardiovascular disease

- Increase the incidence and tendency for thrombosis

The relationship between SHS and coronary heart disease is supported by a study that shows exposure to SHS is associated with increased inflammatory markers, including higher white blood cell counts and levels of C-reactive protein, homocysteine, fibrinogen, and oxidized LDL-C [311]. The intensity of inflammation markers was proportional to the number of years of reported exposure to SHS. Furthermore, subjects with only occasional SHS exposure also experienced increased levels of inflammatory markers, showing that even low SHS exposure is a significant concern. Increased coronary risk is mechanistically mediated by increased platelet aggregation, reduced oxygen uptake and exercise capacity, accelerated lipid peroxidation, and endothelial damage by SHS [312,313,314]. Passive smoke causes arteriosclerosis by altering cholesterol concentrations or by accelerating lipid peroxidation via reductions in serum antioxidant defense [315].

Many elements of tobacco smoke, including CO, nicotine, and polycyclic aromatic hydrocarbons, contribute to the damaging effects on the cardiovascular system. Studies of the effects of tobacco smoke on platelet sensitivity suggest that nicotine is not the sole cause of increased aggregation. Burghuber et al. compared the sensitivity of platelets to the antiaggregatory action of exogenous prostacyclin (PGI2) in nonsmokers and smokers exposed to SHS for 20 minutes. No change was observed in the smoking subjects' platelet sensitivity to PGI2 after SHS exposure, but the smokers' platelets were significantly lower than that of the nonsmoking subjects' before SHS exposure. The nonsmoking subjects experienced significant changes in sensitivity to PGI2 with reported platelet sensitivities matching those of smokers after SHS exposure [316]. However, another study by Benowitz et al. showed that smokers and abstinent smokers with nicotine patches differed significantly in platelet activity despite similar nicotine levels [317]. Thus, nicotine is not the only component of tobacco smoke that mediates increased platelet aggregation.

A British regional heart study examined 4,729 men 40 to 59 years of age and found a 50% to 60% increase in coronary heart disease caused by exposure to SHS [309]. This study is significant because most studies on the relationship between SHS and coronary heart disease either show significant risk increases or only show modest risk increases. Whincup et al. used cotinine measurements to determine passive exposure to smoking. This study noted that although high cotinine levels were associated with an excessive risk of coronary heart disease, they showed little association with the risk of stroke. Whincup et al. offered an explanation for the underestimated association between serum cotinine and coronary heart disease, in that the association tends to decrease over long follow-up periods since assessment of exposure. Finally, this study suggested that risks associated with passive smoking are widespread among nonsmokers.

The American Heart Association's Council on Cardiopulmonary and Critical Care, the Scientific Committee on Tobacco and Health in the United Kingdom, and the California Environmental Protection Agency have all concluded that SHS increases the risk of heart disease [318,319,320].

STROKE

According to findings of the Health and Retirement Study, a national longitudinal study of U.S. adults 50 years of age and older and their spouses, never-smokers with spouses who were current smokers had a 42% increased risk of first stroke. Former smokers married to current smokers had a stroke risk similar to respondents who were current smokers [321].

LUNG DISEASE

Environmental tobacco smoke exposure is associated with respiratory symptoms, asthma, a slight impairment of lung function, and increased bronchial responsiveness [322]. A Swiss study on air pollution and lung diseases with a sample of 4,197 nonsmoking adults, showed that SHS was associated with increased risk of asthma, wheezing, bronchitis, and dyspnea [323]. Greater levels of cumulative exposure to tobacco smoke in the home and workplace are also associated with an increased risk of COPD [324]. It is estimated that a (hypothetical) elimination of SHS in home and work environments would decrease COPD diagnoses in the United States by 18% (or 11% and 7%, respectively).

In a report by Schick and Glantz of unpublished in vivo research done by Philip Morris during the 1980s, inhaled sidestream smoke was found to be four times more toxic per gram of total particulate matter than mainstream smoke. They report that the gas/vapor phase of sidestream smoke is responsible for most of the sensory irritation and respiratory tract epithelium damage that occurs [325].

Asthma

SHS is an established trigger for the onset of asthma in children, and there is growing evidence that it is also a causal factor for asthma in adult nonsmokers [326]. Finland researchers found that subjects exposed to tobacco smoke in the workplace were twice as likely to develop asthma as those who were not exposed. Health effects for adult asthmatics include asthma attacks; increased sensitivity and reduced lung function; and irritation of the eyes, nose, and throat. Exposure to cigarette smoke for just one hour can cause 20% deterioration in short-term lung function of adults with asthma [327].

CANCER

Lung cancer holds the distinction as "the first disease linked definitively" to both active and passive smoking [299,328,329]. Zhong et al., based on epidemiologic studies, estimate a 30% risk of lung cancer in nonsmokers exposed to environmental tobacco smoke. Chinese women have one of the highest incidences of lung cancer in the world, yet active smoking does not appear to be a major risk factor for lung cancer in this population [328]. Smoking among Chinese women is relatively rare, and among those who do smoke, cigarette consumption is limited. However, smoking among Chinese men is especially common, so their spouses are exposed to considerable quantities of environmental tobacco smoke. Thus, nonsmoking Chinese women were an ideal population for a case-control study considering the effects of environmental tobacco smoke on lung cancer. Certain histologic types of lung cancer are more commonly associated with active smoking. The risk of developing squamous cell and small cell cancer is much higher than the risk of developing adenocarcinoma and large cell carcinoma [330,331]. The study by Zhong et al. showed that passive smoking also favors the development of squamous cell and small cell lung cancers over adenocarcinoma and large cell carcinoma [328].

Zhong et al. conducted a meta-analysis study on the relationship between lung cancer and environmental tobacco smoke. They found a 48% increased risk of lung cancer in nonsmoking males exposed to environmental tobacco smoke in their homes, while nonsmoking males had a 29% increased risk of lung cancer if exposed to smoke at work. A 20% increased risk of lung cancer was noted in nonsmoking females exposed to smoke in their homes, while nonsmoking females had a 15% increased risk of lung cancer if exposed to smoke at work. Furthermore, environmental tobacco smoke-exposed nonsmoking women "showed statistically significant monotonic exposure-response relationships." Finally, Zhong et al. found that childhood environmental tobacco smoke exposure did not correspond to an increased risk of lung cancer in adulthood [66].

Genetics may play an influential role in the risk of developing lung cancer from SHS exposure. Polymorphisms in the gene glutathione S-transferase (GST) M1 show a greatly increased risk of developing lung cancer with SHS exposure. GSTM1 is believed to prevent tumorigenesis by detoxifying carcinogens in tobacco smoke. Lung cancer susceptibility has been associated with anomalies in several cytochrome P450 pathways and several GST enzymes that detoxify chemical carcinogens [332,333,334,335,336]. GST enzymes are considered phase II detoxification enzymes, which conjugate glutathione to carcinogens and reactive oxygen species to detoxify them. Two of the four polymorphic gene classes of GSTs, mu (µ) and theta (θ), have been linked to tobacco-associated cancers. The GSTM1 is a variant of the mu class, which contains a null allele that may be inactivated by a deletion of DNA coding sequences [336,337]. Approximately 50% of the white populations of Europe and North America have homozygous null genotypes for the GSTM1 enzymatic activity [338]. Loss of GSTM1 enzymatic activity has been associated with increased risks of various cancers, including tobacco-associated lung cancer, head and neck cancer, larynx cancer, and bladder cancers. Bennett et al. found that SHS-exposed nonsmoking women with the null polymorphism represented 42% to 49% of the lung cancer cases [337]. Women with the homozygous null genotype have a greater risk of tobacco-associated cancer relative to men [339].

GSTTI is an isoenzyme of the theta class of GSTs, which is deactivated by a homozygous deletion in 11% to 18% of whites [338]. United deficiency of GSTT1 and GSTM1 produces a dramatically increased risk for lung cancer in U.S. populations [340]. Kawajri et al. found that a mutant variation in exon 7 of the cytochrome P450 1A1 (CYP1A1) enzyme was associated with higher rates of lung cancer in the Japanese subjects studied [341]. CYP1A1 is known to activate carcinogenic polycyclic aromatic hydrocarbons including the benzo(a)pyrene component of tobacco smoking [342]. Rebbeck et al. found a synergistic increase in lung cancer risk with both homozygous deletions of GSTM1 and the valine allele variant of exon 7 in CYP1A1 [338].

Large-scale genome-wide association studies have identified several novel lung cancer susceptibility genes, including those on chromosomes 5p15.33, 15q24-25.1, and 6p21 [343]. The 5p15.33 region is associated with risks specific to adenocarcinoma of the lung. The 15q25 region contains three nicotine acetylcholine receptor subunit genes. Their polymorphisms have been associated with nicotine dependence [343]. Associations of the 6p21 region have not been consistently replicated among studies [343,344]. Other regions (e.g., 6q23-25, 13q31.3) have also been identified by genome-wide studies as being associated with risk of lung cancer, including some studies specific to African Americans and to those who have never smoked. Further studies are necessary to assess individual susceptibility based on the combination of polymorphisms in multiple genes [343,344,345].

GLUCOSE INTOLERANCE/DIABETES

Houston and colleagues questioned whether active and passive smokers are more likely than nonsmokers to develop clinically-relevant glucose intolerance or diabetes. Of 4657 participants in the Coronary Artery Risk Development In Young Adults (CARDIA) study, 16.7% developed glucose intolerance at 15-year follow-up. Incidence of glucose intolerance was highest among smokers (21.8%), followed by never-smokers with passive smoke exposure (17.2%), then previous smokers (14.4%), and was lowest for never smokers with no passive smoke exposure (11.5%). The risk among current and never smokers remained after adjustment for sociodemographic, biologic, and behavioral factors, but risk in previous smokers was similar to that in never smokers without passive smoke exposure [346]. A meta-analysis conducted by Pan et al. found that both active and passive smoking are associated with significantly increased risks of type 2 diabetes. The risk was increased in individuals who had recently quit smoking, but decreased substantially as time from quitting increased. They also identified a dose-response relation for current smoking and risk of diabetes [347].

SKIN DISORDERS

Setty, Curhan, and Choi prospectively examined over a 14-year period (1991–2005) the relation between smoking status, duration, intensity, cessation, and exposure to SHS and incident psoriasis in 78,532 women from the Nurses' Health Study II. Prenatal and childhood exposure to passive smoke as well as current and past smoking and cumulative measures of smoking were associated with an increased risk of psoriasis. The risk of incident psoriasis among former smokers decreases nearly to that of never smokers 20 years after cessation [348].

WOUND REPAIR

Passive smoking is known to interfere with normal tissue repair and remodeling, though the underlying pathology is not well understood. Passive smoking has been shown to obstruct wound healing by decreasing blood flow to the damaged tissue and hindering granulation tissue formation and function. Tissue repair and remodeling is heavily reliant upon fibroblasts, which migrate to the site of damage, proliferate, and secrete cytokines, growth factors, and extracellular matrix molecules. Wong et al. found that SSW smoke causes cytoskeletal changes in fibroblasts, which may account for decreased fibroblast migration. Furthermore, excess scarring in SHS-exposed individuals is likely due to a combination of prolonged cell survival (due to a cellular stress response invoked by SHS) and the aforementioned decreased cell migration [62].

AGE-RELATED MACULAR DEGENERATION

Khan and colleagues designed a case-control study to investigate a possible relation between smoking and risk of development of age-related macular degeneration (AMD) among whites. Although many risk factors are related to AMD (e.g., aging, hypertension, family history, obesity), they found a strong association between AMD and pack years of cigarette smoking, and the odds ratio increased with the amount smoked. Smoking impairs the functioning of the retinal pigment epithelium, causing buildup on the retina and subsequent damage to Bruch's membrane. Stopping smoking was associated with reduced odds of AMD and the risk in those who had not smoked for over 20 years was comparable to nonsmokers [349].

CERVICAL INTRAEPITHELIAL NEOPLASM (CIN)

Cervical intraepithelial neoplasm (CIN) is a precursor to cervical cancer, which is the fourth most common cause of cancer-related death in women worldwide [350]. Firmly established major risk factors for CIN include active smoking and human papillomavirus (HPV) infection. A 2006 case-control study of Taiwanese women established SHS as a major risk factor for CIN in addition to active smoking and HPV. The authors presented an indirect and a direct potential mechanism for the development of CIN following SHS exposure. CIN could be caused indirectly by immune suppression or directly by a polycyclic aromatic hydrocarbon-DNA adduct [69]. More recent studies continue to suggest an association between SHS and CIN, and while these studies continue to be conducted, few have provided conclusive results [468,469].

NONALCOHOLIC FATTY LIVER DISEASE

Nonalcoholic fatty liver disease is one of the most common liver diseases in the United States. Nonalcoholic fatty liver disease covers a broad range of diseases from steatosis to nonalcoholic steatohepatitis (NASH) and can have dramatically varied underlying pathology. NASH is a significant clinical concern due to potential disease progression resulting in cirrhosis and end-stage liver disease [351]. Yuan et al. employed a mouse model transgenic for human apoB100 to consider the effect of passive smoke on cholesterol and triglyceride levels. They found no significant change in cholesterol levels with passive smoke exposure but a marked increase in triglycerides in the liver. The increased lipid accretion in hepatocytes is consistent with lipid changes seen in nonalcoholic fatty liver disease [63].

16. MEASURING SECONDHAND SMOKE EXPOSURE

Seventy percent to 80% of nicotine is initially metabolized to cotinine, primarily by CYP2A6 [195]. Cotinine is, for the most part, metabolized to 3'-trans-hydroxycotinine, mainly by the same CYP2A6 enzyme [352]. Both nicotine and cotinine undergo N-glucuronidation; however, 3'-hydroxycotinine undergoes O-glucuronidation [353]. Cotinine is also partly metabolized to 3'-trans-hydroxycotinine by CYP2A6 [352]. Cotinine has a half-life of 15 to 20 hours, and its serum concentrations are tenfold higher than nicotine; thus, cotinine is generally used as an index of nicotine exposure [354].

Cotinine can be measured in hair, nails, blood, saliva, or urine samples. Although other biomarkers for environmental tobacco smoke exposure exist, cotinine is currently the most sensitive and specific. Such objective quantification is especially important in studies concerning passive smoke exposure in children, as parental assessment of smoke exposure is frequently unreliable [65,69,277,355,356]. SHS exposure can also be assessed through CO breath analysis, measurement of certain carcinogens (e.g., NNAL can be found in urine, blood, and nails) or benzene, or measurement of respirable suspended particulates in the air [355].

Breath analysis has improved as an assessment tool. It utilizes the monitoring of volatile organic compounds, which are predominantly bloodborne and therefore enable monitoring of different processes in the body. One study utilizing a real-time breath analyzer identified the presence of volatile organic compounds (1,3-butadiene) after SHS exposure in the breath of nonsmokers [357]. While this method of smoking analysis is improving, studies using this tool still suffer issues of sampling and lack of normalization data. Results could be skewed by participants' varying degrees of exposure to other common sources of volatile organic compounds, for example, wood smoke and automobile exhaust [358].

Studies of genetic polymorphisms of genes that modulate cell growth and proliferation provide potentially helpful biomarkers associated with long-term exposure to carcinogens and eventual tumor formation. One such biomarker used to study lung cancer in SHS-exposed patients is the tumor suppressor gene p53. The p53 gene encodes a multifactorial transcription factor that controls cellular response to DNA damage [359]. Husgafvel-Pursiainen et al. found a three- to fourfold increase in the risk of p53 mutation in SHS-exposed patients who develop lung cancer, while in long-term heavy smokers, p53 mutations are found in 50% of patients with lung tumors [360]. Furthermore, Husgafvel-Pursiainen et al. demonstrated that the majority of the p53 mutations were G:C to A:T transitions. The CpG dinucleotide sites were mutational hotspots, accounting for 50% of the reported G:C to A:T substitutions within the p53 gene. Endogenous deaminations of methylated cysteine residues or preferential carcinogen binding are proposed explanations for G:C to A:T substitutions within CpG islands. This evidence supports the role of p53 as a biomarker for both passive and active tobacco-related carcinogenesis [360].

A combination of the measurement of body fluids for cotinine and hair for nicotine, with the questionnaire and interview-derived information, seems to be the optimal method for assessing SHS exposure. Empirical studies show general concordance of reported environmental or biologic measures of SHS exposure [361]. In addition, urinary cotinine is often used for evaluation of smoking-cessation program efficacy, monitoring of pregnancy/other at-risk groups, and assessment of occupational exposure [362].

17. THIRDHAND SMOKE

The term "thirdhand smoke," or "environmental tobacco smoke," has been and is often used synonymously with SHS, but it can be more accurately described as any airborne particulate matter originating from burning tobacco. It is comprised of both active mainstream smoke (tobacco smoke exhaled by active smokers) and sidestream smoke (smoke from the burning end of a cigarette) that is inhaled by nonsmokers, and evidence shows the possibility of harm for a significant period of time after the cigarette/tobacco product has been extinguished.

In a 2009 study by Winickoff et al., more than 80% of national survey respondents (regardless of smoking status) agreed that SHS was harmful to children, but only 43% of smokers and 65% of nonsmokers thought the same of thirdhand smoke (defined as "breathing air in a room today where people smoked yesterday") [363]. Thirdhand smoke, or any exposure to residual tobacco smoke contamination on surfaces or breathing air in a room where smoking previously occurred, can be dangerous. Unfortunately, not all smokers are cognizant of these harms. Many believe that confining smoking to one room in the home or smoking in the absence of children or even smoking outside with all household windows and doors closed is enough to protect their children. Tobacco smoke does not simply disappear after cigarettes are extinguished, and it (and other toxins) may linger even with what is perceived as adequate ventilation.

Hein and colleagues were likely the first to measure nicotine content of household dust. Nicotine has a high affinity for dust particles, and the amount of tobacco smoking that occurs in the home is highly correlated with concentration of nicotine in household dust [364]. According to a 2004 study by Matt et al., vapor components of tobacco smoke "are absorbed onto walls, furniture, clothes, toys, and other objects within 10 minutes to hours after tobacco smoke has been emitted. From there, they are re-emitted into the air over the course of hours to months" [365]. Similar to findings of a 2001 study of hair nicotine levels among children in New Zealand, whether household smokers smoked indoors in the presence of their child or attempted to limit their children's smoke exposure by smoking outside or in the children's absence, the children were not protected from exposure to nicotine in the indoor air [366]. Further, skin-to-skin contact poses additional risk as nicotine was found on the index fingers of 92% of mothers in the sample [365].

Part of the reason behind the danger of thirdhand smoke may be the lead content of tobacco smoke. According to the Environmental Protection Agency, the tobacco leaves used to make cigarettes contain radioactive lead-210. Indeed, increased blood lead levels among youth is directly associated with household smoking and house dust [367]. Mainstream smoke contains at least 58 percutaneous penetration enhancers, which are used to enhance transdermal delivery of drugs. Of these, 69% are hydrophobic or strongly hydrophobic and can therefore readily permeate the skin and likely settle in percutaneous fat for continued exposure long after the cigarette has been extinguished [368]. Further, unpublished research from Philip Morris Co. shows that 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK) forms in sidestream smoke and increases up to 200% per hour during the first six hours after cigarettes are extinguished [369]. NNK has been shown to cause an exaggerated response in microglia (causing them to attack healthy brain cells) and overall neuroinflammation, which can lead to disorders such as multiple sclerosis [370].

Oie and colleagues report that low ventilation in homes can strengthen the effects of indoor pollutants. They found that odds of bronchial obstruction among children was higher in homes where they were exposed to environmental tobacco smoke as well as dampness, textile wallpaper, and plasticizer-containing surfaces [371].

The problem is not confined to homes. In a 2008 study by Matt and colleagues, it was found that cars of people who smoked in their vehicles contained elevated levels of nicotine in dust on surfaces and in the air when compared with cars of nonsmokers [372].

Haussmann et al. performed a study of fresh versus room-aged sidestream smoke to ascertain how the different types of smoke would affect rats. Their study revealed that the room-aged smoke had decreased concentrations of smoke components such as nicotine and total particulate matter. However, levels of CO remained equal to that of the fresh smoke. The rats manifested reserve cell hyperplasia in the nose and hyperplastic and metaplastic epithelial changes in the larynx; these effects were not as profound in those exposed to the room-aged smoke [373]. Rao and colleagues found that lung tissue from mice exposed to aged and diluted sidestream smoke exhibits increased angiogenesis associated with leukocyte rolling and adhesion. This phenomenon may lead to recruitment of inflammatory cells as observed in bronchitis or asthma [374]. These research studies confirm the unpublished research of Philip Morris Co. in the early 1990s, which revealed that aged sidestream smoke is more toxic to lab animals than fresh sidestream smoke [375].

18. INTERVENTIONS FOR SMOKING CESSATION

PRIMARY CARE INTERVENTION

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends that clinicians ask all adults about tobacco use, advise them to stop using tobacco, and provide behavioral interventions and U.S. Food and Drug Administration (FDA)-approved pharmacotherapy for cessation to adults who use tobacco.

http://annals.org/aim/fullarticle/2443060

Last Accessed: May 13, 2019

Level of Evidence: A (There is high certainty that the net benefit is substantial.)

Smoking cessation may be helpful in reducing firsthand and secondhand tobacco smoke exposure by eliminating the source: the smoker(s). Parents and caregivers of young children should receive cessation counseling and/or pharmacotherapy to quit smoking and eliminate the exposure of children to SHS. Parents should also be informed of the importance of a smoke-free environment for children and that it should be instituted before pregnancy. Pregnant women must learn that smoking will likely produce lasting adverse effects on their offspring. Furthermore, smoking parents should be aware that smoking is known to cause and exacerbate asthma, chronic serous otitis, otitis media, respiratory illness, and possibly childhood cancers. A healthcare provider is required to intervene if a child is suffering from one of these disorders. Healthcare providers are responsible for advising smoking parents about the harms of passive smoke as well as how to provide a smoke-free environment for their children [249]. There are many smoking cessation resources that may be provided to patients, including several "quitlines." These hotlines provide free telephone access to a smoking cessation counselor. The National Cancer Institute's quitline is 1-877-44U-QUIT (1-877-448-7848), and both English- and Spanish-speaking assistance is available. The website https://smokefree.gov also offers support, tools, and expert advice through their app, text messaging, and social media networks. Assistance for issues unique to different subgroups, such as veterans, women, adolescents, adults older than 60 years of age, and those who speak Spanish, are also available.

Although nearly 70% of patients who smoke say they would like to quit, only 7.4% are able to do so without help [376,377]. The advice of a physician alone can increase the smoking cessation rate to 10.2% [378]. It is important for physicians to add an inquiry about smoking to the questions routinely asked while a patient's vital signs are being taken (Figure 2). Further assessment using an abbreviated form of the Fagerström Test for Nicotine Dependence can provide information about whether a patient is addicted to or physically dependent on nicotine. The Fagerström test is a question and answer test that rates an individual's nicotine dependence on a scale of 0 to 10 [379].

Figure 2: PATHWAY FOR TOBACCO CESSATION TREATMENT

Source: Modified with permission from Barua RS, Rigotti NA, Benowitz NL, et al. ACC expert consensus decision pathway on tobacco cessation treatment: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2018;72(25):3332-3365.

After the diagnosis of nicotine dependence is made, the next step is to assess the patient's readiness to change. The five-stage model for readiness to change can be applied to addictive behaviors such as smoking. The stages are precontemplation, contemplation, preparation, action, and maintenance. In the precontemplation stage, a patient does not believe that smoking is a problem or refuses to consider smoking cessation. In the contemplation stage, the patient recognizes that smoking is a problem and is thinking about quitting. During the preparation stage, the patient makes specific plans to stop smoking, such as setting a quit date and determining how smoking cessation will be accomplished. In the action stage, the patient stops smoking. Finally, the maintenance stage is marked by the patient's continued abstinence from smoking. Relapse to smoking behavior is common. Patients often cycle through the stages of change several times before reaching stable abstinence [380].

Interventions can be classified into behavioral, pharmacologic, and alternative methods. Behavioral interventions include physician advice and individual, group, and telephone- or Internet-based counseling. Pharmacologic interventions include NRT and sustained-release bupropion. Alternative interventions include hypnosis, acupuncture, exercise, lobeline, anxiolytics, mecamylamine, and opioid agonists [381].

BRIEF INTERVENTION

Evidence Based Practice Recommendation

According to the University of Michigan Health System, healthcare professionals should advise all tobacco users to seriously consider making a quit attempt using a clear and personalized message. Advice as brief as three minutes is effective.

https://www.med.umich.edu/1info/FHP/practiceguides/smoking/smoking.pdf

Last Accessed: May 13, 2019

Strength of Recommendation/Level of Evidence: IA (Generally should be performed based on randomized controlled trials)

Brief intervention training allows healthcare professionals to offer basic support, ensuring that all smokers who come into contact with these health professionals are able to receive help as appropriate. Brief intervention offers short-term professional input, self-help leaflets and videos, and complementary therapies. This type of information can be applicable for smokers at any level. Milch et al. compared the effects of two brief interventions against treatment as usual. The minimal intervention consisted of a smoking status vital sign stamp, which documents the patient's smoking status. The enhanced intervention consisted of a five-question form that assessed the patient's level of cessation readiness and provided cessation counseling prompts for clinicians. Medical record documentation of screening for smoking and cessation advice and self-reported patient smoking cessation rates were collected 8 to 10 months after implementation. Self-reported patient smoking cessation was higher in the enhanced intervention group (12%) compared with the minimal intervention (2%) and control (4%) groups. This demonstrated that even a short questionnaire that assessed readiness to quit and provided documentation of cessation advice improved rates of clinician cessation advice and patient smoking cessation compared with no intervention [382]. In a study by Smith and Burgess of patients admitted to the hospital with diagnoses of coronary artery disease, a minimal intervention (i.e., advice from physicians and nurses and two pamphlets) resulted in 35% of the group confirmed abstinent at 12 months [383].

5 A's

The U.S. Public Health Service Clinical Practice Guideline was updated in 2018, but continues to recommend the 5 A's approach for intervening with the patient who smokes [384,470]:

- Ask about smoking status

- Advise to quit

- Assess willingness to quit

- Assist by suggesting and encouraging the use of problem-solving methods for cessation

- Arrange for follow-up contacts and relapse prevention

Mullen et al. found that simple changes in question format, such as moving away from requiring "yes" or "no" answers and allowing responses such as "I used to smoke" or "I have cut down," increased smoking disclosure by 40% [385]. Every clinician should ask patients about tobacco use and advise them to quit. Abrupt smoking cessation with medical and psychologic assistance is more successful than tapering or "smoking less" [461].

Given the magnitude of tobacco use as a health risk, tobacco use status should be considered a vital sign requiring regular assessment [384,386]. Nevertheless, studies continue to find that clinicians inconsistently practice assessment of tobacco use and advice to quit smoking [387]. The third step of the Five A's approach, after asking and advising, is to assess the patient's willingness to quit. For the patient who is unwilling to quit at this time, the clinician should help increase motivation by discussing the immediate and long-term risks of continued smoking, benefits of quitting, and the patient's perceived barriers to quitting. The clinician should try to make the discussion personally relevant to the patient and include risks and benefits in addition to those related to health [384]. For the patient willing to quit, the clinician should provide assistance, such as helping the patient choose a target quit date in the near future, suggesting appropriate pharmacotherapy, providing social support, advising the patient about the nature and time course of nicotine withdrawal, recommending behavioral and cognitive coping responses to use when the patient experiences urges to smoke, and perhaps making a referral to an intensive behavioral counseling program [384]. The last of the Five A's involves arranging follow-up contact. This strategy is also based on evidence that total contact time predicts treatment outcome [384]. Follow-up contact can take the form of additional office visits, telephone calls, text messages, or even written materials sent through the mail [462]. Such contact communicates the importance of the cessation attempt, provides social support, and offers the opportunity to intercede if problems have developed. Because the risk of relapse is greatest immediately after quitting, follow-up contact ideally should begin close to the target quit date [388].

MOTIVATIONAL INTERVIEWING

Introduced by Miller in 1983, motivational interviewing is a method of counseling designed to enhance patients' motivation to change by helping them explore and resolve their ambivalence about making the change [389]. It is a collaborative, non-confrontational, "guiding" approach. Motivational interviewing for tobacco cessation utilizes active listening to understand how the patient feels about his or her tobacco use in an effort to uncover any ambivalence [384]. The healthcare provider elicits the patient's own views regarding consequences of continuing to use tobacco and benefits of quitting and asks permission to share additional information on risks when necessary. Goals are developed collaboratively, based on the patient's current readiness to change. Originally developed as an intervention for alcohol abuse, it has shown promise as a successful strategy for smoking cessation. Lai et al. reviewed 28 studies and found that motivational interviewing yields a significant increase in quit rate, especially when conducted by primary care physicians or counselors for sessions lasting more than 20 minutes [390,391]. Further, in a randomized, controlled trial, Ruger and colleagues reported that motivational interviewing for smoking cessation actually saves money, and prevents relapse, among low-income pregnant women with $628/quality-adjusted life-year saved versus usual care [392].

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT INDIVIDUALS

Because communication with patients regarding cessation of smoking is a vital aspect of patient care, it is important that discussions and printed materials are provided in the language with which the individual is most comfortable. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between patients and practitioners.

Interpreters are more than passive agents who translate and transmit information back and forth from party to party [393]. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. When providing care for patients for whom English is a second language, the consideration of the use of an interpreter and/or patient education materials in their native language may improve patient understanding and outcomes. The American Heart Association, the American Medical Association, and the American Academy of Family Physicians produce patient education references in several languages. Primary care providers may utilize these in their interactions with patients for whom English is a second language.

TREATING NICOTINE DEPENDENCE

Behavioral Modifications

Behavioral interventions are nonpharmacologic treatments delivered directly to individual smokers [388]. The main disadvantage of this approach is that relatively few smokers (about 5%) are interested in attending specific classes at any given time [394,395]. Therefore, group sessions appear to be the most cost-effective approach to delivering smoking cessation interventions [396]. Although relatively few patients want to go to classes, physicians should still have a list of referral smoking cessation clinics in their area for those smokers who express an interest in attending them and for those who have failed to respond to other approaches. Simple text, app, and web-tailored cessation messages may also be an effective alternative for behavioral support, doubling the cessation rates. This concept has been incorporated into patient support programs provided by several manufacturers of smoking cessation products [394].

There are several behavioral interventions that have empirical support, such as multicomponent coping skills training (e.g., coping response therapy, problem-focused treatment, relapse prevention training, and cognitive-behavioral therapy). This training includes social support and didactic information about nicotine dependence, withdrawal symptoms, and situations that are risks for relapse (e.g., alcohol use, negative moods, or presence of other smokers) as well as training in the use of cognitive and behavioral responses to cope with urges to smoke that reduce the risk of relapse [397,398]. Aversive therapy for smoking cessation, known as rapid smoking, involves smokers in a controlled clinical setting who deeply inhale on cigarettes at six-second intervals. Up to nine cigarettes would be smoked per treatment session to produce strong aversive reactions to cigarettes [399]. Aversive cigarette use greatly declined after the introduction of NRTs, and reviews have concluded that there is insufficient evidence to determine the efficacy of this method for smoking cessation [400,401]. Another behavioral treatment, scheduled reduced smoking, involves three weeks of gradually reduced nicotine intake. In contrast with other smoking cessation strategies involving reduction of smoking, the patient does not control when and where smoking will occur. Rather, an algorithm is used to determine when each cigarette is to be smoked based on the passage of time [402].

Pharmacotherapy

The first-line pharmacologic interventions for smoking cessation are NRT and bupropion [381,403]. However, no pharmacotherapy has been approved for use among pregnant or nursing women. The five forms of NRT available are the patch, gum, lozenge, nasal spray, and inhaler. A Cochrane review found that all commercially available forms of NRT increased the quit rate by 50% to 70%, independent of the intensity of additional support provided to the individual. Although support is beneficial, it does not appear to be essential to the success of NRT [404].

All available pharmacotherapies are safe for non-pregnant or nursing adults. In a 2016 analysis, varenicline outcomes are found to be equal to NRT plus counseling, and varenicline is also associated with a reduced risk of relapse [463]. Bupropion has the added advantage of reducing smoking cessation-related hyperphagia and weight gain. It is also an antidepressant and can ameliorate withdrawal-associated anhedonia and depression.

The nicotine transdermal system, otherwise known as the patch, releases nicotine steadily during an extended period, with blood levels rising within the first 2 to 4 hours and then remaining relatively constant between 8 and 24 hours after application, depending on the product used [405]. A number of transdermal nicotine-replacement systems are available over the counter. Prescribing information inserts for all transdermal nicotine products indicate that they should be used as part of a cessation program; yet, many patients receive the patch without any physician advice or behavioral support [406]. Adverse reactions to transdermal nicotine-replacement systems seldom cause discontinuation of therapy. Thirty percent to 50% of patients experience mild skin irritation with the patch. In most patients, rotating patch application sites can alleviate this problem. Sleep disruption is usually resolved by removing the patch at bedtime [407]. Unfortunately, use of the patch without any behavioral support is not likely to be successful.

The U.S. Food and Drug Administration adopted labeling for the patch, allowing use beyond the standard duration of eight weeks. This decision was based in part on data showing that extended-duration (24-week) transdermal nicotine therapy reduced the risk for smoking lapses and increased the likelihood of recovery to abstinence compared to the standard 8-week duration of therapy [408,409].

Nicotine chewing gum is a type of NRT that may aid in smoking cessation and/or quitting smokeless tobacco. Chewing allows nicotine to be delivered quickly into the bloodstream. Typically available in either 2- or 4-mg doses, nicotine chewing gum is expected to last one to two hours. Release of nicotine from the gum is proportional to the rate of chewing, a feature that allows for self-titration [410]. However, like the patch, nicotine gum is most successful as an adjunct to behavioral interventions. Indeed, Schneider et al. showed that merely dispensing nicotine gum resulted in a lower quit rate with active gum than with placebo treatment (8% nicotine gum, 13% placebo gum) [411].

The nicotine lozenge is similar to a hard candy. It slowly dissolves in the mouth (for 20 minutes or so) to release nicotine to the brain more quickly than the patch. Shiffman, Di Marino, and Pilliteri analyzed two trials of a 21-mg nicotine patch and 4-mg lozenge to assess the efficacy of each in heavy and dependent smokers. Both therapies were found to significantly increase six-month, continuous abstinence in heavy smokers (≥40 cigarettes per day) and the highly dependent (Fagerström score >7) [412].

A 2-mg sublingual nicotine tablet has shown efficacy in several studies and has been approved in Europe to manage nicotine withdrawal [413,414,415]. Interestingly, one study found that being married was strongly associated with smoking cessation while on this medication [416]. Sublingual tablets (2 mg) have similar pharmacokinetics to that of the 2-mg nicotine chewing gum [417]. One study of high-dependence smokers (those who smoked their first cigarette of the day within 30 minutes of waking) found that a 4-mg nicotine lozenge significantly reduced withdrawal symptoms and cravings over six weeks of treatment [418].

Nasal nicotine spray (NNS) was approved by the FDA in 1997. Available by prescription, each spray contains 0.5 mg of nicotine, and a dose is defined as one spray in each nostril. In clinical trials, subjects were allowed to take up to 5 doses/hour, with a maximum of 40 doses/day (40 mg of nicotine). The cessation rates in trials with NNS at 1 year ranged from 15% to 25% [419,420,421]. A meta-analysis of nicotine replacement suggested that NNS and the inhaler might have higher quit rates than the patch or gum [422]. Indeed, nicotine administered via nasal spray is considered to be the next fastest acting delivery method after smoking and requires 11 to 13 minutes for nicotine levels to reach peak plasma concentration [423].

The FDA also approved a nicotine inhalation system consisting of a mouthpiece and a nicotine-containing cartridge. Available with a prescription, each inhaler contains 10 mg of nicotine and 1 mg of menthol, of which 4 mg of nicotine can be extracted and 2 mg are systemically available. Shallow or deep puffing results in similar nicotine absorption. Nicotine is delivered mainly to the oral cavity, throat, and upper respiratory tract, with a minor fraction reaching the lungs. A single inhaler can be used for one 20-minute period of continuous puffing or periodic use of as many as 400 puffs per inhaler. With controlled puffing in laboratory testing, venous plasma nicotine concentrations from a single inhaler puffed 80 times for 20 minutes, averaged 8.1 mcg/L at 30 minutes. Lower concentrations of 6.4 to 6.9 mcg/L have been reported for self-administration under clinical conditions. The time to reach peak plasma concentrations varies but is always significantly longer than with cigarette delivery [424].

Quitting smoking can be a difficult process, even with use of NRT. When subjects were given denicotinized cigarettes along with IV saline or nicotine, the variable most responsible for craving satisfaction, psychologic reward, and craving reduction was the denicotinized cigarette [425]. When ad libitum smoking of preferred brands was also allowed, the combination of nicotine-less cigarette and bolus IV nicotine were the most effective in lowering craving, negative affect, and total amount smoked [89]. Sensations in the tongue, nose, back of mouth, throat, windpipe, and chest showed strong correlation between nicotine-less cigarettes and the usual brand smoked by the subjects, perhaps explaining the strong effects on smoking suppression observed [425]. Therefore, it is important to recognize that while NRT is a key part of cessation therapy, it does not address all aspects of smoking behavior. In addition, certain smoking cessation strategies, such as NRT, have been found to be less effective among women than men. Given that researchers have found that women are 31% less likely to quit smoking successfully, further studies on gender-specific smoking cessation strategies are warranted [471].

Bupropion is an atypical antidepressant that has both dopaminergic and adrenergic actions [426]. In 1998, the slow-release preparation of bupropion became available as a prescription item specifically for smoking cessation, with the trade name Zyban. This treatment could be appropriate for smokers who do not wish to use an NRT or for those whose treatment with NRT has failed. Unlike NRT, smokers begin bupropion treatment one week prior to cessation. The suggested dosage is 300 mg/day, and the duration of treatment is 7 to 12 weeks [427]. A double-blind, placebo-controlled trial randomized patients to placebo or sustained-released bupropion (50 mg twice a day, 150 mg once a day, or 150 mg twice a day) and treated them for six weeks. Smokers with active depression were excluded, though smokers with a history of depression were not. The cessation rates at the end of therapy were 10.5%, 13.7%, 18.3%, and 24.4%, respectively. Follow-up at one year suggested a continued benefit of bupropion therapy [428]. Data from a study of bupropion combined with transdermal nicotine showed high long-term quit rates with the combination therapy [429]. Discontinuation of treatment may be appropriate for individuals unable to achieve significant progress after seven weeks, as success after this point is unlikely [430].

Another effective non-nicotine therapy for smoking cessation is varenicline tartrate (Chantix), a partial agonist selective for nicotine acetylcholine receptor subtypes. Released in 2006, varenicline is available in monthly dose packs (0.5 mg and 1 mg tablets) and is approved for a 12-week course of treatment [403]. Patients able to quit smoking may continue the therapy for an additional 12 weeks for increased likelihood of long-term cessation; however, medication should be stopped and patients should be reassessed if the intervention has not led to smoking cessation [430,431]. Clinical trials reveal that varenicline may be favorable to bupropion for abstinence (44% versus 30%); the medication has also been shown to help at least 20% of patients remain smoke-free for up to one year [432,433]. Recognizing that cessation success rates increase when pharmacologic and behavioral therapies are combined, the manufacturer urges patients to combine use of varenicline with a behavioral support plan. Co-administration of varenicline and transdermal nicotine may exacerbate incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue. One study found varenicline alone to be more effective than other treatment options, while a meta-analysis study found that combination therapy (varenicline and NRT) was more effective than varenicline alone [434,435]. In 2021, the manufacturer halted production of varenicline due to unacceptable levels of nitrosamines [475]. In addition, all lots of 0.5-mg and 1-mg tablets of varenicline have been subject to a voluntary recall.

The two second-line drugs for smoking cessation are clonidine and nortriptyline [381]. Clonidine is an antihypertensive medication that is administered orally or transdermally. It appears to increase the smoking cessation rate by approximately 11%; however, clonidine is known to produce such side effects as dry mouth, dizziness, sedation, and orthostatic hypotension [430,436]. Clonidine has not been approved by the FDA for smoking cessation but has been used with individuals who have failed NRT or bupropion [430]. Nortriptyline is a tricyclic antidepressant that has been used to assist smoking cessation, although this is an unlabeled use [430]. A 12% improvement in cessation over controls has been reported, but the limited number of trials, combined with the adverse side effects (e.g., dry mouth, weight gain, constipation, drowsiness, sexual problems), makes nortriptyline a second-line intervention [381].

Other drugs have also been used in smoking cessation. Silver acetate, which causes cigarettes to have a bad taste, has been used as a smoking cessation aid for many years. But, there appears to be little evidence for a specific effect of silver acetate in promoting quitting [437,438]. The addition of mecamylamine, a ganglionic blocker classified as an antihypertensive agent, to transdermal nicotine replacement has been shown to improve the abstinence rate in smokers compared with use of the patch alone [439,440].

Additional pharmacotherapy options are in the development phase. A nicotine vaccine and other partial agonists for the nicotine receptors are being evaluated [441]. Interference with the liver enzymes that metabolize nicotine is another approach being tested [442].

In addition, it was found that methoxsalen, a compound used to treat skin disorders, reduces the activity of CYP2A6, the enzyme that metabolizes nicotine. This allows for more nicotine, whether from a cigarette or nicotine replacement, to be present in the blood and to remain there longer, which should minimize smokers' craving to smoke. However, methoxsalen has not been proven safe for use in humans and must undergo more trials before it can be used in a smoking cessation program [443]. Tranylcypromine (a monoamine oxidase inhibitor used to treat depression) and tryptamine (substrate of MAO) are also being investigated for this purpose [444].

Withdrawal

Similar to all addictions, nicotine withdrawal elicits a number of clinical consequences. Desire to avoid withdrawal symptoms promotes smoking. Nicotine withdrawal may last for several weeks and include such symptoms as irritability, anxiety, depression, difficulty concentrating, weight gain, restlessness, and impatience [445]. Withdrawal effects can be elicited and observed in those exposed to secondhand smoke as well as in smokers. Intensity of these withdrawal symptoms may be related to the level of nicotine dependence. In 2017, there were an estimated 34 million adults that smoked cigarettes. Although the prevalence of cigarette smoking continues to decline, there is some evidence that this decline is a reflection of a migration to non-cigarette products, especially e-cigarettes [446,456]

19. REDUCING TOBACCO SMOKE EXPOSURE

A dramatic increase in public awareness concerning the dangers of SHS has corresponded to social demand for smoking restrictions. Beginning in the 1990s, McMillen et al. found broad public support in the United States for smoking restrictions in many public places, including child care centers, hospitals, shopping malls, convenience stores, fast-food restaurants, and indoor sporting events [6]. An Irish study by Mulcahy et al. demonstrated dramatic reductions in SHS exposure following a national workplace smoking ban in Ireland. Thus, this study justified such bans given the known adverse effects of SHS, which include lung disease, heart disease, and asthma [356].

Workers suffering the detrimental effects of secondhand tobacco smoke have taken legal actions. For example, a group of 60,000 flight attendants filed a suit alleging that they had endured smoking-related illnesses from being exposed to high concentrations of environmental smoke in airplane cabins when smoking was still allowed on board [447]. Although the tobacco industry (Philip Morris, R.J. Reynolds, Brown and Williamson, the Ligett Group, and the Lorillard Group) made no admission of guilt, it established the Flight Attendant Medical Research Institute (FAMRI), a $300 million not-for-profit research institute, as a part of the settlement for flight attendants who suffered and died due to SHS exposure in air cabins. FAMRI's mission is "to sponsor scientific and medical research for the early detection and cure of diseases and medical conditions caused from exposure to tobacco smoke" [448].

Efforts to regulate tobacco products include the World Health Organization's Framework Convention on Tobacco Control (FCTC). Additionally, legislation has been passed to give the FDA regulatory authority over tobacco. The main reason for these proposals is to minimize death and disease caused by tobacco smoke by reducing the prevalence of its use and the toxicity of its products. Based on scientific studies and tobacco industry documents, it is believed that tobacco products could be made less toxic if their design, content, emissions, and manufacturing were better controlled [449].

Nationwide polls reveal broad public support for increased taxing of tobacco [450]. Since 2002, the average state cigarette tax has increased from 43.4 cents to $1.79 per pack [451,453,473]. In February 2009, President Obama signed a 61.66-cent federal cigarette tax increase into law, bringing the federal cigarette tax to $1.01. This increase resulted in an 8.3% decline in cigarette sales, one of the largest declines in years, and a continuing downward trend of cigarette sales [452,453]. As of 2016, the CDC reported an average national retail price of $6.43 per pack of cigarettes [453]. Increasing the cost of tobacco not only decreases tobacco use by creating a larger economic barrier to smoking, it also motivates people to try to quit.

Effective behavioral and pharmacologic treatments exist and can work if they are affordable, widely available, and used properly in clinics and communities. Smoking cessation group programs have been found to be more effective than minimal treatment programs, although less intensive treatment approaches, when combined with high participation rates, can still influence larger groups. Tobacco policies have reduced cigarette consumption at work and worksite tobacco smoke exposure [454]. Innovative partnerships with public- and population-based organizations to reach smokers and reduce exposure to tobacco have been initiated. There is a high level of support for smoking restrictions in public places to protect nonsmokers from tobacco smoke [455,473]. Due to the 2009 federal tax increase, several health benefits and cost savings are projected, including an increase in the number of children alive today who will not become smokers (1.2 million) and $51.9 billion in long-term healthcare savings from fewer adult and youth smokers over the lifetimes of the adults who quit and kids who never start [452,473].

Though the state and local governments and employers provide protection from tobacco smoke at work, private homes are not subject to such regulation. Educational strategies are needed to increase awareness of personal and childhood tobacco exposure both in and out of the home. As with the business microenvironment, air quality cannot be maintained if smoking is allowed indoors, even with additional ventilation and air-cleaning devices.

20. CONCLUSION

The purpose of this course was to increase awareness of the various implications of tobacco use and exposure and to provide examples of healthcare assessment and treatment. It should be noted that the health complications incorporated here are only part of an exhaustive list of issues linked to tobacco smoke—more findings are uncovered each day. Changes in policy (e.g., taxation, bans in federal and other public establishments, regulation by the FDA) may spur the public to take a second look before using tobacco products or exposing themselves and friends/family to its smoke. However, it is important to continue to combat tobacco use and exposure at the primary care level at every possible opportunity. Brief intervention methods are more helpful than many realize. Further, although cigarettes have historically been implicated for the majority of health problems, it is important to be cognizant of other tobacco products' health effects and the evolving trends of tobacco use.

Works Cited

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.

2. Gold MS. Drugs of Abuse: A Comprehensive Series for Clinicians: Tobacco. New York, NY: Plenum Medical Book Co.; 1995.

3. Goldsmid E (ed). The Project Gutenberg eBook of A Counter-Blaste to Tobacco, by King James I. Available at http://www.gutenberg.org/files/17008/17008-h/17008-h.htm. Last accessed March 29, 2019.

4. Kluger R. Ashes to Ashes: America's Hundred-Year Cigarette War, the Public Health, and the Unabashed Triumph of Philip Morris. New York, NY: Vintage Books; 1997.

5. Cummings KM. Programs and policies to discourage the use of tobacco products. Oncogene. 2002;21(48):7349-7364.

6. Proctor RN. The Nazi war on tobacco: ideology, evidence, and possible cancer consequences. Bull Hist Med. 1997;71(3):435-488.

7. Bachinger E, McKee M. Tobacco policies in Austria during the Third Reich. Int K Tuberc Lung Dis. 2007;11(9):1033-1037.

8. U.S. Department of Health, Education, and Welfare. Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. 1964. Available at https://profiles.nlm.nih.gov/NN/B/B/M/Q/_/nnbbmq.pdf. Last accessed March 29, 2019.

9. General Services Administration Public Building Service. Ask a RAM: What are the Changes in Federal Workplace Smoking Regulations? Available at https://www.gsa.gov/graphics/regions/FocusNewsletter_Spring2009.pdf. Last accessed March 29, 2019.

10. GovTrack.us. H.R. 1256: Family Smoking Prevention and Tobacco Control Act: 111th Congress 2009. Available at https:// www.govtrack.us/congress/bills/111/hr1256. Last accessed March 29, 2019.

11. American Heart Association. Comments on the Family Smoking Prevention and Tobacco Control Act. Available at http:// www.heart.org/idc/groups/heart-public/@wcm/@adv/documents/downloadable/ucm_312249.pdf. Last accessed March 29, 2019.

12. Centers for Disease Control and Prevention. Smoking and Tobacco Use. Fast Facts. Available at https://www.cdc.gov/tobacco/data_statistics/fact_sheets/fast_facts/. Last accessed March 29, 2019.

13. Center for Behavioral Health Statistics and Quality. 2016 National Survey on Drug Use and Health: Detailed Tables. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2017.

14. U.S. Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2014.

15. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Results from the 2011 National Survey on Drug Use and Health: Summary of National Findings. Rockville, MD: U.S. Department of Health and Human Services; 2012.

16. Campaign for Tobacco-Free Kids. Toll of Tobacco in the United States of America. Available at https://www.tobaccofreekids.org/research/factsheets/pdf/0072.pdf. Last accessed April 1, 2019.

17. Perlman SE, Chernoy C, Farley SM, et al. Exposure to secondhand smoke among nonsmokers in New York City in the context of recent tobacco control policies: current status, changes over the past decade, and national comparisons. Nicotine Tob Res. 2016;18(11):2065-2074.

18. Centers for Disease Control and Prevention. Smokeless Tobacco Use in the United States. Available at https://www.cdc.gov/tobacco/data_statistics/fact_sheets/smokeless/use_us/index.htm. Last accessed April 1, 2019.

19. Centers for Disease Control and Prevention. Secondhand Smoke. Available at https://www.cdc.gov/tobacco/basic_information/secondhand_smoke/index.htm. Last accessed April 1, 2019.

20. Ellis JA, Gwynn C, Garg RK, et al. Secondhand smoke exposure among nonsmokers nationally and in New York City. Nicotine Tob Res. 2009;11(4):362-370.

21. Centers for Disease Control and Prevention. Consumption of cigarettes and combustible tobacco—United States, 2000–2015. MMWR. 2016;65(48):1357-1363.

22. United States Government Accountability Office. Tobacco Taxes: Disparities in Rates for Similar Smoking Products Continue to Drive Market Shifts to Lower-Taxed Options. Available at https://www.gao.gov/products/GAO-14-811T. Last accessed April 1, 2019.

23. Campaign for Tobacco-Free Kids. State Cigarette Tax Rates and Rank, Date of Last Increase, Annual Pack Sales and Revenues, and Related Data. Available at https://www.tobaccofreekids.org/assets/factsheets/0099.pdf. Last accessed April 1, 2019.

24. U.S. Food and Drug Administration. Hookah Tobacco (Shisha or Waterpipe Tobacco). Available at https://www.fda.gov/tobaccoproducts/labeling/productsingredientscomponents/ucm482575.htm#references. Last accessed April 2, 2019.

25. Lipari RN, Van Horn SL. Trends in Smokeless Tobacco Use and Initiation: 2002 to 2014. Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration; 2017.

26. U.S. Department of the Treasury, Bureau of Alcohol, Tobacco and Firearms. Tobacco-Subpart B. Definitions of cigars. Federal Register. 1996;141-143.

27. Baker F, Ainsworth SR, Dye JT, et al. Health risks associated with cigar smoking. JAMA. 2000;284(6):735-740.

28. Henningfield JE, Hariharan M, Kozlowski LT. Nicotine content and health risks of cigars. JAMA. 1996;276(23):1857-1858.

29. Boffetta P, Pershagen G, Jöckel KH, et al. Cigar and pipe smoking and lung cancer risk: a multicenter study from Europe.J Natl Cancer Inst. 1999;91(8):697-701.

30. Jolly DH. Exploring the use of little cigars by students at a historically black university. Prev Chronic Dis. 2008;5(3):A82.

31. Delnevo C. Smokers' choice: what explains the steady growth of cigar use in the U.S.? Public Health Rep. 2006;121(2):116-119.

32. Campaign for Tobacco-Free Kids. The Rise of Cigars and Cigar-Smoking Harms. Available at https://www.tobaccofreekids.org/research/factsheets/pdf/0333.pdf. Last accessed April 2, 2019.

33. Kann L, Kinchen S, Shanklin SL, et al. Youth risk behavior surveillance—United States, 2017. MMWR. 2018;67(8):1-479.

34. Nasim A, Blank MD, Berry BM, Eissenberg T. Cigar use misreporting among youth: data from the 2009 Youth Tobacco Survey, Virginia. Prev Chronic Dis. 2012;9:E42.

35. Malson JL, Sims K, Murty R, Pickworth WB. Comparison of the nicotine content of tobacco used in bidis and conventional cigarettes. Tob Control. 2001;10(2):181-183.

36. Venable MJ. Bidis booming/hip cigarette cheaper, but not risk free. The Richmond Times-Dispatch. June 11, 1999.

37. Campaign for Tobacco-Free Kids. Bidis. Available at https://www.tobaccofreekids.org/assets/global/pdfs/en/IW_facts_products_bidis_overview.pdf. Last accessed April 2, 2019.

38. California State Department of Health Services. Evaluation of the health hazard of clove cigarettes. JAMA. 1988;260(24): 3641-3644.

39. Malson JL, Lee EM, Murty R, Moolchan ET, Pickworth WB. Clove cigarette smoking: biochemical, physiological, and subjective effects. Pharmacol Biochem Behav. 2003;74(3):739-745.

40. Knishkowy B, Amitai Y. Water-pipe (narghile) smoking: an emerging health risk behavior. Pediatrics. 2005;116(1):e113-e119.

41. Kiter G, Uçan ES, Ceylan E, Kilinç O. Water-pipe smoking and pulmonary functions. Respir Med. 2000;94(9):891-894.

42. World Health Organization, Study Group on Tobacco Product Regulation. Waterpipe Tobacco Smoking: Health Effects, Research Needs and Recommended Actions by Regulators. Available at https://www.who.int/tobacco/global_interaction/tobreg/Waterpipe%20recommendation_Final.pdf. Last accessed April 2, 2019.

43. Ward KD, Eissenberg T, Gray JN, Srinivas V, Wilson N, Maziak W. Characteristics of U.S. waterpipe users: a preliminary report. Nicotine Tob Res. 2007;9(12):1339-1346.

44. Sepetdjian E, Shihadeh A, Saliba NA. Measurement of 16 polycyclic aromatic hydrocarbons in narghile waterpipe tobacco smoke. Food Chem Toxicol. 2008;46(5):1582-1590.

45. Saleh R, Shihadeh A. Elevated toxicant yields with narghile waterpipes smoked using a plastic hose. Food Chem Toxicol. 2008;46(5):1461-1466.

46. Lewin T. Collegians smoking hookahs…filled with tobacco. The New York Times. April 19, 2006.

47. Smackware. A Sketch Describing the Structure of the Hookah [Adapted]. Available at https://commons.wikimedia.org/wiki/File:Hookah-lookthrough.jpg. Last accessed April 2, 2019.

48. Hoffmann D, Hoffman I, El-Bayoumy K. The less harmful cigarette: a controversial issue: a tribute to Ernst L. Wynder. Chem Res Toxicol. 2001;14(7):767-790.

49. Haag HB, Larson PS, Finnegan JK. Effect of filtration on the chemical and irritating properties of cigarette smoke. AMA Arch Otolaryngol. 1959;69(3):261-265.

50. Brunnemann KD, Yu L, Hoffman D. Assessment of carcinogenic volatile N-nitrosamines in tobacco and in mainstream and sidestream smoke from cigarettes. Cancer Res. 1977;37(9):3218-3222.

51. Tiggelbeck D. Vapor phase modification: an underutilized technology. Proc. 3rd World Conference on Smoking and Health: Modifying the risk for the smoker. 1976 DHEW Publication No. (NIH) 76-1221:507-514.

52. Valavanidis A, Vlachogianni T, Fiotakis K. Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles. Int J Environ Res Public Health. 2009;6(2):445-462.

53. Federal Trade Commission. "Tar," Nicotine, and Carbon Monoxide of Smoke of 1294 Varieties of Domestic Cigarettes for the Year 1998. Washington, DC: Federal Trade Commission; 2000.

54. Federal Trade Commission. Federal Trade Commission Cigarette Report for 2016. Washington, DC: Federal Trade Commission; 2018.

55. Thun MJ, Heath CW. Changes in mortality from smoking in two American Cancer Society prospective studies since 1959. Prev Med. 1997;26(4):422-426.

56. Kozlowski LT, Pillitteri JL, Sweeney CT. Misuse of "light" cigarettes by means of vent blocking. J Subst Abuse. 1994;6(3):333-336.

57. Kozlowski LT, Pope MA, Lux JE. Prevalence of the misuse of ultra-low-tar cigarettes by blocking filter vents. Am J Public Health. 1988;78(6):694-695.

58. Kozlowski LT, Frecker RC, Khouw V, Pope MA. The misuse of "less-hazardous" cigarettes and its detection: hole blocking of ventilated filters. Am J Public Health. 1980;70(11):1202-1203.

59. Byrd GD, Robinson JH, Caldwell WS, deBethizy JD. Comparison of measured and FTC-predicted nicotine uptake in smokers. Psychopharmacology (Berl). 1995;122(2):95-103.

60. Adams JD, Lee SJ, Hoffmann D. Carcinogenic agents in cigarette-smoke and the influence of nitrate in their formation. Carcinogenesis. 1984;5(2):221-223.

61. U.S. Department of Health and Human Services, Office on Smoking and Health. The Health Consequences of Smoking: The Changing Cigarette. A Report of the Surgeon General. Rockville, MD: U.S. Public Health Service, Office of the Surgeon General; 1981.

62. Wong LS, Green HM, Feugate JE, Yadav M, Nothnangel EA, Martins-Green M. Effects of "second-hand" smoke on structure and function of fibroblasts, cells that are critical for tissue repair and remodeling. BMC Cell Biol. 2004;5(1):13.

63. Yuan H, Wong LS, Bhattacharya M. The effects of second-hand smoke on biological processes important in atherogenesis.BMC Cardiovasc Disord. 2007;7:1.

64. Joad JP, Sekizawa S, Chen CY, Bonham AC. Air pollutants and cough. Pulm Pharmacol Ther. 2007;20(4):347-354.

65. Meeker JD, Missmer SA, Cramer DW, Hauser R. Maternal exposure to second-hand tobacco smoke and pregnancy outcome among couples undergoing assisted reproduction. Hum Reprod. 2007;22(2):337-345.

66. Zhong L, Goldberg MS, Parent ME, Hanely JA. Exposure to environmental tobacco smoke and the risk of lung cancer: a meta-analysis. Lung Cancer. 2000;27(1):3-18.

67. Invernizzi G, Ruprecht A, Mazza R, et al. Particulate matter from tobacco versus diesel car exhaust: an educational perspective. Tobacco Control. 2004;13(3):219-221.

68. Preston AM, Rodriguez C, Rivera CE, Sahai H. Influence of environmental tobacco smoke on vitamin C status in children.Am J Clin Nutr. 2003;77(1):167-172.

69. Tsai HT, Tsai YM, Yang SF, et al. Lifetime cigarette smoke and second-hand smoke and cervical intraepithelial neoplasm— a community-based case-control study. Gynecol Oncol. 2007;105(1):181-188.

70. Lans C, Harper T, Georges K, Bridgewater E. Medicinal and ethnoveterinary remedies of hunters in Trinidad. BMC Complement Altern Med. 2001;1:10.

71. Sandler RS, Sandler DP, McDonnell CW, Wurzelmann JI. Childhood exposure to environmental tobacco smoke and the risk of ulcerative colitis. Am J Epidemiol. 1992;135(6):603-8.

72. McCormick AA, Kumagai MH, Hanley K, et al. Rapid production of specific vaccines for lymphoma by expression of the tumor-derived single-chain Fv epitopes in tobacco plants. Proc Natl Acad Sci USA. 1999;96(2):703-708.

73. Ma S, Huang Y, Yin Z, Menassa R, Brandle JE, Jevnikar AM. Induction of oral tolerance to prevent diabetes with transgenic plants requires glutamic acid decarboxylase (GAD) and IL-4. Proc Natl Acad Sci USA. 2004;101(15):5680-5685.

74. Webster DE, Cooney ML, Huang Z, et al. Successful boosting of a DNA measles immunization with an oral plant-derived measles virus vaccine. J Virol. 2002;76(15):7910-7912.

75. Muir DC. Tobacco smoke inhalation. Scand J Respir Dis Suppl. 1974;91:44-46.

76. Pearson MG, Chamberlain MJ, Morgan WK, Vinitski S. Regional deposition of particles in the lung during cigarette smoking in humans. J Appl Physiol. 1985;59(6):1828-1833.

77. Adams L, Lee C, Rawbone R, Guz A. Patterns of smoking: measurement and variability in asymptomatic smokers. Clin Sci (Lond). 1983;65(4):383-392.

78. Darby TD, McNamee JE, van Rossum JM. Cigarette smoking pharmacokinetics and its relationship to smoking behaviour. Clin Pharmacokinet. 1984;9(5):435-449.

79. Grant SG, Woodman G, Newman SP, Pavia D, Clarke SW. Sensory mechanisms in the upper respiratory tract affect the inhalation of cigarette smoke in man. Clin Sci (Lond). 1986;71(1):117-119.

80. Ferron GA. The size of soluble aerosol particles as a function of the humidity of the air: application to the human respiratory tract.J Aerosol Sci. 1977;8(4):251-267.

81. Centers for Disease Control and Prevention. NIOSH Spirometry Training Guide. Available at https://www.cdc.gov/niosh/docs/2004-154c/pdfs/2004-154c.pdf. Last accessed April 4, 2019.

82. Lunell E, Bergström M, Antoni G, Långström B, Nordberg A. Nicotine deposition and body distribution from a nicotine inhaler and a cigarette studied with positron emission tomography. Clin Pharmacol Ther. 1996;59(5):593-594.

83. Jarvis MJ. Why people smoke. BMJ. 2004;328(7434):277-279.

84. Le Houezec J. Role of nicotine pharmacokinetics in nicotine addiction and nicotine replacement therapy: a review. Int J Tuberc Lung Dis. 2003;7(9):811-819.

85. Bandura A. Influence of models' reinforcement contingencies on the acquisition of imitative responses. J Pers Soc Psychol. 1965;1(6):589-595.

86. Turner L, Mermelstein R, Flay B. Individual and contextual influences on adolescent smoking. Ann NY Acad Sci. 2004;1021: 175-197.

87. Carmelli D, Swan GE, Robinette D, Fabsitz R. Genetic influence on smoking: a study of male twins. N Engl J Med. 1992;327(12):829-833.

88. Swan GE. Implications of genetic epidemiology for the prevention of tobacco use. Nicotine Tob Res. 1999;1(Suppl 1):S49-S56.

89. Rose JE, Behm FM, Westman EC, Bates JE, Salley A. Pharmacologic and sensorimotor components of satiation in cigarette smoking. Pharmacol Biochem Behav. 2003;76(2):243-250.

90. Mekemson C, Glantz SA. How the tobacco industry built its relationship with Hollywood. Tob Control. 2002;11(Suppl 1):181-191.

91. Pierce JP, Choi WS, Gilpin EA, Farkas AJ, Berry CC. Tobacco industry promotion of cigarettes and adolescent smoking. JAMA. 1998;279(7):511-515.

92. Glantz SA. Smoking in movies: a major problem and a real solution. Lancet. 2003;362(9380):258-259.

93. Dalton MA, Tickle JJ, Sargent JD, Beach ML, Ahrens MB, Heatherton TF. The incidence and context of tobacco use in popular movies from 1988 to 1997. Prev Med. 2002;34(5):516-523.

94. Dalton MA, Sargent JD, Beach ML, et al. Effect of viewing smoking in movies on adolescent smoking initiation: a cohort study. Lancet. 2003;362(9380):281-285.

95. Tickle JJ, Sargent JD, Dalton MA, Beach ML, Heatherton TF. Favourite movie stars, their tobacco use in contemporary movies, and its association with adolescent smoking. Tob Control. 2001;10(1):16-22.

96. Glantz SA, Kacirk KW, McCulloch C. Back to the future: smoking in movies in 2002 compared with 1950 levels. Am J Public Health. 2004;94(2):261-263.

97. Associated Press. MPAA Makes Smoking Bigger Factor in Ratings. Available at https://www.today.com/id/18601051#.UXF_GEoVTyM. Last accessed April 4, 2019.

98. Pomerleau CS. Co-factors for smoking and evolutionary psychobiology. Addiction. 1997;92(4):397-408.

99. Heath AC, Martin NG. Genetic models for the natural history of smoking: evidence for a genetic influence on smoking persistence. Addict Behav. 1993;18(1):19-34.

100. Madden PA, Heath AC, Pedersen NL, Kaprio J, Koskenvuo MJ, Martin NG. The genetics of smoking persistence in men and women: a multicultural study. Behav Genet. 1999;29(6):423-431.

101. True WR, Heath AC, Scherrer JF, et al. Genetic and environmental contributions to smoking. Addiction. 1997;92(10):1227-1287.

102. Madden PA, Pedersen NL, Kaprio J, Koskenvuo MJ, Martin NG. The epidemiology and genetics of smoking initiation and persistence: crosscultural comparisons of twin study results. Twin Res. 2004;7(1):82-97.

103. Heath AC, Cates R, Martin NG, et al. Genetic contribution to risk of smoking initiation: comparisons across birth cohorts and across cultures. J Subst Abuse. 1993;5(3):221-246.

104. U.S. Department of Health and Human Services. The Health Consequences of Smoking: Nicotine Addiction: A Report of the Surgeon General. Rockville, MD: Office on Smoking and Health; 1988.

105. Silagy C, Lancaster T, Stead L, Mant D, Fowler G. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2002;(4):CD000146.

106. Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2008;(1):CD000146.

107. Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2014;11:CD000146.

108. Russell MA, Feyerabend C. Cigarette smoking: a dependence on high-nicotine boli. Drug Metab Rev. 1978;8(1):29-57.

109. United States of America v. Philip Morris USA Inc., f/k/a Philip Morris Inc., et al. Civil Action No. 99-2496 (GK), Filed September 01, 2005.

110. Edwards JA, Warburton DM. Smoking, nicotine and electrocortical activity. Pharmacol Ther. 1982;19(2):147-164.

111. Domino EF, Ni L, Xu Y, Koeppe RA, Guthrie S, Zubieta JK. Regional cerebral blood flow and plasma nicotine after smoking tobacco cigarettes. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(2):319-327.

112. Domino EF, Minoshima S, Guthrie SK, et al. Effects of nicotine on regional cerebral glucose metabolism in awake resting tobacco smokers. Neuroscience. 2000;101(2):277-282.

113. Pidoplichko VI, DeBiasi M, Williams JT, Dani JA. Nicotine activates and desensitizes midbrain dopamine neurons. Nature. 1997;390(6658):401-404.

114. Corrigall WA, Coen KM, Adamson KL. Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res. 1994;653(1-2):278-284.

115. Ota A, Yasuda N, Okamoto Y, et al. Relationship of job stress with nicotine dependence of smokers—a cross-sectional study of female nurses in a general hospital. J Occup Health. 2004;46(3):220-224.

116. Moller AM, Maaløe R, Pedersen T. Postoperative intensive care admittance: the role of tobacco smoking. Acta Anaesthesiol Scand. 2001;45(3):345-348.

117. Mayo Clinic. COPD. Available at https://www.mayoclinic.org/diseases-conditions/copd/symptoms-causes/syc-20353679. Last accessed April 5, 2019.

118. Berndt A, Leme AS, Shapiro SD. Emerging genetics of COPD. EMBO Mol Med. 2012;4(11):1144-1155.

119. Wiencke JK, Thurston SW, Kelsey KT, et al. Early age at smoking initiation and tobacco carcinogen DNA damage in the lung.J Natl Cancer Institute. 1999;91(7):614-619.

120. Patel BD, Luben RN, Welch AA, et al. Childhood smoking is an independent risk factor for obstructive airways disease in women. Thorax. 2004;59(8):682-686.

121. Arcavi L, Benowitz NL. Cigarette smoking and infection. Arch Intern Med. 2004;164(20):2206-2216.

122. Kark JD, Lebiush M, Rannon L. Cigarette smoking as a risk factor for epidemic a(H1N1) influenza in young men. N Engl J Med. 1982;307(17):1042-1046.

123. Almirall J, González CA, Balanzó X, Bolíbar I. Proportion of community-acquired pneumonia cases attributable to tobacco smoking. Chest. 1999;116(2):375-379.

124. Cecere LM, Williams EC, Sun H, et al. Smoking cessation and the risk of hospitalization for pneumonia. Respir Med. 2012;106(7):1055-1062.

125. Lange P, Vestbo J, Nyboe J. Risk factors for death and hospitalization from pneumonia: a prospective study of a general population. Eur Respir J. 1995;8(10):1694-1698.

126. Charoenca N, Kungskulniti N, Tipayamongkholgul M, et al. Determining the burden of secondhand smoke exposure on the respiratory health of Thai children. Tob Induc Dis. 2013;11(1):7.

127. Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol. 2004;43(10):1731-1737.

128. Menza MA, Grossman N, Van Horn M, Cody R, Forman N. Smoking and movement disorders in psychiatric patients. Biol Psychiatry. 1991;30(2):109-115.

129. Ong MK, Glantz SA. Cardiovascular health and economic effects of smoke free workplaces. Am J Med. 2004;117(1):32-38.

130. Can A, Castro VM, Ozdemir YH, et al. Association of intracranial aneurysm rupture with smoking duration, intensity, and cessation. Neurology. 2017;89(13):1408-1415.

131. Riise T, Nortvedt MW, Ascherio A. Smoking is a risk factor for multiple sclerosis. Neurology. 2003;61(8):1122-1124.

132. Fowler JS, Volkow ND, Wang GJ, et al. Inhibition of monoamine oxidase B in the brains of smokers. Nature. 1996;379(6567): 733-736.

133. Moreno-Gonzalez I, Estrada LD, Sanchez-Mejias E, Soto C. Smoking exacerbates amyloid pathology in a mouse model of Alzheimer's disease. Nat Commun. 2013;4:1495.

134. Centers for Disease Control and Prevention. Lung Cancer: What Are the Risk Factors for Lung Cancer? Available at https:// www.cdc.gov/cancer/lung/basic_info/risk_factors.htm. Last accessed April 5, 2019.

135. Centers for Disease Control and Prevention. Tobacco Use by Youth is Rising: E-Cigarettes Are the Main Reason. Available at https://www.cdc.gov/vitalsigns/youth-tobacco-use. Last accessed April 4, 2019.

136. Davis JL. The Effects of Smoking on Bone Health: Tips to Help You Quit Smoking. Available at https://www.webmd.com/osteoporosis/features/smoking-cigarettes. Last accessed April 25, 2016.

137. Giampietro PF, McCarty C, Mukesh B, et al. The role of cigarette smoking and statins in the development of postmenopausal osteoporosis: a pilot study utilizing the Marshfield Clinic Personalized Medicine Cohort. Osteoporos Int. 2010;21(3):467-477.

138. Walker LM, Preston MR, Magnay JL, Thomas PB, El Haj AJ. Nicotinic regulation of c-fos and osteopontin expression in human-derived osteoblast-like cells and human trabecular bone organ culture. Bone. 2001;28(6):603-608.

139. Centers for Disease Control and Prevention. Smoking During Pregnancy. Available at https://www.cdc.gov/tobacco/basic_information/health_effects/pregnancy/index.htm. Last accessed May 2, 2019.

140. Tostes RC, Carneiro FS, Lee AJ, et al. Cigarette smoking and erectile dysfunction: focus on NO bioavailability and ROS generation. J Sex Med. 2008;5(6):1284-1295.

141. Pasqualotto FF, Umezu FM, Salvador M, Borges E Jr, Sobreiro BP, Pasqualotto EB. Effect of cigarette smoking on antioxidant levels and presence of leukocytospermia in infertile men: a prospective study. Fertil Steril. 2008;90(2):278-283.

142. Ramlau-Hansen CH, Thulstrup AM, Aggerholm AS, Jensen MS, Toft G, Bonde JP. Is smoking a risk factor for decreased semen quality? A cross-sectional analysis. Hum Reprod. 2007;22(1):188-196.

143. Waylen AL, Metwally M, Jones GL, Wilkinson AJ, Ledger WL. Effects of cigarette smoking upon clinical outcomes of assisted reproduction: a meta-analysis. Hum Reprod Update. 2009;15(1):31-44.

144. Lackmann GM, Salzberger U, Töllner U, Chen M, Carmella SG, Hecht SS. Metabolites of a tobacco-specific carcinogen in urine from newborns. J Natl Cancer Inst. 1999;91(5):459-465.

145. Castles A, Adams EK, Melvin CL, Kelsch C, Boulton ML. Effects of smoking during pregnancy: five meta-analyses. Am J Prev Med. 1999;16(3):208-215.

146. Naeye RL. Abruptio placentae and placenta previa: frequency, perinatal mortality, and cigarette smoking. Obstet Gynecol. 1980;55:701-704.

147. Ness RB, Grisso JA, Hirschinger N, et al. Cocaine and tobacco use and the risk of spontaneous abortion. N Engl J Med. 1999;340(5):333-339.

148. Shiverick KT, Salafia C. Cigarette smoking and pregnancy I: ovarian, uterine, and placental effects. Placenta. 1999;20(4):265-272.

149. Bien TH, Burge R. Smoking and drinking: a review of the literature. Int J Addict. 1990;25(12):1429-1454.

150. Campaign for Tobacco-Free Kids. Smoking and Other Drug Use. Available at https://tobaccofreekids.org/research/factsheets/pdf/0106.pdf. Last accessed April 13, 2019.

151. Jackson KM, Sher KJ, Wood PK, Bucholz KK. Alcohol and tobacco use disorders in a general population: short-term and long-term associations from the St. Louis epidemiological catchment area study. Drug Alcohol Depend. 2003;71(3):239-253.

152. Rohde P, Lewinsohn PM, Kahler CW, Seeley JR, Brown RA. Natural course of alcohol use disorders from adolescence to young adulthood. J Am Acad Child Adolesc Psychiatry. 2001;40(1):83-90.

153. Romberger DJ, Grant K. Alcohol consumption and smoking status: the role of smoking cessation. Biomed Pharmacother. 2004;58(2):77-83.

154. Johnson JG, Cohen P, Pine DS, Klein DF, Kasen S, Brook JS. Association between cigarette smoking and anxiety disorders during adolescence and early adulthood. JAMA. 2000;284(18):2348-2351.

155. Quattrocki E, Baird A, Yurgelun-Todd D. Biological aspects of the link between smoking and depression. Harv Rev Psychiatry. 2000;8(3):99-110.

156. Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2014;1:CD000031.

157. Carmody TP. Affect regulation, nicotine addiction, and smoking cessation. J Psychoactive Drugs. 1989;21(3):331-342.

158. Covey LS, Glassman AH, Stetner F. Cigarette smoking and major depression. J Addict Dis. 1998;17(1):35-46.

159. Glassman AH. Cigarette smoking: implications for psychiatric illness. Am J Psychiatry. 1993;150(4):546-553.

160. Stage KB, Glassman AH, Covey LS. Depression after smoking cessation: case reports. J Clin Psychiatry. 1996;57(10):467-469.

161. Vázquez FL, Becoña E. Treatment of major depression associated with smoking cessation. Acta Psychiatr Scand. 1998;98(6):507-508.

162. Bock BC, Goldstein MG, Marcus BH. Depression following smoking cessation in women. J Subst Abuse. 1996;8(1):137-144.

163. Borrelli B, Niaura R, Keuthen NJ, et al. Development of major depressive disorder during smoking-cessation treatment. J Clin Psychiatry. 1996;57(11):534-538.

164. Amering M, Bankier B, Berger P, Griengl H, Windhaber J, Katschnig H. Panic disorder and cigarette smoking behavior. Compr Psychiatry. 1999;40(1):35-38.

165. Breslau N, Kilbey M, Andreski P. Nicotine dependence, major depression, and anxiety in young adults. Arch Gen Psychiatry. 1991;48(12):1069-1074.

166. Pohl R, Yeragani VK, Balon R, Lycaki H, McBride R. Smoking in patients with panic disorder. Psychiatry Res. 1992;43(3):253-262.

167. Cosci F, Knuts IJ, Abrams K, Griez EJ, Schruers KR. Cigarette smoking and panic: a critical review of the literature. J Clin Psychiatry. 2010;71(5):606-615.

168. Farris SG, Allan NP, Morales PC, Schmidt NB, Zvolensky MJ. Does successful smoking cessation reduce anxious arousal among treatment-seeking smokers? J Anxiety Disord. 2015;36:92-98.

169. Diwan A, Castine M, Pomerleau CS, Meador-Woodruff JH, Dalack GW. Differential prevalence of cigarette smoking in patients with schizophrenic vs. mood disorders. Schizophr Res. 1998;33(1-2):113-118.

170. Lohr JB, Flynn K. Smoking and schizophrenia. Schizophr Res. 1992;8(2):93-102.

171. Ziedonis DM, Kosten TR, Glazer WM, Frances RJ. Nicotine dependence and schizophrenia. Hosp Community Psychiatry. 1994;45(3):204-206.

172. Hall RG, Duhamel M, McClanahan R, et al. Level of functioning, severity of illness, and smoking status among chronic psychiatric patients. J Nerv Ment Dis. 1995;183(7):468-471.

173. Brown RW, Maple AM, Perna MK, Sheppard AB, Cope ZA, Kostrzewa RM. Schizophrenia and substance abuse comorbidity: nicotine addiction and the neonatal quinpirole model. Dev Neurosci. 2012;34(2-3):140-151.

174. Boggs DL, Carlson J, Cortes-Briones J, Krystal JH, D'Souza DC. Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia. Curr Pharm Des. 2014;20(31):5077-5092.

175. Decina P, Caracci G, Sandik R, Berman W, Mukherjee S, Scapicchio P. Cigarette smoking and neuroleptic-induced parkinsonism. Biol Psychiatry. 1990;28(7):502-508.

176. Sandyk R. Cigarette smoking: effects on cognitive functions and drug-induced parkinsonism in chronic schizophrenia.Int J Neurosci. 1993;70(3-4):193-197.

177. Weiser M, Reichenberg A, Grotto I, et al. Higher rates of cigarette smoking in male adolescents before the onset of schizophrenia: a historical-prospective cohort study. Am J Psychiatry. 2004;161(7):1219-1223.

178. Tsoi DT, Porwal M, Webster AC. Interventions for smoking cessation and reduction in individuals with schizophrenia. Cochrane Database Syst Rev. 2013;2:CD007253.

179. Centers for Disease Control and Prevention. Cigarette Smoking During Pregnancy: United States, 2016. Available at https:// www.cdc.gov/nchs/products/databriefs/db305.htm. Last accessed April 13, 2019.

180. Centers for Disease Control and Prevention. How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease. A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services; 2010.

181. Dietz PM, England LJ, Shapiro-Mendoza CK, Tong VT, Farr SL, Callaghan WM. Infant morbidity and mortality attributable to prenatal smoking in the United States. Am J Prev Med. 2010;39(1):45-52.

182. Buka SL, Shenassa ED, Niaura R. Elevated risk of tobacco dependence among offspring of mothers who smoked during pregnancy: a 30-year prospective study. Am J Psychiatry. 2003;160(11):1978-1984.

183. Osler M, Clausen J, Ibsen KK, Jensen G. Maternal smoking during childhood and increased risk of smoking in young adulthood.Int J Epidemiol. 1995;24(4):710-714.

184. Centers for Disease Control and Prevention. Smoking and Tobacco Use: Smoking in the Movies. Available at https://www.cdc. gov/tobacco/data_statistics/fact_sheets/youth_data/movies/index.htm. Last accessed April 4, 2019.

185. Ohida T, Kaneita Y, Osaki Y, et al. Is passive smoking associated with sleep disturbance among pregnant women? Sleep. 2007;30(9):1155-1161.

186. Mosier HD Jr, Jansons RA. Distribution and fate of nicotine in the rat fetus. Teratology. 1972;6(3):303-311.

187. Suzuki K, Horiguchi T, Comas-Urrutia AC, Mueller-Heubach E, Morishima HO, Adamsons K. Placental transfer and distribution of nicotine in the pregnant rhesus monkey. Am J Obstet Gynecol. 1974;119(2):253-262.

188. Pastrakuljic A, Schwartz R, Simone C, Derewlany LO, Knie B, Koren G. Transplacental transfer and biotransformation studies of nicotine in the human placental cotyledon perfused in vitro. Life Sci. 1998;63(26):2333-2342.

189. Luck W, Nau H, Hansen R, Steldinger R. Extent of nicotine and cotinine transfer to the human fetus, placenta and amniotic fluid of smoking mothers. Dev Pharmacol Ther. 1985;8(6):384-395.

190. Sastry BV. Placental toxicology: tobacco smoke, abused drugs, multiple chemical interactions, and placental function. Reprod Fertil Dev. 1991;3(4):355-372.

191. Demir R, Demir AY, Yinanc M. Structural changes in placental barrier of smoking mother: a quantitative and ultrastructural study. Pathol Res Pract. 1994;190(7):656-667.

192. Aubard Y, Magne I. Carbon monoxide poisoning in pregnancy. BJOG. 2000;107(7):833-838.

193. Klebanoff MA, Levine RJ, Clemens JD, DerSimonian R, Wilkins DG. Serum cotinine concentration and self-reported smoking during pregnancy. Am J Epidemiol. 1998;148(3):259-262.

194. Jauniaux E, Gulbis B, Acharya G, Thiry P, Rodeck C. Maternal tobacco exposure and cotinine levels in fetal fluids in the first half of pregnancy. Obstet Gynecol. 1999;93(1):25-29.

195. Dempsey D, Jacob P III, Benowitz NL. Nicotine metabolism and elimination kinetics in newborns. Clin Pharmacol Ther. 2000;67(5):458-465.

196. Loebstein R, Lalkin A, Koren G. Pharmacokinetic changes during pregnancy and their clinical relevance. Clin Pharmacokinet. 1997;33(5):328-343.

197. Dempsey D, Jacob P III, Benowitz NL. Accelerated metabolism of nicotine and cotinine in pregnant smokers. J Pharmacol Exp Ther. 2002;301(2):594-598.

198. Muneoka K, Ogawa T, Kamei K, et al. Prenatal nicotine exposure affects the development of the central serotonergic system as well as the dopaminergic system in rat offspring: involvement of route of drug administrations. Brain Res Dev Brain Res. 1997;102(1):117-126.

199. Slotkin TA. Fetal nicotine or cocaine exposure: which one is worse? J Pharmacol Exp Ther. 1998;285(3):931-945.

200. Slotkin TA, Lappi SE, McCook EC, Lorber BA, Seidler FJ. Loss of neonatal hypoxia tolerance after prenatal nicotine exposure: implications for sudden infant death syndrome. Brain Res Bull. 1995;38(1):69-75.

201. Kinney HC, O'Donnell TJ, Kriger P, White WS. Early developmental changes in (3H) nicotine binding in the human brainstem. Neuroscience. 1993;55(4):1127-1130.

202. Lewis KW, Bosque EM. Deficient hypoxia awakening response in infants of smoking mothers: possible relationship to sudden infant death syndrome. J Pediatr. 1995;127(5):691-696.

203. Roy TS, Seidler FJ, Slotkin TA. Prenatal nicotine exposure evokes alterations of cell structure in hippocampus and somatosensory cortex. J Pharmacol Exp Ther. 2002;300(1):124-133.

204. Stick S. Pediatric origins of adult lung disease. 1. The contribution of airway development to paediatric and adult lung disease. Thorax. 2000;55(7):587-594.

205. Sekhon HS, Proskocil BJ, Clark JA, Spindel ER. Prenatal nicotine exposure increases connective tissue expression in foetal monkey pulmonary vessels. Eur Respir J. 2004;23(6):906-915.

206. Collins MH, Moessinger AC, Kleinerman J, et al. Fetal lung hypoplasia associated with maternal smoking: a morphometric analysis. Pediatr Res. 1985;19(4):408-412.

207. Maritz GS, Windvogel S. Chronic maternal nicotine exposure during gestation and lactation and the development of the lung parenchyma in the offspring: response to nicotine withdrawal. Pathophysiology. 2003;10(1):69-75.

208. Economides D, Braithwaite J. Smoking, pregnancy and the fetus. J R Soc Health. 1994;114(4):198-201.

209. Philipp K, Pateisky N, Endler M. Effects of smoking on uteroplacental blood flow. Gynecol Obstet Invest. 1984;17(4):179-182.

210. Tolson CM, Seidler FJ, McCook EC, Slotkin TA. Does concurrent or prior nicotine exposure interact with neonatal hypoxia to produce cardiac cell damage? Teratology. 1995;52(5):298-305.

211. Navarro HA, Mills E, Seidler FJ, et al. Prenatal nicotine exposure impairs beta-adrenergic function: persistent chronotropic subsensitivity despite recovery from deficits in receptor binding. Brain Res Bull. 1990;25(2):233-237.

212. Slotkin TA, Saleh JL, McCook EC, Seidler FJ. Impaired cardiac function during postnatal hypoxia in rats exposed to nicotine prenatally: implications for perinatal morbidity and mortality, and for sudden infant death syndrome. Teratology. 1997;55(3): 177-184.

213. Hafström O, Milerad J, Sandberg KL, Sundell HW. Cardiorespiratory effects of nicotine exposure during development. Respir Physiol Neurobiol. 2005;149(1-3):325-341.

214. Tomaselli GF, Marbán E. Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res. 1999;42(2):270-283.

215. Sartiani L, Cerbai E, Lonardo G, et al. Prenatal exposure to carbon monoxide affects postnatal cellular electrophysiological maturation of the rat heart: a potential substrate for arrhythmogenesis in infancy. Circulation. 2004;109(3):419-423.

216. Lampl M, Kuzawa CW, Jeanty P. Prenatal smoke exposure alters growth in limb proportions and head shape in the midgestation human fetus. Am J Hum Biol. 2003;15(4):533-546.

217. Lampl M, Kuzawa CW, Jeanty P. Growth patterns of the heart and kidney suggest inter-organ collaboration in facultative fetal growth. Am J Hum Biol. 2005;17(2):178-194.

218. DiFranza JR, Aligne CA, Weitzman M. Prenatal and postnatal environmental tobacco smoke exposure and children's health. Pediatrics. 2004;113(4 Suppl):1007-1015.

219. Simpson WJ. A preliminary report on cigarette smoking and the incidence of prematurity. Am J Obstet Gynecol. 1957;73(4): 807-815.

220. Bernstein IM, Mongeon JA, Badger GJ, Solomon L, Heil SH, Higgins ST. Maternal smoking and its association with birth weight. Obstet Gynecol. 2005;106(5 Pt 1):986-991.

221. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2002. Natl Vital Stat Rep. 2003;52(10):1-113.

222. Ontario Medical Association. Rethinking stop-smoking medications: treatment myths and medical realities (update 2008).Medical Rev. 2008;75:22-34.

223. Aagaard-Tillery KM, Porter TF, Lane RH, Varner MW, Lacoursiere DY. In utero tobacco exposure is associated with modified effects of maternal factors on fetal growth. Am J Obstet Gynecol. 2008;198(1):66.e1-66.e6.

224. Akalin-Sel T, Campbell S. Understanding the pathophysiology of intra-uterine growth retardation: the role of the "lower limb reflex" in redistribution of blood flow. Eur J Obstet Gynecol Reprod Biol. 1992;46(2-3):79-86.

225. Hammarén-Malmi S, Tarkkanen J, Mattila PS. Analysis of risk factors for childhood persistent middle ear effusion. Acta Otolaryngol. 2005;125(10):1051-1054.

226. Stathis SL, O'Callaghan DM, Williams GM, Najman JM, Andersen MJ, Bor W. Maternal cigarette smoking during pregnancy is an independent predictor for symptoms of middle ear disease at five years' postdelivery. Pediatrics. 1999;104(2):e16.

227. Hecht SS, Hoffmann D. Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke. Carcinogenesis. 1988;9(6):875-884.

228. Shopland DR (ed). The Health Consequences of Smoking: Cancer: A Report of the Surgeon General. Rockville, MD: U.S. Public Health Service Office on Smoking and Health; 1982.

229. Myers SR, Spinnato JA, Pinorini-Godly MT, Cook C, Boles B, Rodgers GC. Characterization of 4-aminobiphenyl-hemoglobin adducts in maternal and fetal blood-samples. J Toxicol Environ Health. 1996;47(6):553-566.

230. Hofhuis W, de Jongste JC, Merkus PJ. Adverse health effects of prenatal and postnatal tobacco smoke exposure on children.Arch Dis Child. 2003;88(12):1086-1090.

231. Boffetta P, Trédaniel J, Greco A. Risk of childhood cancer and adult lung cancer after childhood exposure to passive smoke: a meta-analysis. Environ Health Perspect. 2000;108(1):73-82.

232. Cooper C, Harvey N, Cole Z, Hanson M, Dennison E. Developmental origins of osteoporosis: the role of maternal nutrition.Adv Exp Med Biol. 2009;646:31-39.

233. Fried PA, Watkinson B. 12- and 24-month neurobehavioural follow-up of children prenatally exposed to marijuana, cigarettes and alcohol. Neurotoxicol Teratol. 1988;10(4):305-313.

234. Kristjansson B, Fried PA, Watkinson B. Maternal smoking during pregnancy affects children's vigilance performance. Drug Alcohol Depend. 1989;24(1):11-19.

235. Naeye RL, Peters EC. Mental development of children whose mothers smoked during pregnancy. Obstet Gynecol. 1984;64(5): 601-607.

236. Streissguth AP, Barr HM, Martin DC, Herman CS. Effects of maternal alcohol, nicotine, and caffeine use during pregnancy on infant mental and motor development at eight months. Alcohol Clin Exp Res. 1980;4(2):152-164.

237. Kotimaa AJ, Moilanen I, Taanila A, et al. Maternal smoking and hyperactivity in 8-year-old children. J Am Acad Child Adolesc Psychiatry. 2003;42(7):826-833.

238. Thapar A, Fowler T, Rice F, et al. Maternal smoking during pregnancy and attention deficit hyperactivity disorder symptoms in offspring. Am J Psychiatry. 2003;160(11):1985-1989.

239. Orlebeke JF, Knol DL, Verhulst FC. Child behavior problems increased by maternal smoking during pregnancy. Arch Environ Health. 1999;54(1):15-19.

240. Brook JS, Brook DW, Whiteman M. The influence of maternal smoking during pregnancy on the toddler's negativity. Arch Pediatr Adolesc Med. 2000;154(4):381-385.

241. Brennan PA, Grekin ER, Mednick SA. Maternal smoking during pregnancy and adult male criminal outcomes. Arch Gen Psychiatry. 1999;56(3):215-219.

242. Ferguson DM, Woodward LJ, Horwood LJ. Maternal smoking during pregnancy and psychiatric adjustment in late adolescence. Arch Gen Psychiatry. 1998;55:721-727.

243. Hellström-Lindahl E, Nordberg A. Smoking during pregnancy: a way to transfer the addiction to the next generation? Respiration. 2002;69(4):289-293.

244. Chan-Yeung M, Dimich-Ward H. Respiratory health effects of exposure to environmental tobacco smoke. Respirology. 2003;8(2):131-139.

245. Cook DG, Strachan DP. Health effects of passive smoking-10: summary of effects of parental smoking on the respiratory health of children and implications for research. Thorax. 1999;54(4):357-366.

246. Miller T, Rauh VA, Glied SA, et al. The economic impact of early life environmental tobacco smoke exposure: early intervention for developmental delay. Environ Health Perspect. 2006;114(10):1585-1588.

247. Ueda Y, Stick SM, Hall G, Sly PD. Control of breathing in infants born to smoking mothers. J Pediatr. 1999;135(2 Pt 1):226-232.

248. Samet JM, Yang G. Passive smoking, women and children. In: Samet JM, Yoon SY (eds). Women and the Tobacco Epidemic: Challenges for the 21st Century. Geneva: The World Health Organization in collaboration with the Institute for Global Tobacco Control and the Johns Hopkins School of Public Health; 2001.

249. Johansson A, Hermansson G, Ludvigsson J. How should parents protect their children from environmental tobacco-smoke exposure in the home? Pediatrics. 2004;113(4):e291-e295.

250. Law KL, Stroud LR, LaGasse LL, Niaura R, Liu J, Lester BM. Smoking during pregnancy and newborn neurobehavior. Pediatrics. 2003;111(6 Pt 1):1318-1323.

251. Abou-Donia MB, Abdel-Rahman A, Goldstein LB, et al. Sensorimotor deficits and increased brain nicotinic acetylcholine receptors following exposure to chlorpyrifos and/or nicotine in rats. Arch Toxicol. 2003;77(8):452-458.

252. Gospe SM Jr, Zhou SS, Pinkerton KE. Effects of environmental tobacco smoke exposure in utero and/or postnatally on brain development. Pediatr Res. 1996;39(3):494-498.

253. Navarro HA, Seidler FJ, Schwartz RD, Baker FE, Dobbins SS, Slotkin TA. Prenatal exposure to nicotine impairs nervous system development at a dose which does not affect viability or growth. Brain Res Bull. 1989;23(3):187-192.

254. Slotkin TA. Cholinergic systems in brain development and disruption by neurotoxicants: nicotine, environmental tobacco smoke, organophosphates. Toxicol Appl Pharmacol. 2004;198(2):132-151.

255. Hutchinson S, Glantz S, Zhu BQ, et al. In-utero and neonatal exposure to secondhand smoke causes vascular dysfunction in newborn rats. J Am Coll Cardiol. 1998;32(5):1463-1467.

256. Török J, Gvozdjáková A, Kucharská J, et al. Passive smoking impairs endothelium-dependent relaxation of isolated rabbit arteries. Physiol Res. 2000;49(1):135-141.

257. Kallio K, Jokinen E. Tobacco smoke exposure is associated with attenuated endothelial function in 11-year-old healthy children. Circulation. 2007;115(25):3205-3212.

258. Simko F, Braunova Z, Kucharska J, Bada V, Kyselovic J, Gvozdjakova A. Passive smoking induced hypertrophy of the left ventricle: effect of captopril. Pharmamazie. 1999;54(4):314.

259. Neufeld EJ, Mietus-Snyder M, Beiser AS, Baker AL, Newburger JW. Passive cigarette smoking and reduced HDL cholesterol levels in children with high risk lipid profiles. Circulation. 1997;96(5):1403-1407.

260. Moskowitz WB, Schwartz PF, Schieken RM. Childhood passive smoking, race and coronary artery disease: the MCV Twin Study. Medical College of Virginia. Arch Pediatr Adolesc Med. 1999;153(5):446-453.

261. Feldman J, Shenker IR, Etzel RA, et al. Passive smoking alters lipid profiles in adolescents. Pediatrics. 1991;88(2):259-264.

262. Centers for Disease Control and Prevention. Sudden Unexpected Infant Death and Sudden Infant Death Syndrome: Data and Statistics. Available at https://www.cdc.gov/sids/data.htm. Last accessed April 13, 2019.

263. Klonoff-Cohen HS, Edelstein SL, Lefkowitz ES, et al. The effect of passive smoking and tobacco exposure through breast milk on sudden infant death syndrome. JAMA. 1995;273(10):795-798.

264. Matturri L, Ottaviani G, Lavezzi AM. Maternal smoking and sudden infant death syndrome: epidemiological study related to pathology. Virchows Arch. 2006;449(6):697-706.

265. Zhang K, Wang X. Maternal smoking and increased risk of sudden infant death syndrome: a meta-analysis. Leg Med (Tokyo). 2013;15(3):115-121.

266. Milerad J, Rajs J, Gidlund E. Nicotine and cotinine levels in pericardial fluid in victims of SIDS. Acta Paediatr. 1994;83(1):59-62.

267. Dunn A, Zeise L (eds). Health Effects of Exposure to Environmental Tobacco Smoke. Sacramento, CA: California Environmental Protection Agency, Office of Environmental Health Hazard Assessment; 1997.

268. Tsimoyianis GV, Jacobson MS, Feldman JG, et al. Reduction in pulmonary function and increased frequency of cough associated with passive smoking in teenage athletes. Pediatrics. 1987;80(1):32-36.

269. Lynn WR (ed). The Health Consequences of Involuntary Smoking: A Report of the Surgeon General, 1986. Rockville, MD: United States Public Health Service Office on Smoking and Health; 1986.

270. U.S. Surgeon General's Advisory Committee on Smoking and Health. Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service, 1964. Washington, DC: U.S. Department of Health, Education, and Welfare; 1964.

271. Hanrahan JP, Tager IB, Segal MR, et al. The effect of maternal smoking during pregnancy on early infant lung function. Am Rev Respir Dis. 1992;145(5):1129-1135.

272. Chhabra D, Sharma S, Kho AT, et al. Fetal lung and placental methylation is associated with in utero nicotine exposure. Epigenetics. 2014;9(11):1473-1484.

273. Etzel RA. How environmental exposures influence the development and exacerbation of asthma. Pediatrics. 2003;112(1 Pt 2): 233-239.

274. Institute of Medicine Committee on the Assessment of Asthma and Indoor Air. Clearing the Air: Asthma and Indoor Air Exposures. Washington, DC: National Academy Press; 2000.

275. Spahn JD, Szefler SJ. The etiology and control of bronchial hyperresponsiveness in children. Curr Opin Pediatr. 1996;8(6):591-596.

276. Conboy-Ellis K. Asthma pathogenesis and management. Nurse Pract. 2006;31(11):24-37.

277. Karadag B, Karakoç F, Ceran O, Ersu R, Inan S, Dagli E. Does passive smoke exposure trigger acute asthma attack in children? Allergol Immunopathol (Madr). 2003;31(6):318-323.

278. Aligne CA, Moss ME, Auinger P, Weitzman M. Association of pediatric dental caries with passive smoking. JAMA. 2003;289(10):1258-1264.

279. Wilson KM, Finkelstein JN, Blumkin AK, Best D, Klein JD. Micronutrient levels in children exposed to secondhand tobacco smoke. Nicotine Tob Res. 2011;13(9):800-808.

280. David GL, Koh WP, Lee HP, Yu MC, London SJ. Childhood exposure to environmental tobacco smoke and chronic respiratory symptoms in non-smoking adults: the Singapore Chinese Health Study. Thorax. 2005;60(12):1052-1058.

281. Sandler DP, Everson RB, Wilcox AJ, Browder JP. Cancer risk in adulthood from early life exposure to parents' smoking. Am J Public Health. 1985;75(5):487.

282. Peppone LJ, Piazza KM, Mahoney MC, et al. Associations between adult and childhood secondhand smoke exposures and fecundity and fetal loss among women who visited a cancer hospital. Tob Control. 2009;18(2):115-120.

283. Strohsnitter WC, Hatch EE, Hyer M, et al. The association between in utero cigarette smoke exposure and age at menopause.Am J Epidmiol. 2008;167(6):727-733.

284. Collishaw NE, Kirkbride J, Wigle DT. Tobacco smoke in the workplace: an occupational health hazard. Can Med Assoc J. 1984;131(10):1199-1204.

285. Navas-Acien A, Peruga A, Breysse P, et al. Secondhand tobacco smoke in public places in Latin America, 2002–2003. JAMA. 2004;291(22):2741-2745.

286. Castellan RM, Chosewood LC, Trout D, et al. Current Intelligence Bulletin 67: Promoting Health and Preventing Disease and Injury Through Workplace Tobacco Policies. Morgantown, WV: National Institute for Occupational Safety and Health; 2015.

287. Samet JM, Spengler JD. Indoor environments and health: moving into the 21st century. Am J Public Health. 2003;93(9):1489-1493.

288. Fichtenberg CM, Glantz SA. Effect of smoke-free workplaces on smoking behavior: systematic review. BMC. 2002;325:188-191.

289. Bauer JE, Hyland A, Li Q, Steger C, Cummings KM. A longitudinal assessment of the impact of smoke-free worksite policies on tobacco use. Am J Public Health. 2005;95(6):1024-1029.

290. International Agency for Research on Cancer. Evaluating the effectiveness of smoke-free polices. In: IARC Handbooks of Cancer Prevention, Tobacco Control. Vol. 13. Lyon: World Health Organization, International Agency for Research on Cancer; 2009.

291. Hopkins DP, Razi S, Leeks KD, Priya Kalra G, Chattopadhyay SK, Soler RE. Smokefree policies to reduce tobacco use: a systematic review. Am J Prev Med. 2010;38(2 Suppl):S275-S289.

292. Callinan JE, Clarke A, Doherty K, Kelleher C. Legislative smoking bans for reducing secondhand smoke exposure, smoking prevalence and tobacco consumption. Cochrane Database Syst Rev. 2010;4:CD005992.

293. Eisner MD, Smith AK, Blanc PD. Bartenders' respiratory health after establishment of smokefree bars and taverns. JAMA. 1998;280(22):1909-1914.

294. Lambert WE, Samet JM, Spengler JD. Environmental tobacco smoke concentrations in no-smoking and smoking sections of restaurants. Am J Public Health. 1993;83(9):1339-1341.

295. Chang C, Leighton J, Mostashari F, McCord C, Frieden TR. The New York City Smoke-free Air Act: second-hand smoke as a worker health and safety issue. Am J Ind Med. 2004;46(2):188-195.

296. Fujishiro K, Hinckley Stukovsky KD, Diez Roux A, Landsbergis P, Burchfiel C. Occupational gradients in smoking behavior and exposure to workplace environmental tobacco smoke: The Multi-Ethnic Study of Atherosclerosis (MESA). J Occup Environ Med. 2012;54(2):136-145.

297. Repace J. Flying the smoky skies: secondhand smoke exposure of flight attendants. Tob Control. 2004;13(Suppl 1):i8-i19.

298. Enstrom JE, Kabat GC. Environmental tobacco smoke and coronary heart disease mortality in the United States: a meta-analysis and critique. Inhal Toxicol. 2006;18(3):199-210.

299. Glantz SA, Parmley WW. Passive smoking and heart disease: epidemiology, physiology, and biochemistry. Circulation. 1991;83(1): 1-12.

300. Institute of Medicine Committee on Secondhand Smoke Exposure and Acute Coronary Events. Secondhand Smoke Exposure and Cardiovascular Effects: Making Sense of the Evidence. Washington, DC: National Academies Press; 2010.

301. Glantz SA, Parmley WW. Even a little secondhand smoke is dangerous. JAMA. 2001;286(4):462-463.

302. Sargent RP, Shepard RM, Glantz SA. Reduced incidence of admissions for myocardial infarction associated with public smoking ban: before and after study. BMJ. 2004;328(7446):977-980.

303. Mitka M. Secondhand smoke an acute heart risk? JAMA. 2004;291(2):2688-2689.

304. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics—2019 update: a report from the American Heart Association. Circulation. 2016;139:e56-e528.

305. Lusis AJ. Atherosclerosis. Nature. 2000;407(6801):233-241.

306. Abraham D, Distler O. How does endothelial cell injury start? The role of endothelin in systemic sclerosis. Arthritis Res Ther. 2007;9(Suppl 2):S2.

307. Okamoto Y, Kihara S, Ouchi N, et al. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2002;106(22):2767-2770.

308. U.S. Department of Health and Human Services. Reducing the Health Consequences of Smoking: 25 Years of Progress. A Report of the Surgeon General: 1989 Executive Summary. Washington, D.C.: Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 1989.

309. Whincup PH, Gilg JA, Emberson JR, et al. Passive smoking and risk of coronary heart disease and stroke: prospective study with cotinine measurement. BMJ. 2004;329(7459):200-205.

310. U.S. Department of Health and Human Services. The Health Benefits of Smoking Cessation. A Report of the Surgeon General: 1990. Rockville, MD: U.S. Public Health Service, Office on Smoking and Health; 1990.

311. Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. Effect of exposure to secondhand smoke on markers of inflammation: the ATTICA study. Am J Med. 2004;116(3):145-150.

312. Glantz SA, Parmley WW. Passive smoking and heart disease: mechanisms and risk. JAMA. 1995;273(13):1047-1053.

313. He J, Vupputuri S, Allen K, Prerost MR, Hughes J, Whelton PK. Passive smoking and the risk of coronary heart disease— a meta-analysis of epidemiologic studies. N Engl J Med. 1999;340(12):920-926.

314. Kawachi I, Colditz GA, Speizer FE, et al. A prospective study of passive smoking and coronary heart disease. Circulation. 1997;95(10):2374-2379.

315. Valkonen M, Kuusi T. Passive smoking induces atherogenic changes in low-density lipoprotein. Circulation. 1998;97(20): 2012-2016.

316. Burghuber OC, Punzengruber C, Sinzinger H, Haber P, Silberbauer K. Platelet sensitivity to prostacyclin in smokers and non-smokers. Chest. 1986;90(1):34-38.

317. Benowitz NL, Fitzgerald GA, Wilson M, Zhang Q. Nicotine effects on eicosanoid formation and hemostatic function: comparison of transdermal nicotine and cigarette smoking. J Am Coll Cardiol. 1993;22(4):1159-1167.

318. California Environmental Protection Agency, Office of Environmental Health Hazard Assessment. National Cancer Institute, Smoking and Tobacco Control Monographs. Monograph 10: Health Effects of Exposure to Environmental Tobacco Smoke. Available at https://cancercontrol.cancer.gov/brp/tcrb/monographs/10/index.html. Last accessed May 2, 2019.

319. Scientific Committee on Tobacco and Health. Report of the Scientific Committee on Tobacco and Health. Available at https://www.gov.uk/government/publications/report-of-the-scientific-committee-on-tobacco-and-health. Last accessed May 2, 2019.

320. Taylor AE, Johnson DC, Kazemi H. Environmental tobacco smoke and cardiovascular disease: a position paper from the Council on Cardiopulmonary and Critical Care, American Heart Association. Circulation. 1992;86(2):699-702.

321. Glymour MM, Defries TB, Kawachi I, Avendano M. Spousal smoking and incidence of first stroke: the Health and Retirement Study. Am J Prev Med. 2008;35(3):245-248.

322. Janson C. The effect of passive smoking on respiratory health in children and adults. Int J Tuberc Lung Dis. 2004;8(5):510-516.

323. Leuenberger P, Schwartz J, Ackerman-Liebrich U, et al. Passive smoking exposure in adults and chronic respiratory symptoms (SAPALDIA study). Am J Respir Crit Care Med. 1994;150(5 Pt 1):1222-1228.

324. Eisner MD, Balmes J, Katz PP, Trupin L, Yelin EH, Blanc PD. Lifetime environmental tobacco smoke exposure and the risk of chronic obstructive pulmonary disease. Environ Health. 2005;4(1):7.

325. Schick S, Glantz S. Philip Morris toxicological experiments with fresh sidestream smoke: more toxic than mainstream smoke.Tob Control. 2005;14(6):396-404.

326. Jaakkola MS, Piipari R, Jaakkola N, Jaakkola JJ. Environmental tobacco smoke and adult-onset asthma: a population-based incident case-control study. Am J Public Health. 2003;93(12):2055-2060.

327. Dahms TE, Bolin JF, Slavin RG. Passive smoking: effects on bronchial asthma. Chest. 1981;80(5):530-534.

328. Zhong L, Goldberg MS, Gao YT, Jin F. A case-control study of lung cancer and environmental tobacco smoke among nonsmoking women living in Shanghai, China. Cancer Causes Control. 1999;10(6):607-616.

329. Murphy TD. Passive Smoking and Lung Disease. Available at https://emedicine.medscape.com/article/1005579-overview. Last accessed April 13, 2016.

330. Khuder SA. Effect of cigarette smoking on major histological types of lung cancer: a meta-analysis. Lung Cancer. 2001;31(2-3): 139-148.

331. HealthCommunities.com. Lung Cancer. Available at http://www.healthcommunities.com/lung-cancer/types.shtml. Last accessed April 13, 2019.

332. Ketterer B, Harris JM, Talaska G, et al. The human glutathione S-transferase supergene family, its polymorphism, and its effects on susceptibility to lung cancer. Environ Health Perspect. 1992;98:87-94.

333. Kihara M, Kihara M, Noda K. Risk of smoking for squamous and small cell carcinomas of the lung modulated by combinations of CYP1A1 and GSTM1 gene polymorphisms in a Japanese population. Carcinogenesis. 1995;16(10):2331-2336.

334. McWilliams JE, Sanderson BJ, Harris EL, Richert-Boe KE, Henner WD. Glutathione S-transferase M1 (GSTM1) deficiency and lung cancer risk. Cancer Epidemiol Biomarkers Prev. 1995;4(6):589-594.

335. Saarikoski ST, Voho A, Reinikainen M, et al. Combined effect of polymorphic GST genes on individual susceptibility to lung cancer. Int J Cancer. 1998;77(4):516-521.

336. Seidegård J, Vorachek WR, Pero RW, Pearson WR. Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proc Natl Acad Sci USA. 1988;85(19):7293-7297.

337. Bennett WP, Alavanja MC, Blomeke B, et al. Environmental tobacco smoke, genetic susceptibility, and risk of lung cancer in never-smoking women. J Natl Cancer Inst. 1999;91(23):2009-2014.

338. Rebbeck TR. Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev. 1997;6(9):733-743.

339. Tang DL, Rundle A, Warburton D, et al. Associations between both genetic and environmental biomarkers and lung cancer: evidence of a greater risk of lung cancer in women smokers. Carcinogenesis. 1998;19(11):1949-1953.

340. Kelsey KT, Spitz MR, Zuo ZF, Wiencke JK. Polymorphisms in the glutathione S-transferase class mu and theta genes interact and increase susceptibility to lung cancer in minority populations (Texas, United States). Cancer Causes Control. 1997;8(4):554-559.

341. Kawajiri K, Nakachi K, Imai K, Watanabe J, Hayashi S. The CYP1A1 gene and cancer susceptibility. Crit Rev Oncol Hematol. 1993;14(1):77-87.

342. Kawajiri K, Nakachi K, Imai K, Hayashi S, Watanabe J. Individual differences in lung cancer susceptibility in relation to polymorphisms of P-450IA1 gene and cigarette dose. Princess Takamatsu Symp. 1990;21:55-61.

343. Yokota J, Shiraishi K, Kohno T. Genetic basis for susceptibility to lung cancer: recent progress and future directions. Adv Cancer Res. 2010;109:51-72.

344. Trunog T, Hung RJ, Amos CI, et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J Natl Cancer Inst. 2010;102(13):959-971.

345. Walsh KM, Gorlov IP, Hansen HM et al. Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 regions identifies functional and histology-specific lung cancer susceptibility loci in African-Americans. Cancer Epidemiol Biomarkers Prev. 2013;22(2): 251-260.

346. Houston TK, Person SD, Pletcher MJ, Liu K, Iribarren C, Kiefe CI. Active and passive smoking and development of glucose intolerance among young adults in a prospective cohort: CARDIA study. BMJ. 2006;332(7549):1064-1069.

347. Pan A, Wang Y, Talaei M, Hu FB, Wu T. Relation of active, passive, and quitting smoking with incident type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015;3(12):958-967.

348. Setty AR, Curhan G, Choi HK. Smoking and the risk of psoriasis in women: Nurses' Health Study II. Am J Med. 2007;120(11): 953-959.

349. Khan JC, Thurlby DA, Shahid H, et al. Smoking and age related macular degeneration: the number of pack years of cigarette smoking is a major determinant of risk for both geographic atrophy and choroidal neovascularisation. Br J Ophthalmol. 2006;90(1):75-80.

350. World Health Organization. Cervical Cancer. Available at https://www.who.int/cancer/prevention/diagnosis-screening/cervical-cancer/en. Last accessed April 13, 2019.

351. Yu AS, Keeffe EB. Nonalcoholic fatty liver disease. Rev Gastroenterol Disord. 2002;2(1):11-19.

352. Messina ES, Tyndale RF, Sellers EM. A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmacol Exp Ther. 1997;282(3):1608-1614.

353. Benowitz NL, Jacob P III. Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther. 1994;56(5):483-493.

354. Lambers DS, Clark KE. The maternal and fetal physiologic effects of nicotine. Semin Perinatol. 1996;20(2):115-126.

355. Benowitz NL. Biomarkers of environmental tobacco smoke exposure. Environ Health Perspect. 1999;107(Suppl 2):349-355.

356. Mulcahy M, Evans DS, Hammond SK, Repace JL, Byrne M. Secondhand smoke exposure and risk following the Irish smoking ban: an assessment of salivary cotinine concentrations in hotel workers and air nicotine levels in bars. Tob Control. 2005;14(6):384-388.

357. Gordon SM, Wallace LA, Brinkman MC, Callahan PJ, Kenny DV. Volatile organic compounds as breath biomarkers for active and passive smoking. Environ Health Perspect. 2002;110(7):689-698.

358. Agency for Toxic Substances and Disease Registry. Draft of Toxicological Profile for 1, 3-butadiene. Available at https://www.atsdr.cdc.gov/toxprofiles/tp28-c1.pdf. Last accessed April 22, 2019.

359. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88(3):323-331.

360. Husgafvel-Pursiainen K, Boffetta P, Kannio A, et al. p53 mutations and exposure to environmental tobacco smoke in a multicenter study on lung cancer. Cancer Res. 2000;60(11):2906-2911.

361. Hovell MF, Zakarian JM, Wahlgren DR, Matt GE, Emmons KM. Reported measures of environmental tobacco smoke exposure: trials and tribulations. Tob Control. 2000;9(Suppl 3):III22-III28.

362. Haufroid V, Lison D. Urinary cotinine as a tobacco-smoke exposure index: a minireview. Int Arch Occup Environ Health. 1998;71(3):162-168.

363. Winickoff JP, Friebely J, Tanski SE, et al. Beliefs about the health effects of "thirdhand" smoke and home smoking bans. Pediatrics. 2009;123:e74-e79.

364. Hein HO, Suadicani P, Skov P, Gyntelberg F. Indoor dust exposure: an unnoticed aspect of involuntary smoking. Arch Environ Health. 1991;46(2):98-101.

365. Matt GE, Quintana PJ, Hovell MF, et al. Households contaminated by environmental tobacco smoke: sources of infant exposures. Tob Control. 2004;13(1):29-37.

366. Al-Delaimy WK, Crane J, Woodward A. Passive smoking in children: effect of avoidance strategies, at home as measured by hair nicotine levels. Arch Environ Health. 2001;56(2):117-122.

367. Bonanno LJ, Freeman NCG, Greenberg M, Lioy PJ. Multivariate analysis on levels of selected metals, particulate matter, VOC, and household characteristics and activities from the midwestern states NHEXAS. Appl Occup Environ Hyg. 2001;16(9): 859-874.

368. Smith CJ, Perfetti TA, Garg R, Martin P, Hansch C. Percutaneous penetration enhancers in cigarette mainstream smoke.Food Chem Toxicol. 2004;42(1):9-15.

369. Schick SF, Glantz S. Concentrations of the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in sidestream cigarette smoke increase after release into indoor air: results from unpublished tobacco industry research. Cancer Epidemiol Biomarkers Prev. 2007;16(8):1547-1553.

370. Ghosh D, Mishra MK, Das S, Kaushik DK, Basu A. Tobacco carcinogen induces microglial activation and subsequent neuronal damage. J Neurochem. 2009;110(3):1070-1081.

371. Oie L, Nafstad P, Botten G, Magnus O, Jaakkola JK. Ventilation in homes and bronchial obstruction in young children. Epidemiology. 1999;10(3):294-299.

372. Matt GE, Quintana PJ, Hovell MF, et al. Residual tobacco smoke pollution in used cars for sale: air, dust, and surfaces. Nicotine Tob Res. 2008;10(9):1467-1475.

373. Haussmann HJ, Anskeit E, Becker D, et al. Comparison of fresh and room-aged cigarette sidestream smoke in a subchronic inhalation study on rats. Toxicol Sci. 1998;41(1):100-116.

374. Rao SP, Sikora L, Hosseinkhani MR, Pinkerton KE, Sriramarao P. Exposure to environmental tobacco smoke induces angiogenesis and leukocyte trafficking in lung microvessels. Exp Lung Res. 2009;35(2):119-135.

375. Schick S, Glantz SA. Sidestream cigarette smoke toxicity increases with aging and exposure duration. Tob Control. 2006;15(6): 424-429.

376. Godoy P, Castilla J, Mayoral JM, et al. Smoking may increase the risk of influenza hospitalization and reduce influenza vaccine effectiveness in the elderly. Eur J Public Health. 2018;28(1):150-155.

377. Centers for Disease Control and Prevention. Quitting smoking among adults—United States, 2000–2015. MMWR. 2017;65(52):1457-1464.

378. Jorenby DE, Fiore MC. The Agency for Health Care Policy and Research smoking cessation clinical practice guideline: basics and beyond. Prim Care. 1999;26(3):513-528.

379. Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström Test for nicotine dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict. 1991;86(9):1119-1127.

380. Prochaska JO, DiClemente CC, Norcross JC. In search of how people change: applications to addictive behaviors. Am Psychol. 1992;47(9):1102-1114.

381. Marlow SP, Stoller JK. Smoking cessation. Respir Care. 2003;48(12):1238-1254; discussion 1254-1256.

382. Milch CE, Edmunson JM, Beshansky JR, Griffith JL, Selker HP. Smoking cessation in primary care: a clinical effectiveness trial of two simple interventions. Prev Med. 2004;38(3):284-294.

383. Smith PM, Burgess E. Smoking cessation initiated during hospital stay for patients with coronary artery disease: a randomized controlled trial. CMAJ. 2009;180(13):1297-1303.

384. Fiore MC, Jaen CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update: Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service; 2008.

385. Mullen PD, Carbonari JP, Tabak ER, Glenday MC. Improving disclosure of smoking by pregnant women. Am J Obstet Gynecol. 1991;165(2):409-413.

386. Ahluwalia JS, Gibson CA, Kenney RE, Wallace DD, Resnicow K. Smoking status as a vital sign. J Gen Intern Med. 1999;14(7): 402-408.

387. Doescher MP, Saver BG. Physicians' advice to quit smoking: the glass remains half empty. J Fam Pract. 2000;49(6):543-547.

388. Brandon TH. Behavioral tobacco cessation treatments: yesterday's news or tomorrow's headlines? J Clin Oncol. 2001;19(18 Suppl):64S-68S.

389. Miller WR. Motivational interviewing with problem drinkers. Behavioural Psychotherapy. 1983;11:147-172.

390. Lai DT, Cahill K, Qin Y, Tang, JL. Motivational interviewing for smoking cessation. Cochrane Database Syst Rev. 2010;(1):CD006936.

391. Lindson-Hawley N, Thompson TP, Begh R. Motivational interviewing for smoking cessation. Cochrane Database Syst Rev. 2015;3:CD006936.

392. Ruger JP, Weinstein MC, Hammond SK, Kearney MH, Emmons KM. Cost-effectiveness of motivational interviewing for smoking cessation and relapse prevention among low-income pregnant women: a randomized controlled trial. Value Health. 2008;11(2):191-198.

393. Lee E. Cross-cultural communication: therapeutic use of interpreters. In: Lee E (ed). Working with Asian Americans: A Guide for Clinicians. New York, NY: The Guilford Press; 1997: 477-489.

394. Thompson RS, Michnich ME, Friedlander L, Gilson B, Grothaus LC, Storer B. Effectiveness of smoking cessation interventions integrated into primary care practice. Med Care. 1988;26(1):62-76.

395. Maciosek MV, Coffield AB, Flottemesch TJ, Edwards NM, Solberg LI. Greater use of preventive services in U.S. health care could save lives at little or no cost. Health Aff (Milwood). 2010;29(9):1656-1660.

396. Cromwell J, Bartosch WJ, Fiore MC, Hasselblad V, Baker T. Cost-effectiveness of the clinical practice recommendations in the AHCPR guideline for smoking cessation. JAMA. 1997;278(21):1759-1766.

397. Hall S, Rugg D, Tunstall C, Jones RT. Preventing relapse to cigarette smoking by behavioral skill training. J Consult Clin Psychol. 1984;52(3):372-382.

398. Stevens VJ, Hollis JF. Preventing smoking relapse using an individually tailored skills-training technique. J Consult Clin Psychol. 1989;57(3):420-424.

399. Tiffany ST, Martin EM, Baker TB. Treatments for cigarette smoking: an evaluation of the contributions of aversion and counseling procedures. Behav Res Ther. 1986;24(4):437-452.

400. Hajek P, Stead LF. Aversive smoking for smoking cessation. Cochrane Database Syst Rev. 2004;(3):CD000546.

401. Hajek P, Stead LF. Aversive smoking for smoking cessation. Cochrane Database Syst Rev. 2000;(2):CD000546.

402. Cinciripini PM, Lapitsky LG, Wallfisch A, Mace R, Nezami E, Van Vunakis H. An evaluation of a multicomponent treatment program involving scheduled smoking and relapse prevention procedures: initial findings. Addict Behav. 1994;19(1):13-22.

403. Pfizer Inc. Chantix (Varenicline) Tablets. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021928s008lbl.pdf. Last accessed April 22, 2019.

404. Stead LF, Perera R, Bullen C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2012:CD000146.

405. Gorsline J, Okerholm RA, Rolf CN, Moos CD, Hwang SS. Comparison of plasma nicotine concentrations after application of nicoderm (nicotine transdermal system) to different skin sites. J Clin Pharmacol. 1992;32(6):576-581.

406. Orleans CT, Resch N, Noll E, et al. Use of transdermal nicotine in a state-level prescription plan for the elderly: a first look at "real-world" patch users. JAMA. 1994;271:601-607.

407. Prochazka AV. New developments in smoking cessation. Chest. 2000;117(4 Suppl 1):169S-175S.

408. Schnoll RA, Patterson F, Wileyto EP, et al. Effectiveness of extended-duration transdermal nicotine therapy: a randomized trial. Ann Intern Med. 2010;152(3):144-151.

409. Schnoll RA, Goelz PM, Veluz-Wilkins A, et al. Long-term nicotine replacement therapy: a randomized clinical trial. JAMA Intern Med. 2015;175(4):504-511.

410. Frishman WH, Ky T, Ismail A. Tobacco smoking, nicotine, and nicotine and non-nicotine replacement therapies. Heart Dis. 2001;3(6):365-377.

411. Schneider NG, Jarvik ME, Forsythe AB, Read LL, Elliott ML, Schweiger A. Nicotine gum in smoking cessation: a placebo-controlled, double-blind trial. Addict Behav. 1983;8(3):253-261.

412. Shiffman S, Di Marino ME, Pillitteri JL. The effectiveness of nicotine patch and nicotine lozenge in very heavy smokers.J Subst Abuse Treat. 2005;28(1):49-55.

413. Hurt RD. New medications for nicotine dependence treatment. Nicotine Tob Res. 1999;1(Suppl 2):S175-S179, S207-S210.

414. Molander L, Lunell E, Fagerström KO. Reduction of tobacco withdrawal symptoms with a sublingual nicotine tablet: a placebo controlled study. Nicotine Tob Res. 2000;2(2):187-191.

415. Tønnesen P, Mikkelsen K, Bremann L. Nurse-conducted smoking cessation in patients with COPD using nicotine sublingual tablets and behavioral support. Chest. 2006;130(2):334-342.

416. Sun H, Guo S, Chen DF, et al. Family support and employment as predictors of smoking cessation success: a randomized, double-blind, placebo-controlled trial of nicotine sublingual tablets in Chinese smokers. Am J Drug Alcohol Abuse. 2009;35(3):183-188.

417. Molander L, Lunell E. Pharmacokinetic investigation of a nicotine sublingual tablet. Eur J Clin Pharmacol. 2001;56(11):813-819.

418. Shiffman S. Effect of nicotine lozenges on affective smoking withdrawal symptoms: secondary analysis of a randomized, double-blind, placebo-controlled clinical trial. Clin Ther. 2008;30(8):1461-1475.

419. Hjalmarson A, Franzon M, Westin A, Wiklund O. Effect of nicotine nasal spray on smoking cessation: a randomized, placebo-controlled, double-blind study. Arch Intern Med. 1994;154(22):2567-2572.

420. Schneider NG, Olmstead R, Mody FV, et al. Efficacy of a nicotine nasal spray in smoking cessation: a placebo-controlled, double-blind trial. Addiction. 1995;90(12):1671-1682.

421. Sutherland G, Stapleton JA, Russell MA, et al. Randomised controlled trial of nasal nicotine spray in smoking cessation. Lancet. 1992;340(8815):324-329.

422. Silagy C, Mant D, Fowler G, Lodge M. Meta-analysis on efficacy of nicotine replacement therapies in smoking cessation. Lancet. 1994;343(8890):139-142.

423. Schneider NG, Lunell E, Olmstead RE, Fagerström KO. Clinical pharmacokinetics of nasal nicotine delivery: a review and comparison to other nicotine systems. Clin Pharmacokinet. 1996;31(1):65-80.

424. Schneider NG, Olmstead RE, Franzon MA, Lunell E. The nicotine inhaler: clinical pharmacokinetics and comparison with other nicotine treatments. Clin Pharmacokinet. 2001;40(9):661-684.

425. Rose JE, Behm FM, Westman EC, Johnson M. Dissociating nicotine and nonnicotine components of cigarette smoking. Pharmacol Biochem Behav. 2000;67(1):71-81.

426. Ascher JA, Cole JO, Colin JN, et al. Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry. 1995;56(9):395-401.

427. Hughes JR, Goldstein MG, Hurt RD, Shiffman S. Recent advances in the pharmacotherapy of smoking. JAMA. 1999;281(1):72-76.

428. Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med.1997;337(17):1195-1202.

429. Fiscella K, Franks P. Cost-effectiveness of the transdermal nicotine patch as an adjunct to physicians' smoking cessation counseling. JAMA. 1996;275(16):1247-1251.

430. Lexicomp Online. Available at https://online.lexi.com. Last accessed April 22, 2019.

431. Tonstad S, Tønnesen P, Hajek P, et al. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA. 2006;296(1):64-71.

432. Gonzales D, Rennard SI, Nides M, et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs. sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA. 2006;296(1):47-55.

433. Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs. placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006;296(1):56-63.

434. Mills EJ, Wu P, Lockhart I, Thorlund K, Puhan M, Ebbert JO. Comparisons of high-dose and combination nicotine replacement therapy, varenicline, and bupropion for smoking cessation: a systematic review and multiple treatment meta-analysis. Ann Med. 2012;44(6):588-597.

435. Chang PH, Chiang CH, Ho WC, Wu PZ, Tsai JS, Guo FR. Combination therapy of varenicline with nicotine replacement therapy is better than varenicline alone: a systematic review and meta-analysis of randomized controlled trials. BMC Public Health. 2015;22:689.

436. Gourlay SG, Stead LF, Benowitz NL. Clonidine for smoking cessation. Cochrane Database Syst Rev. 2000;(2):CD000058.

437. Lancaster T, Stead LF. Silver acetate for smoking cessation. Cochrane Database Syst Rev. 2000;(2):CD000191.

438. Lancaster T, Stead LF. Silver acetate for smoking cessation. Cochrane Database Syst Rev. 2012;9:CD000191.

439. Lancaster T, Stead LF. Mecamylamine (a nicotine antagonist) for smoking cessation (review). Cochrane Database Syst Rev. 2000;(2):CD001009.

440. Rose JE, Behm FM, Westman EC, Levin ED, Stein RM, Ripka GV. Mecamylamine combined with nicotine skin patch facilitates smoking cessation beyond nicotine patch treatment alone. Clin Pharmacol Ther. 1994;56(1):86-99.

441. Bergen AW, Caporaso N. Cigarette smoking. J Natl Cancer Inst. 1999;91(16):1365-1375.

442. Fagerström K. New perspectives in the treatment of tobacco dependence. Monaldi Arch Chest Dis. 2003;60(3):179-183.

443. National Institute on Drug Abuse. Medication Reduces Metabolism of Nicotine, Decreasing Urge to Smoke. Available at https://archives.drugabuse.gov/news-events/news-releases/2000/07/medication-reduces-metabolism-nicotine-decreasing-urge-to-smoke. Last accessed April 22, 2019.

444. Zhang W, Kilicarslan T, Tyndale RF, Sellers EM. Evaluation of methoxsalen, tranylcypromine, and tryptamine as specific and selective CYP2A6 inhibitors in vitro. Drug Metab Dispos. 2001;26(6):897-902.

445. Hughes JR, Higgins ST, Bickel WK. Nicotine withdrawal versus other drug withdrawal syndromes: similarities and dissimilarities. Addiction. 1994;89(11):1461-1470.

446. Centers for Disease Control and Prevention. Current cigarette smoking among adults—United States, 2016. MMWR. 2018;67(2);54-59.

447. Josefson D. U.S. flight attendants win settlement over passive smoking. BMJ. 1997;315(7114):968.

448. Flight Attendant Medical Research Institute. Mission Statement. Available at http://www.famri.org/about_famri/mission_statement.html. Last accessed April 22, 2019.

449. Henningfield JE, Benowitz NL, Connolly GN, et al. Reducing tobacco addiction through tobacco product regulation. Tob Control. 2004;13(2):132-135.

450. Campaign for Tobacco-Free Kids. Voters Across the Country Support Significant Increases in Cigarette Taxes. Available athttps://www.tobaccofreekids.org/research/factsheets/pdf/0026.pdf. Last accessed April 22, 2019.

451. Campaign for Tobacco-Free Kids. Raising Tobacco Taxes: A Win-Win-Win. Available at https://www.tobaccofreekids.org/assets/factsheets/0385.pdf. Last accessed April 22, 2019.

452. Cancer Action Network. 94-Cent Federal Cigarette Tax Increase: New Revenue, Public Health Benefits, and Cost Savings. Available at https://www.fightcancer.org/policy-resources/94-cent-federal-cigarette-tax-increase-new-revenue-public-health-benefits-and-cost. Last accessed May 2, 2019.

453. Centers for Disease Control and Prevention. Trends in State and Federal Cigarette Tax and Retail Price—United States, 1970–2016. Available at https://www.cdc.gov/tobacco/infographics/economics/index.htm. Last accessed May 2, 2019.

454. Eriksen MP, Gottlieb NH. A review of the health impact of smoking control at the workplace. Am J Health Promot. 1998;13(2): 83-104.

455. Green E, Courage C, Rushton L. Reducing domestic exposure to environmental tobacco smoke: a review of attitudes and behaviours. J R Soc Promot Health. 2003;123(1):46-51.

456. Wang TW, Asman K, Gentzke AS, et al. Tobacco product use among adults—United States, 2017. MMWR. 2018;67(44):1225-1232.

457. National Institute on Drug Abuse. DrugFacts: Electronic Cigarettes (e-Cigarettes). Available at https://www.drugabuse.gov/publications/drugfacts/electronic-cigarettes-e-cigarettes. Last accessed April 2, 2019.

458. U.S. Food and Drug Administration. FDA's Deeming Regulations for E-Cigarettes, Cigars, and All Other Tobacco Products. Available at https://www.fda.gov/tobaccoproducts/labeling/rulesregulationsguidance/ucm394909.htm. Last accessed April 2, 2019.

459. Singh T, Arrazola RA, Corey CG, et al. Tobacco use among middle and high school students—United States, 2011–2015.MMWR. 2016;65(14):361-367.

460. National Center for Health Statistics. Early Release of Selected Estimates Based on Data from January–September 2018 National Health Interview Survey. Available at https://www.cdc.gov/nchs/nhis/releases/released201903.htm. Last accessed March 29, 2019.

461. Lindson-Hawley N, Banting M, West R, Michie S, Shinkins B, Aveyard P. Gradual versus abrupt smoking cessation: a randomized, controlled noninferiority trial. Ann Intern Med. 2016;164(9):585-592.

462. Scott-Sheldon LA, Lantini R, Jennings EG, et al. Text messaging-based interventions for smoking cessation: a systematic review and meta-analysis. JMIR. 2016;4(2).

463. Baker TB, Piper ME, Stein JH, et al. Effects of nicotine patch vs. varenicline vs combination nicotine replacement therapy on smoking cessation at 26 weeks: a randomized clinical trial. JAMA. 2016;315(4):371-379.

464. U.S. Food and Drug Administration. FDA Takes New Steps to Address Epidemic of Youth E-Cigarette Use, Including a Historic Action. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm620184.htm. Last accessed April 2, 2019.

465. U.S. Food and Drug Administration. Youth Tobacco Use: Results from the National Youth Tobacco Survey. Available at https://www.fda.gov/TobaccoProducts/PublicHealthEducation/ProtectingKidsfromTobacco/ucm405173.htm. Last accessed April 1, 2019.

466. Heger A, Sator M, Walch K, Pietrowski D. Smoking decreases endometrial thickness in IVF/ICSI patients. Geburtshilfe Frauenheilkd. 2018;78(1):78-82.

467. Mojtabai R, Crum RM. Cigarette smoking and onset of mood and anxiety disorders. Am J Public Health. 2013;103(9):1656-1665.

468. Feng RM, Hu SY, Zhao FH, et al. Role of active and passive smoking in high-risk human papillomavirus infection and cervical intraepithelial neoplasia grade 2 or worse. J Gynecol Oncol. 2017;28(5):e47.

469. Min KJ, Lee JK, So KA, Kim MK. Association between passive smoking and the risk of cervical intraepithelial neoplasia 1 in Korean women. J Epidemiol. 2018;28(1):48-53.

470. American College of Cardiology. 2018 ACC expert consensus decision pathway on tobacco cessation treatment. J Am Coll Cardiol. 2018;72(25):3332-3365.

471. Tomko RL, Saladin ME, Baker NL, et al. Sex differences in subjective and behavioral responses to stressful and smoking cues presented in the natural environment of smokers. Nicotine Tob Res. 2018; [Epub ahead of print].

472. U.S. Food and Drug Administration. FDA Announces Comprehensive Regulatory Plan to Shift Trajectory of Tobacco-Related Disease, Death. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm568923.htm. Last accessed April 23, 2019.

473. Campaign for Tobacco-Free Kids. Raising Cigarette Taxes Reduces Smoking, Especially Among Kids (And the Cigarette Companies Know it). Available at https://www.tobaccofreekids.org/assets/factsheets/0146.pdf. Lat accessed April 22, 2019.

474. U.S. Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, M.D., on Actions to Advance our Comprehensive Plan to Reduce Tobacco-Related Disease and Death, Through New Efforts to Improve the Tobacco Product Application Review Process, Including a Newly Proposed Rule. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm634652.htm. Last accessed April 23, 2019.

475. U.S. Food and Drug Administration. FDA Updates and Press Announcements on Nitrosamine in Varenicline (Chantix). Available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-nitrosamine-varenicline-chantix. Last accessed March 15, 2022.

Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Primary care interventions to prevent tobacco use in children and adolescents: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(8):552-557. Available at http://annals.org/aim/fullarticle/1748857. Last accessed May 13, 2019.

2. U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement.Ann Intern Med. 2014;160(5):330-338. Available at http://annals.org/aim/fullarticle/1809422. Last accessed May 13, 2019.

3. Tobacco exposure. In: Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Bethesda, MD: National Heart, Lung, and Blood Institute; 2011. Available at https://www.nhlbi.nih.gov/node/80308. Last accessed May 13, 2019.

4. U.S. Preventive Services Task Force. Behavioral and pharmacotherapy interventions for tobacco smoking cessation in adults, including pregnant women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015;163(8):622-634. Available at http://annals.org/aim/fullarticle/2443060. Last accessed May 13, 2019.

5. University of Michigan Health System. Tobacco Treatment. Ann Arbor, MI: University of Michigan Health System; 2012. Available at https://www.med.umich.edu/1info/FHP/practiceguides/smoking/smoking.pdf. Last accessed May 13, 2019.

94923 • Animal-Related Health Risks

Sharon Holt, DVM, MBA, ADN

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

There are many potential diseases, or zoonoses, that can spread from animals to humans, and the public has many misconceptions about what to do after a potential exposure to a zoonotic source. With basic precautions, most zoonoses are preventable or avoidable. In this course, methods of prevention are discussed as well as general treatment guidelines. Patient education points are also included, as it is an important part of the process of preventing exposure to zoonoses.

Table of Contents

94923 • Animal-Related Health Risks

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. HISTORY

3. DEFINITIONS

HOST CHARACTERISTICS

VECTORS

TRANSMISSION

MORBIDITY, PREVALENCE, AND MORTALITY

4. CLASSIFICATION AND REPORTING

AGENTS

5. TICKBORNE DISEASES

LYME DISEASE

TULAREMIA

ROCKY MOUNTAIN SPOTTED FEVER

EHRLICHIOSIS

BABESIOSIS

6. VIRAL ZOONOTIC DISEASES

WEST NILE VIRUS

ZIKA VIRUS

DENGUE FEVER

RABIES

AVIAN INFLUENZA

SWINE INFLUENZA

HANTAVIRUS SYNDROMES

LYMPHOCYTIC CHORIOMENINGITIS (LCM)

BOVINE SPONGIFORM ENCEPHALITIS (BSE)

7. PROTOZOAL ZOONOTIC DISEASES

TOXOPLASMOSIS

GIARDIASIS

MALARIA

8. BACTERIAL ZOONOTIC DISEASES

ANTHRAX

VIBRIO AND CHOLERA

BOTULISM

SALMONELLOSIS

BRUCELLOSIS

9. PARASITIC ZOONOTIC DISEASES

TRICHINOSIS

TAPEWORMS

ANISAKIASIS

10. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

94923 • Animal-Related Health Risks

Education Category. Infection Control / Internal Medicine

Release Date. 05/01/2020

Expiration Date. 04/30/2023

Course Overview

There are many potential diseases, or zoonoses, that can spread from animals to humans, and the public has many misconceptions about what to do after a potential exposure to a zoonotic source. With basic precautions, most zoonoses are preventable or avoidable. In this course, methods of prevention are discussed as well as general treatment guidelines. Patient education points are also included, as it is an important part of the process of preventing exposure to zoonoses.

Audience

This course is designed for physicians, nurses, and allied health staff involved in identifying, treating, and preventing zoonotic diseases, including West Nile virus, Lyme disease, and avian influenza.

Course Objective

The purpose of this course is to increase the awareness of zoonotic diseases and their management in both prevention and care. There are many potential diseases that can spread from animals to humans, and with basic precautions, most zoonoses are preventable or at least avoidable. The public has many misconceptions about what to do after a potential exposure to a zoonotic source, and healthcare professionals are often the first to help and answer questions.

Learning Objectives

Upon completion of this course, you should be able to:

1. Reflect on the history of zoonotic diseases.

2. Define the hosts and host characteristics associated with zoonotic diseases.

3. Compare the types of vectors and transmission of zoonotic diseases.

4. Discuss the classification of zoonotic diseases.

5. Identify the common pathogens involved in the spread of infection from animals to humans.

6. Discuss the clinical presentation, diagnosis, and treatment of Lyme disease.

7. Outline characteristics and treatment of other tickborne zoonotic diseases, including tularemia, Rocky Mountain spotted fever (RMSF), and ehrlichiosis.

8. Discuss the clinical presentation, diagnosis, and treatment of West Nile virus infection.

9. Describe the characteristics and treatment of other viral zoonotic diseases, including avian influenza.

10. Discuss the background, clinical presentation, and prevention of bovine spongiform encephalitis (BSE) and its resulting disease in humans, variant Creutzfeldt-Jakob disease (vCJD).

11. Identify some of the common protozoal zoonotic diseases.

12. Describe the characteristics and treatment of anthrax infection.

13. Identify other common bacterial zoonotic diseases, including cholera.

14. Recall the characteristics of common parasitic zoonotic diseases and appropriate treatment.

15. Outline the role of an interpreter in treating non-English-proficient patients.

Faculty

Sharon Holt, DVM, MBA, ADN, graduated from Ohio University with a Bachelor's degree in fine art in 1977. She returned to Greater Hartford Community College and she earned an Associate degree in nursing in 1979. She later received a Master's in business administration in marketing management in 1983 from University of Hartford. She received her doctorate in veterinary medicine from Tufts University School of Veterinary Medicine in 1997. Dr. Holt has been working in wildlife medicine for more than 15 years and has lectured on the subject at the University of Massachusetts. Her nursing background includes acute care, emergency room, critical care, clinic settings, and case management for a non-profit visiting nurse association. She currently owns her own veterinary practice in Massachusetts and provides veterinary vaccine clinics in western Massachusetts.

Faculty Disclosure

Contributing faculty, Sharon Holt, DVM, MBA, ADN, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

In this era of globalization and rapid world travel, diseases that were once localized to a country or region or that were uncommon in developed countries are now found in new or widespread areas. Examples include avian influenza, West Nile encephalitis, plague, "mad cow disease," rabies, and to a lesser extent, Lyme disease. These and many other diseases belong to a category known as zoonoses, or zoonotic diseases.

A zoonosis is an infection transmitted from a vertebrate animal to humans. The animal is the natural host and may simply be a carrier of the infectious agent without suffering any disease from the infection itself. This is the case in many diseases that are persistently difficult to control, such as infection with certain roundworms. The host may act only as the reservoir, with a vector being the actual source of the exposure and subsequent infection. Some diseases, such as Lyme disease, babesiosis, and Rocky Mountain spotted fever (RMSF), are transmitted to humans and other non-target hosts through insect (arthropod) vectors. The animal host may become ill from the infection, but the signs of illness can be quite different in human cases or the organism may target different organ systems when infecting other than the definitive host animal. The environment and degree of susceptibility will also determine whether transmission actually occurs after an exposure. Immunosuppressed individuals, the elderly, children, and pregnant women may have a greater susceptibility to illness caused by some zoonotic infections.

2. HISTORY

Several zoonoses have been known and documented as animal-to-human diseases from much earlier times. Rabies was known and written of many centuries ago, as were ringworm, tetanus, and plague (Yersinia pestis). For example, the bite of a "mad dog" was known to transmit rabies in the 1300s, though obviously the knowledge of the virus came much more recently [1]. The invention of the light microscope by Leeuwenhoek in the late 1600s allowed visualization of the agents of zoonoses for the first time. Bacteria and parasites could be seen, and the connection between a disease and its causative agent could be confirmed.

Tapeworms, liver flukes, and roundworms were readily seen with the early microscopes. Linnaeus began classification in the mid-1700s and was the first to describe many zoonotic parasites in an early edition of Systema Naturae[2]. The smaller parasites have been identified and described as the microscope's capability has advanced to recognize the role of microscopic agents in zoonotic diseases. Protozoa of zoonotic importance were not identified until the early 1900s, and smaller organisms are still being discovered today.

More refined microscopes and the use of stains allowed for the description of bacterial agents of disease in the 1870s. The ability to culture bacteria began in 1881, and most bacteria were quickly described in the next 20 years [3]. The ability to culture an organism allowed confirmation that the same agent present in a host animal could be the causative agent of a human disease. This is the basis of Koch's postulate: confirmation of the disease by isolating the proposed agent and then reproducing the disease by introducing the isolate into a host animal [4].

In 1934, the electron microscope allowed viruses to be visualized for the first time [5]. Most were known to exist from cellular changes seen with the light microscope, but once the viruses could be visually identified, they were quickly classified. If a carrier state exists or if only a small number of the host's population carry the disease, discovery of the etiology is more difficult. There may be an intermediate host or vector yet to be identified that is involved in the transmission.

It is interesting to note that various religions have historically had dietary restrictions that had the effect of curtailing the spread of foodborne zoonoses by limiting certain food products. For example, Jewish and Muslim religions banned the consumption of pork and other animals that rooted for food. Certain insect species that carry parasitic diseases can be accidentally ingested when the food animal roots in the ground. In some cases, the infected insect may be a part of the animal's regular diet.

Many processes and even whole industries have been developed as public health measures to deal with zoonoses. Pasteurization of milk, meat inspection, vaccinations, and insect control measures are examples of public health practices in the United States that are specifically aimed at preventing zoonotic diseases. Individual steps can be taken as well, such as boiling water that is of uncertain purity and cooking meat and fish properly. Improving the health of the public will require more education about food and safety issues if many of the dangerous zoonoses are to be avoided.

3. DEFINITIONS

HOST CHARACTERISTICS

A host is an animal (including humans) that can support an infective agent of a zoonotic disease. Many agents require more than one host to complete their lifecycle. The definitive host is an animal that supports an organism in the final reproduction phase of its lifecycle. Without the definitive host, normal reproduction of the organism will not occur. The secondary or intermediate host is needed in multiple lifecycle agents for some phase of their development. For example, the dog flea (Ctenocephalides canis) and the cat flea (Ctenocephalides felis) are the intermediate hosts for the dog tapeworm Dipylidium caninum. Ingestion of the flea, which carries the infective agent, leads to infection with the tapeworm.

A dead-end or aberrant host is one in which the organism can survive, perhaps only briefly, but from which it cannot reproduce or transmit disease. Such is the case with eastern equine encephalomyelitis (EEE) and the horse. The virus cannot continue to spread from an infected horse because it will kill the animal before it has a chance to reproduce. The horse in this situation is a sentinel for EEE, because the incubation period is shorter in horses than in humans. Deaths in horses from the infection will be seen prior to documented human cases in the same area. Many horses are vaccinated against the disease in endemic areas, so the number of sentinels may be very small. Eastern encephalomyelitis (EE) in humans carries a high case fatality rate (33% to 70%), and the sentinel serves as an early warning that human cases may soon be presenting at emergency rooms in the same vicinity [6]. Transmission does not occur between horse and human, as both are aberrant hosts. Another animal must serve as the reservoir. In many cases, the zoonosis is seen only sporadically because the vector that transmits the disease is not present. In addition, the reservoir can vary in its carrier status from year to year.

An animal may be the natural host for the disease, and humans or other animals may be aberrant hosts. The actual signs and symptoms of the disease in the aberrant host may be a result of the organism's inability to support itself in the wrong animal host. The aberrant host may be significantly different anatomically or physiologically, making the agent unable to find a suitable site in which to exist. Digestive tracts vary tremendously between different mammalian, avian, and reptilian species. This can lead to a disease agent searching for a part in the aberrant host's body that is similar to the natural host. The aberrant host may not even have the same organ system that the agent requires to grow. This is the case in diseases that are manifested by migration of parasites throughout organs while they search for a target organ or system that is reasonably similar to that of the regular host. In some cases, the agent is in an environment so unlike what it is searching for that it will not produce a zoonosis. Humans are constantly exposed to many agents that do not affect us, such as heartworm.

Parasites have evolved through natural selection in ways that, under normal circumstances, will not render a healthy definitive host incapacitated. Natural selection eliminates parasites that kill their hosts before reproduction and transmission can be successfully achieved. Most have a symbiotic relationship and affect the animal in subtle ways, such as slower weight gain or a decrease in egg production. For an animal to actually appear unhealthy usually requires a fairly heavy infestation with parasites. Obviously, seriously infected animals or those sick from other causes would be more vulnerable to the effects of a heavy parasite load.

Like parasitic diseases, most bacterial and fungal infections tend not to impact the definitive host in such a severe manner as to be immediately noticeable. Some zoonotic bacteria are normal flora or commensals in one animal and pathogenic in another species. Pasteurella spp. in a cat's mouth are considered normal flora but can be a difficult-to-treat zoonosis when transferred to a human via a bite wound. Escherichia coli contamination of meat is another example of normal flora from an animal making the consumer ill.

Viruses produce more variability in the degree of illness seen in the hosts. Reproduction of a virus occurs at the cellular level in the host, with either a cell's RNA or DNA. There are groups of RNA viruses that are transmitted through arthropod vectors, but most require some type of direct contact, such as a bite wound. Not being independent organisms, these viruses require direct transmission or a vector that can transmit effectively while maintaining the viability of the virus. Most are sensitive to temperature fluctuations and other environmental factors.

VECTORS

An insect that allows multiplication or growth of an agent while it is in the host is a biologic vector, as with the earlier example of the flea. Ticks and mosquitoes are biologic vectors for many zoonoses. Some of the more serious zoonoses transmitted by arthropods are Lyme disease, RMSF, Q fever, malaria, plague, and West Nile encephalitis. Insects can also transmit less serious diseases, such as tapeworms and some species of trematodes (parasitic flatworms).

Mechanical vectors can be something as simple as shoes carrying disease from work to home. Airborne sources or fomites can transmit diseases such as tuberculosis from animal to human or from human to animal. Meat or other animal-derived consumer products can carry zoonotic agents. For example, pork products are likely sources of trichinosis.

TRANSMISSION

Transmission of zoonoses can be either direct or indirect. A disease that is directly transmitted from an animal to humans usually requires close or intimate contact. As examples, direct transmission occurs when the act of touching a ringworm lesion on a cat directly results in infection, or when rabies is transmitted from the bite of a rabid animal. Indirect transmission occurs with the presence of a vector between animal and human. Insects, inanimate objects, or animal food products can all be sources of indirect transmission of a zoonosis. Some insects can transmit an infectious agent in their bite, as in the case of ticks and mosquitoes. Flies, such as the housefly, can carry many pathogenic organisms in their mouth parts and on their feet. They can spread a zoonosis by contaminating open wounds or other breaks in the skin of the host. Many arthropods, such as the horse fly (Tabanus spp.), bite and spread disease in the same manner.

There are associated risk factors that determine transmission rate. As noted, immunocompromised individuals, the elderly, and the very young may be at greater risk, depending on the zoonosis. Pregnant women are at risk for zoonoses that can cross placental barriers or potentially cause spontaneous abortion.

The time of year affects the shedding rates of some parasites. Many viruses and bacteria have temperature preferences that affect the time of year that they are most frequently seen. Some parasites reproduce at intervals that coincide with their definitive host's reproduction cycle. In this way, they increase their numbers when more hosts are potentially less able to combat the organism with natural immune capabilities. The environment will also affect the transmission rate of some organisms. Sunlight, pH, air quality, humidity, and temperature are classic variables used to determine the degree of transmission rate for a zoonosis and the agent's survivability in the environment.

State public health departments have surveillance plans for the more serious zoonotic diseases [7]. National public health concerns are also under the surveillance of the Centers for Disease Control and Prevention (CDC) and other organizations [7]. Global surveillance is monitored by several international concerns, including the World Health Organization (WHO) [7]. Depending on the degree of risk of a particular disease and how serious a threat it is, a report of a zoonosis will be considered an epidemic when a predetermined number has been exceeded. In animals, this is called an epizootic. If the disease occurs worldwide, it is referred to as a pandemic (panzootic). Even when a zoonosis is only an individual exposure without associated serious risks, the state public health department may be interested in being informed of the incidence, if only for monitoring purposes.

MORBIDITY, PREVALENCE, AND MORTALITY

Morbidity refers to individuals who become ill in the susceptible population in any outbreak. The susceptible population might be an isolated village or an entire country, depending on the disease and its transmission characteristics. The mortality rate is the number of individuals in the susceptible population who die of the illness over a specific period of time. The prevalence rate is the number of individuals out of the potential population who are ill at any one time or specified period of time. The case fatality rate is simply the fraction of known affected individuals who die, expressed as a percentage; for example, a zoonotic outbreak of 50 confirmed cases with 5 deaths would have a case fatality rate of 10%. This percentage gives a sense of the severity of the zoonosis, especially when the number of actual cases may be low. For example, Ebola carries a high case fatality rate, 80% to 90% in some regions, and rabies is nearly 100% fatal when untreated anywhere it occurs [8,9].

4. CLASSIFICATION AND REPORTING

The scope and multitude of zoonotic diseases are too great for a single course to cover. There are a tremendous number of zoonoses that are not seen commonly in the United States but that are of major importance in other countries. These will not be addressed in detail, but healthcare professionals should have an idea of the basic concepts of the zoonoses and the agents that cause them. This knowledge can help serve the patient who has a recent travel history outside the United States and presents with a mysterious illness. If the illness is unexplained, a zoonotic disease may be considered when taking the history. Contacting an appropriate agency for assistance may be indicated. The CDC can provide information about specific diseases in different countries if a local resource, such as the Public Health Office, is not able to help. The United States Department of Agriculture (USDA) can also assist in identifying specific zoonoses prevalent in different countries and can caution travelers about what types of things to avoid in terms of food and animal products while traveling. In addition, the USDA carefully monitors agricultural products brought into the country.

There are many ways of categorizing common zoonoses. In this course, zoonoses will be categorized by causative agent initially, and some important specific zoonoses will be discussed in detail. Parasites are responsible for many zoonotic diseases, so the type of illness manifested can be similar for different species of parasite [10]. Bacterial agents are also a common etiology, as are viruses [10]. Although it is commonly overlooked, humans can transmit diseases to animals as well. For example, tuberculosis has been passed to elephants in zoos and primates in research facilities.

Some zoonoses are reportable by law for either animal or human cases. Typhus and tuberculosis are prime examples [11]. A classification system for zoonotic disease cases has been developed, with a rank of 1 to 5, with subclassifications that should be utilized when determining if a case report or notification is necessary (Table 1). This classification system has been agreed upon internationally and drafted by the American Public Health Association (APHA), which derived it from guidelines written by the WHO [12]. International animal zoonoses with serious risk are reportable to the Office International des Epizooties (OIE) [12]. Generally, if in doubt, there is no harm in reporting, because the case report could be helpful at some later date.

Table 1: CLASSIFICATION SYSTEM FOR REPORTING ZOONOTIC CASES

Class

Reporting Requirement

Subclass

Types of Diseases/Conditions

1

Case report is universally required by International Health Regulations (IHR) or as a Disease Under Surveillance by the World Health Organization (WHO).

1A

Diseases subject to IHR or those that are internationally important and are quarantinable (e.g., plague, yellow fever)

1B

Diseases under surveillance by the WHO (e.g., some forms of typhus)

2

Case report is regularly required whenever disease occurs.

2A

Notification to local health officials by expedient means (i.e., telephone report). Quick reporting could make a difference in preventing additional cases. Botulism or other clostridial infections fall into this category.

Notification by most practical means, as with trichinosis

3

Selectively reportable in recognized endemic areas. These are diseases that are not an issue in some locales and at the same time are significant problems in other areas.

3A

Where it is reportable, treat the disease as a 2A (e.g., Lyme disease in some areas)

Where it is reportable, treat as with 2B (e.g., Rocky Mountain spotted fever)

4

Obligatory report of epidemics. No case report is required, but make a prompt telephone report of unknown outbreaks or other diseases of public health importance.

NA

Food poisoning

5

Official report is not ordinarily justifiable. Those diseases are not as easily transmitted and/or are sporadic in occurrence. Outbreaks do not have control measures and are of low risk, but epidemiological interest exists.

NA

Common cold

Source: [12]

AGENTS

Parasites

Parasites that can cause disease directly in the host (not just transmission of a zoonosis) are represented in five different phyla: the pentastomida, nematodes, trematodes, cestodes, and protozoa (Table 2) [10].

Table 2: PARASITIC ZOONOSES

Agent

Disease in Humans

Nematodes

Ancylostoma braziliense

Cutaneous larva migrans

Ancylostoma caninum

Cutaneous larva migrans

Anisakis marina

Anisakiasis

Baylisascaris procyonis

Visceral larva migrans

Bunostomum phlebotomum

Cutaneous larva migrans

Capillaria aerophila

Capillariasis

Capillaria hepatica

Capillariasis

Haemonchus contortus

Trichostrongyliasis

Ostertagia spp.

Trichostrongyliasis

Toxocara canis

Visceral larva migrans

Toxocara cati

Visceral larva migrans

Trichinella spiralis

Trichinosis

Uncinaria stenocephala

Cutaneous larva migrans

Trematodes

Echinostoma ilocanum

Echinostomiasis

Fasciola gigantica

Fascioliasis

Fasciola hepatica

Fascioliasis

Fasciolopsis buski

Fasciolopsiasis

Paragonimus westermani

Paragonimiasis

Schistosoma japonicum

Schistosomiasis

Schistosoma mansoni

Schistosomiasis

Cestodes

Diphyllobothrium latum

Fish tapeworm

Diphyllobothrium spp.

Sparganosis

Dipylidium caninum

Dog tapeworm

Echinococcus granulosus

Hydatidosis

Echinococcus multilocularis

Hydatidosis

Taenia saginata

Beef tapeworm

Taenia solium

Pork tapeworm

Protozoa

Babesia bovis

Piroplasmosis/Babesiosis

Babesia microti

Piroplasmosis/Babesiosis

Balantidium coli

Balantidiasis

Cryptosporidium parvum

Cryptosporidiosis

Entamoeba histolytica

Amebiasis

Giardia lamblia (intestinalis)

Giardiasis

Leishmania mexicana

American leishmaniasis

Plasmodium spp.

Malaria

Sarcocystis hominis (bovihominis)

Sarcocystosis

Toxoplasma gondii

Toxoplasmosis

Source: Compiled by Author

The pentastomida are very primitive, worm-like parasites that primarily infect the lungs of reptiles. Human infection is by the larval stage. The spleen, liver, and/or lungs may be infected, but fortunately, the disease is self-limiting and usually not significant. While no fatalities have been reported, because any parasite is a foreign protein, a hypersensitivity reaction is a possible outcome with any of the parasitic zoonoses.

Nematodes are commonly referred to as roundworms, with hookworm being a common example. There are many zoonotic forms of nematode infections. One example is trichinosis, which will be discussed in detail later in this course. In general, most nematode zoonoses are transmitted through ingestion of the egg stage of the organism [10]. When in the feces, the eggs will hatch into the infective larval stage after 24 hours in most species. Occasionally, the larval phase of the parasite will penetrate the skin, usually through the sole of the foot because an individual has walked barefoot where larval forms of the nematode are present. This form of infection is referred to as cutaneous larval migrans. It is one of the better reasons not to walk barefoot in a city park, an unfamiliar backyard, or a veterinarian's office.

Trematodes, commonly called flukes or flatworms, are usually transmitted via ingestion [10]. As with the nematodes, some species can penetrate the skin and migrate to various organs. Most hatch in the gastrointestinal tract and migrate to other areas of the body to cause infection, unless they penetrate the skin. The liver and lungs are the most commonly affected tissues in a human host by the adult form of the agent.

Cestodes or tapeworms are primarily gastrointestinal parasites, but one type (Taenia spp.) can encyst in organs and cause severe disease, with occasional associated fatalities in humans [14]. These parasites reproduce by shedding segments (proglottids), so some species can autoinfect the host via the fecal-oral route. Some transmit by biologic vectors that are ingested by other hosts.

Protozoa are well documented as gastrointestinal parasites and can cause serious levels of disease [10]. Being the smallest of the parasites, they can inhabit a number of different locations in a host, including red blood cells (e.g., malaria) and the mucosal cells of the intestines. Another example is Giardia, which inhabit the brush border of intestinal epithelial cells. They produce diarrhea, which can be mild to severe depending on the agent causing the disease, the parasite burden present, and the underlying state of health of the host. Most protozoa spread via the fecal-oral route. Unlike the larger intestinal parasites, which are identified using routine direct stool sampling techniques where the eggs are "floated" up out of the fecal material for identification, protozoa can be difficult to detect because of their very small size.

Bacteria

The range of zoonotic diseases from bacteria is wider than that from parasites, although the total number of agents is less. Cholera, tularemia, shigellosis, salmonellosis, plague, and cat scratch fever are examples of gram-negative bacteria that can cause serious zoonotic diseases (Table 3). Gram-positive bacterial zoonoses include botulism, anthrax, Hansen disease (leprosy), and listeriosis. Diseases caused by spirochetes (specific types of gram-negative bacteria) include Lyme disease and leptospirosis. Some of the rickettsial diseases (gram-negative) are Rocky Mountain spotted fever, Q fever, and psittacosis.

Table 3: BACTERIAL ZOONOSES

Agent

Disease in Humans

Gram-Negative Bacteria

Aeromonas hydrophila

Vibriosis

Bartonella henselae

Cat scratch fever

Brucella abortus

Brucellosis

Brucella canis

Brucellosis

Brucella melitensis

Brucellosis

Brucella suis

Brucellosis

Campylobacter jejuni

Campylobacter enteritis

Escherichia coli

Colibacillosis

Francisella tularensis

Tularemia

Pasteurella haemolytica

Pasteurellosis

Pasteurella multocida

Pasteurellosis

Salmonella arizonae

Arizona infection

Salmonella spp.

Salmonellosis

Shigella spp.

Shigellosis

Vibrio spp.

Vibriosis/cholera

Yersinia enterocolitica

Yersiniosis

Yersinia pestis

Plague

Yersinia pseudotuberculosis

Yersiniosis

Gram-Positive Bacteria

Bacillus anthracis

Anthrax

Clostridium spp.

Clostridial histotoxic infection

Clostridium botulinum

Botulism

Clostridium tetani

Tetanus

Erysipelothrix rhusiopathiae

Erysipeloid

Listeria monocytogenes

Listeriosis

Mycobacterium spp.

Tuberculosis

Mycobacterium leprae

Hansen disease (leprosy)

Staphylococcus aureus

Staphylococcosis/food poisoning

Streptococcus spp.

Streptococcosis

Spirochetes

Borrelia spp.

Lyme disease

Borrelia spp.

Endemic relapsing fever

Leptospira spp.

Leptospirosis

Rickettsiales

Chlamydia psittaci

Psittacosis

Coxiella burnetii

Q fever

Ehrlichia chaffeensis

Ehrlichiosis

Ehrlichia ewingii

Ehrlichiosis

Rickettsia rickettsii

Rocky Mountain spotted fever (RMSF)

Rickettsia typhi

Murine typhus

Source: Compiled by Author

Bacteria can be transmitted via all of the routes discussed, and more than one avenue of transmission may occur with the same agent. For example, tularemia can be transmitted by a bite wound from an infected cat or rabbit or from an arthropod source [15]. Tuberculosis is primarily transmitted by inhalation but can also be transmitted by the ingestion of raw milk [15].

Most bacterial zoonoses are treatable with appropriate antibiotics, antitoxin where applicable (e.g., tetanus), and supportive care [15]. However, recognition of the disease in a timely fashion is critical for a positive outcome in some bacterial zoonoses that can be fatal if not treated promptly.

Viruses

There are many viruses that may be transmitted from animals to humans (Table 4). Viral transmission can be through direct contact, bites, arthropods, airborne inhalants, and other vectors. Treatment and prevention are specific to each disease. Some, such as rabies, have vaccines available, but most must be managed by careful preventive measures and universal precautions rather than pre- or postexposure treatments.

Table 4: VIRAL ZOONOSES

Agent

Disease in Humans

DNA Virus

Herpes viruses B and T

Simian herpes

RNA Viruses

Arthropod-borne (Arboviruses)

Group A

Group B

Encephalomyelitis (EE)

St. Louis encephalitis

Yellow fever

Coronaviruses (novel type)

SARS, MERS, COVID-19

Chikungunya virus

Chikungunya fever

Ebola virus

Ebola disease

Hepatitis A virus

Hepatitis infection

Influenza virus

Influenza infection

Avian influenza

Lymphocytic choriomeningitis virus

Lymphocytic choriomeningitis

Marburg virus

Marburg disease

Rabies virus

Rabies

Source: Compiled by Author

Zoonotic DNA viruses of concern include herpes simian B and T virus. Simian B virus causes simian herpes in humans, which carries a 70% to 85% case fatality rate [16]. A bite wound from an infected monkey or contamination of broken skin with saliva is usually required for transmission; however, it is now known that infection can also occur though contamination of the mucous membranes or eyes [16]. Fortunately, people generally do not have direct contact with the species of monkeys that are carriers of herpes B unless they work in zoos or research facilities that house them.

Most zoonotic viruses are RNA viruses. Rabies, Ebola, yellow fever, and the hemorrhagic fevers are examples of RNA viruses with serious zoonotic potential. Other viral zoonoses are fairly common and include West Nile encephalopathy, avian influenza, and the hantavirus syndromes. These will be discussed in detail later in this course.

5. TICKBORNE DISEASES

Tickborne zoonoses include Lyme disease, Rocky Mountain spotted fever (RMSF), tularemia, and babesiosis. These diseases are of significant medical interest.

LYME DISEASE

Lyme disease was first described as a zoonotic disease in 1975, although the rash common to this illness was originally documented in Sweden in 1909 [1]. After being reported as an arthritic process in a cluster of children in and around Lyme, Connecticut, it has become the most commonly reported vector-borne disease in the United States [17]. In 2018, state health departments reported 33,666 confirmed or probable cases of Lyme disease to the CDC [18]. The geographic distribution of high incidence areas has expanded over the past decade as the number of counties with an incidence of 10 or more confirmed cases per 100,000 persons increased from 324 in 2008 to 415 in 2018. The disease is concentrated heavily in the Northeast, middle Atlantic, and upper Midwest. Pennsylvania has had the greatest number of cases in recent years.

The primary agent of Lyme disease is the spirochetal organism Borrelia burgdorferi; however, in the United States, there are at least one other bacteria (Borrelia mayonii), two other known genospecies, and as many as 40 disease-causing subspecies of Borrelia[19,20,235]. The host reservoir, in most instances, appears to be the white-footed mouse (Peromyscus leucopus) [21]. White-footed mice are small and reddish brown in color with a tail that is usually shorter than their body length [22]. They do not commonly come into human habitation sites, preferring stone walls, fields, brush piles, and even old birds' nests as places in which to live. They are not likely to carry the agent or vector into a home as they tend to avoid such habitats.

The primary Lyme disease vectors are the ticks Ixodes scapularis or Ixodes dammini in the eastern United States and Ixodes pacificus in the West [18]. Other Ixodes spp. ticks, also known as deer ticks, can carry the organism in some of the less disease-prevalent areas [23,24].

The vector has an interesting two-host lifecycle requiring both the white-footed mouse and the white tail deer (Odocoileus virginianus). The tick spends the first two years on the mouse host, and then it spends its third and final year on the deer, which is the definitive host. The spirochete B. burgdorferi does not reproduce well in the deer, only in the mouse. Disease rates are much higher in areas where both the white-footed mouse and high deer populations coexist. Research has shown it takes the nymph stage of the tick 72 hours and the adult 96 hours to transmit the disease to humans [17]. Finding a tick on a body can be difficult, considering a nymph, when fully engorged, is the size of a poppy seed, and more than 15 adults could fit on a dime. In addition, the saliva of the tick contains a local anesthetic agent, so the bite is not usually felt [17]. Fortunately, ticks in the smaller larval phase do not transmit disease. The larva has not yet fed on the reservoir and therefore cannot contain the spirochete.

As noted, Lyme disease is the leading arthropod zoonosis reported in the United States [18]. Although there is a year-round occurrence of Lyme disease, the ticks are most active in the spring and fall, when the ambient daytime temperature is in the 50s and the ticks have reached the maturation stage and must seek their final host. New cases cluster around the months after the spring and fall tick activity periods. Ticks climb up grasses and low shrubs and wait for deer to brush past or stop to browse. They will drop onto any animal that comes close enough to touch the vegetation where they are waiting. Ticks in the nymph stage tend to crawl on the lower grasses, as they are coming from ground dwelling mice. Adult ticks have more commonly dropped off a deer or an aberrant host. The adults are more adept at moving greater distances and can climb higher in the vegetation. Adult ticks will remain on the deer until engorged and will drop off when ready to lay their eggs. It is important to remove engorged adult ticks without rupturing or smashing the body, as this could release thousands of eggs.

Lyme disease has an extremely variable expression between species [25]. The hosts of B. burgdorferi can be asymptomatic or carriers. No outward signs of disease have been reported in mice or deer, but because they are wild animals, there may be unrecorded signs. Among domestic animals, the dog is the most commonly affected; however, no rash is seen in dogs, even with experimentally inoculated animals.

Diagnosis

Humans can have varied and severe reactions to Lyme disease; most organ systems have the potential to be affected. B. burgdorferi has an affinity for cartilage cells and the transitional cells of the urinary bladder.

The first signs of Lyme disease are usually flu-like symptoms and joint pain. In an elderly person, pre-existing arthritis may complicate early diagnosis. Three distinct stages have been described in patients with untreated infections [25]. Stage 1 (early localized stage) occurs 3 to 30 days after the tick bite and is associated with the appearance of the characteristic "bull's-eye" skin lesion of erythema migrans. Various sources estimate that approximately 70% to 80% of the documented infections will have the characteristic expanding rash [18]. This initial stage may show the nonspecific clinical signs of malaise, headache, arthralgia, fever, myalgia, and regional lymphadenopathy. If they never see a rash, many patients will not consider Lyme disease as the source of their symptoms.

Stage 2 (early disseminated stage) develops through hematogenous spread and is evident after days to weeks post-tick bite [18,26]. Possible manifestations include subtle encephalitis with headache and cognitive difficulty, stiff neck, cranial neuropathy (with facial palsy being a common finding), cerebellar ataxia, motor and sensory radiculoneuritis, myelitis, and visual disturbances. This stage is associated with acute neuroborreliosis in a significant number of cases [18,26]. Most patients with neuroborreliosis are affected by meningitis, facial nerve palsy, and/or radiculitis, with only a limited number having parenchymal spinal cord or brain involvement [238].

Stage 3 (late disseminated stage) is the chronic phase, which may appear months to years after the initial infection [18]. Various names for this stage have been proposed and are currently used, including post-Lyme syndrome, post-Lyme disease syndrome, post-treatment chronic Lyme disease, or chronic Lyme disease [238]. One of the most common findings in this stage is oligoarthritis, with the knee being the most frequently affected joint, although other joints can become inflamed [18,26]. Pain is usually out of proportion to the swelling [18]. Musculoskeletal pain, spinal radiculopathy with paresthesias, encephalopathy, and the symptom complex of fibromyalgia or chronic fatigue syndrome may be present. This stage is associated with chronic borreliosis; consequently, cardiac arrhythmias, respiratory compromise, and spread to the entire nervous system are liable to occur. It is suspected that fibromyalgia may be a long-term sequela to chronic Lyme disease. If untreated, chronic expression results in potentially crippling arthritic changes as well as organ system involvement. The organism can establish itself in the bladder wall and reoccur with another exposure or stress from another illness [23].

Concurrent infection with other tickborne diseases occurs in approximately 4% of Lyme-positive patients [27]. The combination of Lyme disease and either Ehrlichia chaffeensis, or an as yet undefined Ehrlichia or babesiosis can cause overwhelming illness for some individuals. Those concurrently infected will have the additional discomfort of dealing with changes in their circulatory system, as erythrocytes or leukocytes are infected and cannot deal with the demands of mounting an immune response to Lyme disease. Ehrlichia infections usually produce a high fever in the initial infection period [28]. The rare patients who go on to develop acute respiratory distress syndrome have a high correlation of concurrent infection with Ehrlichia[29].

Many of the symptoms of Lyme disease are caused by the body's immune system. Because the spirochete infects the cartilage cells intracellularly, the neutrophils concentrate in the region, resulting in a pain similar to the pain of rheumatoid arthritis. Damage to the cartilage cell and subsequent pain is caused by neutrophils attacking both infected and healthy cells. The amount of discomfort and joint destruction varies among patients depending upon their individual immune response.

Clinical suspicion from history, signs, and symptoms is paramount in the diagnosis of Lyme disease [18]. Patients can present with a variety of clinical findings, and not all classic signs or symptoms are present in those with active Lyme disease. If patients have a rash and recognize it as visceral migrans, it may be too early for other symptoms to be noted or for testing to yield positive results. Additionally, early but inadequate antibiotic treatment may prevent full antibody development in patients who are still clinically ill [30]. Varying severity and expression can make Lyme disease difficult to diagnose in some patients. The criteria as set by the CDC do not always fit the signs, symptoms, and test results. This can be very frustrating for patients as well as medical professionals. A few good diagnostic procedures are available, although they require diligent interpretation.

Laboratory Tests

The CDC recommends sampling blood with a two-step process [18]. The first test should include an enzyme-linked immunosorbent assay (ELISA) or, rarely, an indirect immunofluorescence assay (IFA); however, false positives occur with cross reactions to other spirochetes, such as syphilis, mononucleosis, some autoimmune diseases, and oral cavity flora. If the first step is positive or indeterminate, the second step should be performed. The second step, the Western blot test, identifies antibodies for the different spirochetes [18]. Serologic assays for immunoglobulin G (IgG) and M (IgM) are frequently used blot tests. In any serologic testing, a comparison test repeated after an interval of a few weeks should be performed. Antibody levels should be monitored over this period of time to determine if the disease is worsening or improving as determined by the immune system's reaction. The CDC recommends that ELISA or IFA should always be performed before immunoblot testing in order to decrease the likelihood of false positive results [18].

It is important to caution patients that exposure based on serology does not necessarily mean active disease. Many individuals have titers deemed positive without evidence of Lyme disease, and individuals may have evidence of disease without positive titers. The levels of IgG in the serum can remain high for many years [18].

The most definitive diagnosis is made with a combination of positive ELISA and specific Western blot results [18,23]. Western blot serology is both more sensitive and more specific than ELISA. It is prudent to check the laboratory standards for what is deemed positive, as there is variability between individual testing laboratories. It is highly recommended that the laboratory report and specify the bands. Many will just list the test as positive, equivocal, or negative.

The specific antibodies of importance appear as bands on the Western blot assay. The antibody bands are individual molecular weights of specific antibodies against B. burgdorferi antigens that give specific evidence of exposure to the agent. In reporting the bands, the designation kDa stands for kilo Daltons of molecular weight and Osp refers to the outer surface protein of the organism. The bands that are most specific to Lyme disease are 23-25 kDa (Osp C), 31kDa (Osp A), 34 kDa (Osp B), 39 kDa, 41 kDa and 83-93 kDa [31]. IgG and IgM Western blot assays have the same antibody band specificity. Ideally, both should be performed at the same time. IgM can be positive as early as one week after exposure, and the positive response can last for the first six to eight weeks. IgG takes longer to respond and has some varying levels of response.

The CDC requires that two of three bands (i.e., 23, 39, 41 kDa) on the IgM or five of ten bands (i.e., 18, 21, 28, 30, 39, 41, 45, 58, 66, 93 kDa) on the IgG be present to positively diagnose Lyme disease [18,32,33,34]. This can be an insurance issue for some patients. If the national standard criteria are not met in the testing procedure, some insurance companies may deny payment. In some cases, the IgM test will be slightly more reactive, and this will meet the CDC criteria. In cases that seem to be Lyme disease but for which standard testing is not yielding a positive answer, the IgM Western blot can be a very helpful tool.

The Lyme Urine Antigen Test (LUAT) was once used widely as a diagnostic tool and is still used by some laboratories [26]. However, because of unreliability and inconsistencies, the U.S. Food and Drug Administration (FDA) has advised against the use of this test for the diagnosis of Lyme disease. In addition, they recommend that polymerase chain reaction (PCR) analysis on inappropriate tissues, such as blood or urine, not be accepted as diagnostic, and that Western blot tests only be interpreted according to validated criteria [33]. Like the CDC, the FDA advises initial testing be done by ELISA or IFA and specimens that are positive or equivocal be followed up with a standardized Western blot assay [33]. As of 2017, CDC recommends and has validated only this two-step process for Lyme disease testing [18].

As noted, PCR technology is also available for testing. Appropriate sources most likely to contain the agent are serum, cerebrospinal fluid (CSF), and synovial fluid. The result is positive in approximately 30% of patients with active Lyme disease [34]. Disadvantages of PCR testing include the likelihood of false-negative results due to a sparsity of spirochetes in infected tissues. Inexperience with PCR also can yield false-positive results when care is not taken to prevent contamination and when incorrect primers are used to prepare the specimen. PCR may be useful in confirming persistent or recurrent disease, because a positive result is highly specific for exposure to B. burgdorferi. However, the test has not been standardized and is not currently used in routine testing [34]. In general, all of these tests can be negative or inconclusive, and the patient can still have Lyme disease as documented with electron microscopy, but this is not a practical test due to cost and time issues. At this time, there are no good imaging procedures to help in the diagnosis of Lyme disease, and there are certainly no definitive test procedures that warrant withholding or denying treatment [26]. Treatment is usually indicated even if all, or almost all, routine diagnostic procedures are negative when there is a strong clinical suspicion of Lyme disease based on history and physical findings.

Treatment

Evidence Based Practice Recommendation

According to the International Lyme and Associated Diseases Society, clinicians should promptly offer antibiotic prophylaxis for known Ixodes tick bites in which there is evidence of tick feeding, regardless of the degree of tick engorgement or the infection rate in the local tick population. The preferred regimen is 100–200 mg of doxycycline twice daily for 20 days. Other treatment options may be appropriate on an individualized basis.

https://www.tandfonline.com/doi/full/10.1586/14787210.2014.940900

Last Accessed: April 17, 2020

Strength of Recommendation/Level of Evidence: Recommendation, very low-quality evidence

Prompt and complete treatment of early Lyme disease with antibiotics is important to prevent the development of chronic Lyme disease and/or chronic neuroborreliosis and their troublesome sequelae. The International Lyme and Associated Diseases Society (ILADS) suggests that Lyme disease should be treated with doxycycline as the antibiotic of choice for prophylaxis following an Ixodes tick bite with known feeding, irrespective of the amount of tick engorgement or the local tick population infection rate [35]. Where doxycycline is contraindicated, antibiotics known to be effective for treating Lyme disease, such as amoxicillin, azithromycin, or cefuroxime, may be substituted. The recommended adult dose and prophylactic regimen is 100–200 mg doxycycline twice daily for 20 days [35].

According to ILADS guidelines, the treatment of erythema migrans rash in adults is a four- to six-week regimen with recommended first-line antibiotics, including amoxicillin 1,500–2,000 mg daily in divided doses, cefuroxime 500 mg twice daily, or doxycycline 100 mg twice daily [35]. Studies in Europe have shown that a minimum of 21 days of azithromycin 250–500 mg daily is equally or more effective than these three agents and may be considered, particularly for patients that place a high value on minimizing the number of days taking antibiotics. The recommended pediatric regimen is also four- to six-weeks of treatment of amoxicillin 50 mg/kg/day in three divided doses (maximum daily dose: 1,500 mg), cefuroxime 20–30 mg/kg/day in two divided doses (maximum daily dose: 1,000 mg), and azithromycin 10 mg/kg on day 1 then 5–10 mg/kg daily (maximum daily dose: 500 mg) [35]. Doxycycline is an additional option for children 8 years of age and older at 4 mg/kg/day in two divided doses (maximum daily dose: 200 mg). Higher daily doses of the individual agents may be appropriate in adolescents [35]. Patients should be instructed regarding the importance of completing the entire course of antibiotics; if a dose is missed, the course should be continued at the next regularly scheduled time and the missed dose taken at the end. Studies have found no evidence that treatment regimens of longer duration than those recommended result in better outcomes for patients whose rash is resolved, but they do increase the chance for antibiotic-related adverse events [35].

Patients who have not fully recovered (i.e., erythema migrans rash still visible) at the end of initial treatment but who show a strong-to-moderate response should be continued on the same agent; a dosage increase of the same antibiotic or switch to another first-line agent (or tetracycline) is recommended for a moderate response [35]. Patients with minimal or absent response should be prescribed two first-line agents. Injectable penicillin G benzathine or intravenous ceftriaxone may be considered for these patients and also for those with disease progression or recurrence [35]. This aggressive treatment is required if neurologic symptoms are present in either the acute or chronic stages or if quality of life impairments are significant or rapidly progressive.

Treatment of neuroborreliosis and chronic Lyme disease has been addressed by the American Academy of Neurology in a guideline reaffirmed in 2014. Three major recommendations are made [238]:

- Parenteral penicillin, ceftriaxone, and cefotaxime are probably safe and effective treatments for peripheral nervous system Lyme disease and for central nervous system Lyme disease with or without parenchymal involvement (Level B recommendation).

- Oral doxycycline is probably a safe and effective treatment for peripheral nervous system Lyme disease and for central nervous system Lyme disease without parenchymal involvement (Level B recommendation). Amoxicillin and cefuroxime axetil may provide alternatives, but supporting data are lacking.

- Prolonged courses of antibiotics do not improve the outcome of post-Lyme syndrome, are potentially associated with adverse events, and are therefore not recommended (Level A recommendation).

Doxycycline (suggested dosage: 200 mg daily for 14 days) is the only recommended oral regimen for neuroborreliosis, as it has shown a response rate of 98.6% that of parenteral penicillin or ceftriaxone in an aggregation of data from eight studies [238]. Symptomatic treatment is recommended if therapy fails to resolve arthritis and if PCR results from synovial fluid or tissue are negative [239]. Treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular injections of corticosteroids, or disease modifying anti-rheumatic drugs, such as hydroxychloroquine; referral to a rheumatologist is also recommended.

Patients with Lyme disease can frequently be frustrated with the long-term nature of the treatment and will need support, especially to maintain the antibiotic regimens. The long-term effects can also be very discouraging for the unfortunate patients who eventually develop the syndrome, which mimics fibromyalgia or chronic fatigue syndrome. Fortunately, it appears that early treatment, and in most cases even late treatment, can prevent or eliminate these sequelae [18,23].

Prevention

As with any disease, prevention is the best solution. Educating people about how the disease is transmitted and its early signs will help reduce the overall incidence and lessen the severity in those who receive early treatment. The following advice should be given to patients, family, and friends.

If walking where ticks might be present, wear clothing that provides protection from tick exposure. Bare legs should not be exposed and socks should be pulled up over pant legs. Ticks are not able to get through clothing to exposed skin, but they can climb up socks and reach exposed skin if the pant legs are not inside the socks. Long-sleeve tops and having long hair under control will help as well. Clothing should be removed and washed on arrival home. A thorough tick check should be completed, especially in body creases such as the groin and the axilla (armpit) [18]. Many people have been fooled into thinking ticks were freckles and have not removed them before they became engorged. It is most important that embedded ticks be removed promptly. If the capitulum, or head, is broken off, it may cause a local reaction. Borrelia is actually in the body of the tick, so transmission likelihood will decrease the faster the body is removed. It takes at least 24 to 36 hours of contact by the tick for the disease to be transmitted.

Though the organism is shed in the urine of mammals, no transmission has been documented to have occurred from urine exposure. Pregnant women should be especially alert when in areas known to have ticks, as there appears to be placental transmission of Lyme disease [18]. Some question this, despite evidence that some infants have positive titers after maternal antibodies should have disappeared. For now, erring on the side of caution would seem prudent. Lyme disease, unlike its close relative syphilis, has not been shown to be a sexually transmitted infection.

Dogs and cats can bring ticks into the house. Usually, once on an animal, the tick will remain and not drop off unless the animal has been treated with repellents. Most products to repel ticks will prevent them from ever getting into the house, as they will not remain on the dog or cat long enough to get indoors. Some products are designed to kill the tick if it does succeed in embedding [18].

Public health strategies have included methods to curtail deer populations. This is one way to lower the incidence of Lyme disease in local human inhabitants, because without the definitive host for the tick, the tick population will decrease. It will take a few years after the reduction of the deer population to see a drop in the number of human cases. This is because the newer generation of ticks on the mice will remain at a higher level. In fact, ticks may seem more numerous for the first two to three years after lowering the deer population because of the lack of the correct definitive host.

Insecticides, such as permethrin, and insect repellents, especially n, n-diethyl-m toluamide (DEET) in a concentration of at least 20% to 30%, can be very useful if used properly. Permethrin kills ticks on contact and can be used in a backyard, around a house, or on clothing. DEET is a well-known repellent that can be applied to clothing or exposed skin [18,36]. Some have suggested placing pesticide applicators at deer feeding stations to kill ticks on the deer that come to feed. Of course, controlling the mouse population will also help to reduce the number of cases.

Finally, it is important to know how to properly remove ticks. Petroleum jelly, mineral oil, heat, nail polish, or other materials should not be applied to the tick or immediate area. Embedded ticks are best removed with fine-tipped tweezers. The tick should be grasped as close to the body as possible and removed with a gentle steady pull. Even if all of the mouth parts are not removed, the threat of Lyme disease is very unlikely because B. burgdorferi is usually located in only the midgut and salivary glands of the tick. The area where the tick was located can be washed and cleansed with an antiseptic [18].

Vaccination

The FDA approved the first vaccine for human use, LYMErix, in 1998 [23]. However, in 2002 the manufacturer announced that they were discontinuing production of the vaccine, citing low demand; it is no longer commercially available [23]. When available, the results of trials showed a 50% vaccine efficacy in the first year after vaccinations were given as two injections approximately two months apart. The effectiveness of the vaccine increased to 75% in the second year, after a single booster; however, those who were previously vaccinated are no longer protected [37]. Investigation has been conducted to develop a new human vaccine [26,37].

TULAREMIA

Tularemia is primarily a disease of rural populations, although occasional urban cases have occurred. The infective organism, Francisella tularensis, is a gram-negative intracellular coccobacillus with very marked pathogenic infectivity [38,39]. Humans can become infected by ingestion of or contact with contaminated water, food (e.g., rabbit meat), or soil; handling infected animal tissues; the bites of infective mammals, such as cats; or the bite of infective ticks, biting flies, or mosquitoes. Person-to-person transmission does not occur [38,39].

Tularemia occurs naturally in a wide variety of animals, including mice, rabbits, squirrels, water rats, and voles, which acquire the disease by bites from mosquitoes, flies, and ticks. Animals can also become infected by contact with contaminated soils. Rabbits are the most commonly infected animals in the United States. The disease is endemic throughout much of North America and Europe, with the south central and western states being the most involved in the United States [40,41]. In Europe, most tularemia cases are reported in the northern and central regions, especially Scandinavia and the former Soviet Union.

Classification

There are several classification systems for clinical tularemia. One such system categorizes tularemia as either ulceroglandular (occurring in the majority of patients) or typhoidal [42]. Ulceroglandular disease is characterized by lesions on the skin or mucous membranes (including conjunctiva), lymph nodes larger than 1 centimeter, or both. Typhoidal tularemia describes systemic manifestation of the disease without skin or mucous membrane lesions [38,42]. In addition to these two types, pneumonic tularemia, caused by inhalation and primarily manifesting as pleuropneumonic disease, also occurs [38,42]. Pneumonic tularemia is often considered a type of typhoidal tularemia.

Typhoidal Tularemia

As noted, typhoidal tularemia is an acute, nonspecific febrile illness and is not associated with prominent lymphadenopathy or skin lesions [38]. This type of tularemia is caused by inhalation or ingestion of bacilli and may involve significant gastrointestinal symptoms. It is believed that this type would be most prevalent during an act of bioterrorism [39,42].

The incubation period is usually 3 to 5 days (range: 1 to 21 days), although aerosol exposures have been shown to result in incapacitation in the first day [38,42]. Symptoms may include fever with chills, headache, myalgia, sore throat, anorexia, nausea, vomiting, diarrhea, abdominal pain, and cough [42]. Patients may develop tularemia sepsis and/or pneumonia, which can be fatal. This syndrome manifests with hypotension, respiratory distress syndrome, renal failure, disseminated intravascular coagulation, and shock [42].

Pneumonic tularemia results from inhalation of infected aerosols or spread of existing, untreated disease. Hemorrhagic inflammation of the airways is an early sign [38]. Radiologic studies show pleuritis with adhesions and effusions and peribronchial infiltrates; hilar lymphadenopathy is also common [38,42]. These signs, however, are not always present. Patients may develop acute respiratory distress syndrome and require mechanical ventilation [42].

Ulceroglandular Tularemia

Ulceroglandular tularemia occurs in 70% to 80% of cases [41]. It is generally caused by an arthropod bite or by handling the carcass of an infected small mammal, such as a wild rabbit; transmission has also been reported from ingestion of or contact with contaminated water, exposure to contaminated mud or animal bites, and exposure to aerosolized water droplets or dust from contaminated soil or grains [38,41,42,43,44]. A local papule develops at the inoculation site, with progression to a pustule and ulceration within a few days. The ulcer may be covered by an eschar [38,41]. Lymphadenopathy may also occur [41]. The nodes are usually tender and may become fluctuant, rupture, or persist for months to years [41]. In most cases, there is a single ulcer with raised borders. Other symptoms include fever, chills, headache, and cough [41].

Ulceroglandular tularemia is characterized by the presence of a small, ulcerated papule at the site of a tick bite or other contaminated break in the skin, followed by tender regional adenopathy and fever. A variation of this syndrome is oropharyngeal tularemia, presenting with subacute to chronic exudative pharyngitis/tonsillitis, cervical adenopathy, low-grade fever, and malaise (easily confused with infectious mononucleosis). Oropharyngeal tularemia likely arises from direct transmission via the hands or by droplet nuclei or dust arising from handling the carcass or dressing out meat from an infected animal [41,42]. Finally, there is a well-described oculoglandular form of tularemia, whereby inadvertent direct inoculation of the eye, as from touching the face or eyebrow after handling a dead wild animal results in a unilateral conjunctivitis and preauricular adenopathy [38,41].

Diagnosis

Diagnosis of tularemia requires a high index of suspicion, as the disease often presents with nonspecific symptoms [41]. A history of tick bite or exposure to wild game (e.g., rabbit, deer) provides a clue. The diagnosis can be made by recovery of the organism from blood, ulcers, conjunctival exudates, sputum, pleural fluid, lymph nodes, gastric washings, or pharyngeal exudates. Because the organism is difficult to isolate and constitutes a potential danger to laboratory personnel, serologic evidence of infection in a patient with a compatible clinical syndrome is commonly used for diagnosis [41].

There are several biologic variants (biovars) or subspecies of F. tularensis. Type A is considered to be more virulent, while the European biovar, F. tularensis var. palaearctic, typically causes a milder form of the disease [38]. Both types can be identified with direct fluorescent antibody (dFA) analysis, which gives a presumptive diagnosis of tularemia. Direct examination with gram stain may not be helpful because F. tularensis is a weakly staining pleomorphic gram-negative coccobacillus that may be difficult to identify. F. tularensis can be grown in appropriate cultures, but may not be identifiable for 48 hours. Antibody or other serologic tests and/or culture are necessary for confirmation of the diagnosis. The antibody detection assays include ELISA, tube, and microagglutination, but significant antibodies may not appear until 10 to 14 days after the onset of the illness [38]. A positive dFA test on a culture can confirm the diagnosis.

It should be reinforced that significant personal safety precautions be taken when handling tissues or other samples possibly containing F. tularensis, as it is among the top 10 most common causes of laboratory-associated infections in the United States [45].

Treatment and Prevention

All forms of tularemia may be treated with streptomycin or gentamicin [38,41]. Gentamicin may be more readily available and easier to administer [41]. Also, because streptomycin has been associated with ototoxicity in fetuses, gentamicin is the drug of choice for pregnant women [46]. Doxycycline or ciprofloxacin are also acceptable alternatives [38].

When using aminoglycosides parenterally, the dosage must be calibrated to the patient's renal function (as estimated by the creatinine clearance), taking into account the expected reduction in renal function associated with aging. The adults, the starting dosage of streptomycin is 1–2 g administered intramuscularly (IM) every 12 hours for 7 to 14 days [46]. In very sick patients, streptomycin may be given initially at 15 mg/kg IM every 12 hours, then adjusted downward once there is clinical improvement. This is also the common pediatric dose [46]. The usual adult starting dose for gentamicin is 3–5 mg/kg/day IV or IM once a day (or in three divided doses), to achieve a peak serum level of at least 5 mcg/ml and a trough level <2 mg/kg. This is continued for 7 to 14 days [46].

Doxycycline is a good alternative for patients who are not seriously ill; the dosage is 100 mg IV or orally twice daily at 12 hour intervals for 14 to 21 days; however, relapses are reported to occur more often than with aminoglycoside therapy. Unfortunately, fully virulent streptomycin-resistant organisms have been described. In these cases, ciprofloxacin may be used at a dose of 400 mg IV twice a day (may switch to 500 mg orally twice a day when indicated), although ciprofloxacin use for tularemia treatment is not FDA approved [46].

As with all tickborne diseases, prevention begins with wearing appropriate clothing while in areas where ticks may be present. Also, contact with animals that might harbor the disease should be avoided. If working with domestic animals, be aware of tick infestations and wear protective clothing if contact with possibly infected animals is necessary [41]. The use of tick repellents, such as DEET or the newer plant-derived agents, applied to the clothing or lightly on the skin can be helpful. Wearing light-colored clothing so that ticks can be spotted more easily and tucking pant legs into socks is also recommended. Ticks should be removed as soon as possible after being discovered on the body. Ulcers or wounds in patients with tularemia should be covered and contact isolation maintained as F. tularensis can be shed from such lesions for one month or longer.

No licensed vaccine is available for protection against tularemia; however, a live vaccine strain (LVS) may be given to at-risk laboratory personnel as an investigational new drug (IND) [47]. This vaccine is not commonly available in the United States [240]. An attenuated vaccine was used in the former Soviet Union to immunize tens of millions of people, and was subsequently sold to the U.S. military in 1956. Testing of the vaccine in military personnel proved it to be safe and reasonably effective; however, the scarification technique (similar to small pox inoculation) used to administer the vaccine is inconvenient and highly variable.

ROCKY MOUNTAIN SPOTTED FEVER

RMSF is the most common rickettsial disease in the United States. The incidence of RMSF and other rickettsial infections has increased over the past two decades, from 495 reported cases of spotted fever rickettsiosis in 2000, to more than 6,000 cases in 2017 [48]. The case fatality rate for rickettsial infection has declined since the 1940s, when tetracycline antibiotics cane into use. Using surveillance data, the CDC estimates that the current case fatality rate for all spotted fever rickettsioses is roughly 0.5%, somewhat higher for RMSF [48].

RMSF is caused by the organism Rickettsia rickettsii and is found throughout most of the Western hemisphere and in all states except Maine, Hawaii, and Alaska. The disease is most prevalent from April to September in the coastal Atlantic states but may occur year round in the warmer and southern states. This seasonality varies in different regions according to the climate and tick vectors involved [48].

The wood tick, Dermacentor andersoni, is the principal vector in the western regions of the United States, while the dog tick, Dermacentor variabilis, is more prevalent in the eastern and southern states. The incidence of RMSF is highest (8 cases per million) in adults 55 to 64 years of age; the incidence in children 5 to 9 years of age is 4 cases per million [48]. Human-to-human transmission is not documented and does not appear to occur [40,48,49].

Clinical Presentation and Diagnosis

The classical presentation of RMSF includes the sudden onset of headache, fever, chills, and an erythremic exanthem that appears within the first few days after the symptoms. The lesions are first present on the palms, soles, wrists, forearms, and ankles. The rash then appears on the buttocks, axilla, trunk, face, and neck. The lesions are initially pink and macular and blanch with pressure but later become maculopapular and petechial [48]. Occasionally, the lesions coalesce and become regions of ecchymosis and ulceration.

Symptoms usually appear within 2 to 14 days after the tick bite and can also include malaise, myalgia, nausea, and vomiting [48]. In rare cases, severe respiratory distress, circulatory failure, and neurologic complications may occur; this is especially true for patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

The tick bite is remembered by 50% to 70% of patients who develop a tickborne disease [40]. As with the other tick-disseminated zoonoses, this is a helpful clue in establishing a diagnosis. Other information, such as exposure to high grass and tick-infested areas, contact with dogs, similar illnesses in family members or pets, or history of recent travel to areas of high incidence also can help establish a diagnosis [48]. If a rash is present, a skin biopsy and PCR or immunohistochemical staining for Rickettsia can be used. These tests have good sensitivity (70%) when applied to tissue specimens collected during the acute phase of illness and before antibiotic treatment has been started [48].

IFA with R. rickettsii antigen is the gold-standard serologic test for diagnosis of RMSF. The test is performed on two paired serum samples. The first sample should preferably be taken in the first week of symptoms; the second sample should be taken two to four weeks later. In most cases, the first IgG titer is low or negative, and the second typically shows a fourfold increase in IgG antibody levels. IgM antibodies usually rise at the same time as IgG (i.e., near the end of the first week of illness), but they are less specific than IgG antibodies and more likely to result in a false positive. Both IgM and IgG levels can remain elevated for months or longer after RMSF has resolved, and they can be detected in up to 10% of currently healthy people who were previously exposed to R. rickettsii or a similar organism. For these reasons, clinicians requesting IgM serologic titers should also request a concurrent IgG titer [48].

Treatment and Prevention

The treatment of RMSF should begin immediately when the disease is suspected and not be delayed until a firm diagnosis is made during the convalescent period. The recommended first-line treatment is doxycycline. The recommended dosage for adults is 100 mg every 12 hours. The recommended dosage for children who weigh less than 45 kg is 2.2 mg/kg body weight, twice daily [48]. Treatment is most effective at preventing death if doxycycline is started in the first five days of symptoms. If the patient is treated within the first five days of infection, fever generally subsides within 24 to 72 hours. The minimum duration of therapy is five to seven days, though doxycycline should be continued until the patient has been afebrile for at least three days. Severely ill patients may require longer periods of treatment before fever resolves [48].

Doxycycline to treat suspected RMSF in children is standard practice recommended by both the CDC and the American Academy of Pediatrics Committee on Infectious Diseases. For patients with life-threatening allergies to doxycycline and in some pregnant patients for whom the clinical course of RMSF appears mild, chloramphenicol may be considered as an alternative antibiotic. Oral formulations of chloramphenicol are not available in the United States, and use of this drug carries the potential for other adverse risks (e.g., aplastic anemia, grey baby syndrome, increased fatality risk) [46,48]. The standard treatment duration is 7 to 14 days [48]. The use of fluoroquinolones is not recommended at this time because their benefit has not been documented [40,48,49]. The preventive measures are the same as for the other tickborne diseases.

EHRLICHIOSIS

Ehrlichiosis is an emerging tickborne disease caused by Ehrlichia spp., gram-negative rickettsial organisms that infect human leukocytes. Ehrlichiosis was first recognized in the United States in the 1980s and became a reportable disease in 1999 [28]. The number of reported cases of ehrlichiosis has increased steadily, from 200 cases in 2000 to 1,799 cases in 2018 [28].

Most human disease is the result of infection with E. chaffeensis, but infection with E. ewingii was designated a separately reportable disease in 2008 [28]. In 2009, four cases of ehrlichiosis were attributed to a newly discovered Ehrlichia species closely related to E. muris, a species not found in the United States previously [53]. This section will focus mainly on E. chaffeensis infection, also referred to as human monocytotropic (or monocytic) ehrlichiosis.

Humans become infected through the bite of infected ticks; the lone star tick (Amblyomma americanum) is the primary vector for E. chaffeensis, and the white tail deer is the most common reservoir [28,54]. Cases are predominantly reported in the summer (June and July) in the southeast and south-central United States, which generally corresponds with areas in which lone star ticks exist [28]. The states with the highest concentration of all reported cases are Missouri, Arkansas, and Oklahoma [28].

Clinical Presentation and Diagnosis

The clinical presentation of ehrlichiosis is very similar to that of RMSF, though the incidence of rash is less common. After an incubation period of one to two weeks, a patient with ehrlichiosis will typically present with acute onset of fever and one or more of the following symptoms or signs [28]:

- Headache

- Myalgia

- Malaise

- Anemia

- Leukopenia

- Thrombocytopenia

- Elevated hepatic transaminases

Nausea, vomiting, and diarrhea also occur in some patients. A non-pruritic skin rash may also develop (in 60% of children, but less than 30% of adults), with appearance ranging from maculopapular to petechial [28]. In some patients, the rash may resemble that often seen with RMSF, making careful differential diagnosis vital.

Diagnosis is generally made based on clinical presentation and clinical evidence and confirmed by IFA, PCR, or isolation of E. chaffeensis in cell culture. IFA using E. chaffeensis antigen, performed on paired serum samples, is the gold-standard serologic diagnostic test [28]. Any tests completed in the first week should be repeated after two to four weeks, as antibodies may not be present in sufficient quantities to be detected in the first week.

The CDC recommends that healthcare providers consider Heartland virus testing in patients who develop fever, leukopenia, and thrombocytopenia who have tested negative for Ehrlichia. Heartland virus was first isolated in Northwestern Missouri in 2009; since then, more than 50 cases of Heartland virus disease have been reported from states in the Midwestern and Southern United States [268]. The virus likely is transmitted through the Lone Star tick or other arthropods [55].

Treatment and Prevention

Doxycycline is the first-line treatment for adults and children of all ages and should be initiated immediately if ehrlichiosis is suspected [28]. The recommended regimen is 100 mg twice daily for adults or 2.2 mg/kg twice daily for children weighing less than 45.4 kg [28]. For patients with severe diseases or who are hospitalized, intravenous administration is preferred. Treatment should continue for at least three days after the fever subsides and until evidence of clinical improvement, usually at least five to seven days [28]. Prevention should focus on measures established for all tickborne diseases.

BABESIOSIS

Babesiosis is the only tickborne zoonosis in the United States caused by a protozoan, Babesia microti. Two other Babesia species, B. bovis and B. divergens, can be zoonotic as well but are less commonly identified [52]. Babesiosis is most prevalent in the United States in the Northeast and upper Midwest and usually peaks during the warm months [52]. B. microti is transmitted by the Ixodes scapularis (blacklegged deer tick). Rodents are the primary reservoir for human cases [52].

Historically, the description of the early recognition of babesiosis parallels Lyme disease. The first case was documented on Nantucket Island, Massachusetts, in 1969 in an elderly woman whose case was described as a "malaria-like" illness. B. microti was identified, and the island's hospital began regularly treating cases shortly after identification and diagnosis of the first case [51].

Clinical Presentation and Diagnosis

Many cases of babesiosis remain subclinical. In fact, some young patients may be asymptomatic carriers for years. Those individuals who become ill may experience influenza-like symptoms, with fever, headache, malaise, myalgia, and hemolytic anemia and hemoglobinuria of varying severity. These symptoms usually occur within one week; jaundice and renal failure may follow [40,52]. Risk factors for severe disease include asplenia, advanced age, and immunodeficiency states. As noted, the clinical presentation may resemble malaria. The disease can be fatal in patients who have a prior history of splenectomy [52]. Animals other than humans with babesiosis have a very similar course.

Diagnosis of human babesiosis requires a high index of suspicion because the clinical manifestations are nonspecific. Examination of a blood smear from a suspected individual with infection will reveal the characteristic red blood cell parasite inclusions that resemble a Maltese cross. Fluorescent antibody serology and PCR amplification are available for diagnosis when the evaluation of the smear is not conclusive [52].

Treatment and Prevention

All cases of active babesiosis require treatment with a combination of either atovaquone plus azithromycin or clindamycin plus quinine (for severely ill patients) [52]. The suggested doses for adults include 750 mg of atovaquone two times per day for 7 to 10 days plus an initial oral dose of 500–1,000 mg azithromycin (decreasing to 250–1,000 mg/day as appropriate). An alternative is clindamycin 600 mg orally three times per day or 300–600 mg IV four times per day plus quinine 650 mg orally three times per day [36,40,163].

In severely ill patients with high titers of parasitemia (greater than 10%), significant hemolysis, or renal, hepatic, or pulmonary compromise, a partial or complete red blood cell exchange transfusion may be lifesaving. Patients in hemolytic crisis should be treated for shock, with particular consideration for maintaining renal function to counteract the potential damage from hemoglobinuria. The medical regimen is aimed at preventing anemia from becoming severe [40,49].

Individuals who have previously undergone splenectomy should exercise extreme caution in Ixodes tick territory. A thorough tick check should be done after being in the woods. Insect repellent will provide deterrent but should not be relied upon for complete protection against any arthropod vector. Rodent control measures can help reduce the reservoir numbers around the home and yard [52].

6. VIRAL ZOONOTIC DISEASES

Several human viral diseases can be contracted from animals, some by means of an intermediate arthropod vector important to the life cycle of the virus, others by direct contact or inhalation of aerosols released by the animal or generated from the contaminated environment. Well-described mosquito-borne viral zoonoses include West Nile and similar forms of viral encephalitis, Zika virus (ZIKV) disease, and Dengue. Rabies is unique in its association with the bite of an infected wild of domestic mammal. Avian and swine influenza, hantavirus, and novel coronavirus infections have more complex modes of transmission involving direct (touch) contact and/or inhalation of infectious aerosols created by handling the host animal, processing a food product, or cleaning the immediate environment. Bovine spongiform encephalopathy ("mad cow disease") will be included in this section because the infective organism, a prion, is closer to a virus than the other zoonotic organisms.

WEST NILE VIRUS

The West Nile district of Uganda was the site of the first documented human case of West Nile virus in 1937. The virus was later identified in a serious outbreak of meningoencephalitis in Israel in the late 1950s. The first human cases in the United States occurred in the New York City area in 1999, where seven deaths were reported [56]. It has since been documented throughout the entire continental United States. A total of 47 states and the District of Columbia reported West Nile virus infections in people, birds, or mosquitoes in 2019 [58]. Overall, 917 human cases of West Nile virus disease have been reported to the CDC, of which 607 (66%) were classified as neuroinvasive disease (e.g., meningitis, encephalitis, flaccid paralysis) [58]. Hawaii, Alaska, Puerto Rico, and the Virgin Islands have been free of the disease; however, the disease has spread throughout the contiguous United States and Canada. In Canada, Ontario and Quebec have experienced the most cases [36,57]. The states with the greatest number of cases in the United States in 2019 were California (214), Arizona (174), Colorado (121), Nevada (44), and New Mexico (40) [58]. Most cases occur between June and September, but as the disease has spread into the warmer southern and southwestern states, year-round exposures have become more frequent [36,57].

The West Nile virus is a single-stranded RNA flavivirus, similar in many respects to the virus that causes St. Louis encephalitis. Kunjin virus, present in Australia, is closely related to West Nile virus [59]. The virus is primarily transmitted by the Culex spp. mosquito, although it has been isolated from several other species. The Culex is an overwintering mosquito, meaning that adults can survive throughout the winter. The virus has also been documented to live throughout the winter while in the mosquito. Because a blood-feeding arthropod is the vector, the virus is called an arbovirus [60].

West Nile virus is transmitted from the primary reservoir, birds, to a vertebrate host after being maintained in a bird-mosquito-bird cycle. More than 160 species of birds have been documented to harbor the virus. Passerine birds have been noted to be the most commonly affected type of birds [56]. This group includes perching species such as songbirds and sparrows. The passerine group, crows, and many other common birds in the United States and around the world are evidently capable of being the amplifying host, in which the West Nile virus can replicate and markedly increase in number. It is also possible that other animals can harbor and amplify the organism. In a somewhat alarming finding, investigators confirmed that farmed alligators in Florida were capable of serving as an amplifying reservoir for West Nile virus. Humans and domestic animals that become infected with the organism are aberrant hosts, and the viremia is usually brief and low-grade [56,61,62,63].

Clinical Presentation

Most (70% to 80%) human West Nile virus infections are subclinical and unapparent. Approximately 20% of those who contract the virus experience a mild febrile illness called West Nile fever [36,64]. Only about 1 out of 150, or less than 1%, of those infected will develop severe neurologic effects [36]. Among patients with neuroinvasive disease, the case fatality rate is approximately 10% [58]. Although the full spectrum of West Nile fever cases in the United States has not been determined, there are degrees of clinical involvement that can be noted [64,65].

The mild infection of West Nile fever appears after an incubation period of about 2 to 14 days and lasts for 2 to 6 days [36]. It is described as a febrile illness of sudden onset accompanied by malaise, anorexia, nausea, vomiting, headache, and myalgia. Some patients complain of eye pain and upper respiratory symptoms, and there may be a rash or lymphadenopathy [36]. Interestingly, the macular, papular, or morbilliform erythematous rash and lymphadenopathy seen in earlier outbreaks of the disease were not common in the more recent cases [56].

More severe infections have occurred in older patients and those with coexisting morbidities. The rate of severe neurologic disease was 10 times higher for patients 50 to 59 years of age and 43 times higher for those older than 80 years of age. This indicates that advanced age is the most significant factor involved in the development of severe disease [64]. In recent outbreaks, encephalitis was more common than meningitis. Hospitalized patients demonstrated significant fever, weakness, gastrointestinal symptoms, and cognitive changes. Several experienced muscle weakness and a flaccid paralysis with the more common neurologic findings being ataxia and extrapyramidal signs, myelitis, optic neuritis, seizures, polyradiculitis, and cranial nerve abnormalities. The constellation of findings is similar to other viral encephalitides and cannot be distinguished from them clinically [36].

The clinical signs of West Nile meningitis can include nuchal rigidity, Kernig or Brudzinski sign, and photophobia or phonophobia. A fever of 38 degrees C or more, or hypothermia of 35 degrees C or less, help to make the diagnosis. West Nile encephalitis can present with lethargy, an altered level of consciousness, or a personality change lasting more than 24 hours. There may also be focal neurologic deficits, seizures, and all of the usual findings seen with a viral encephalopathy [56,65].

The acute flaccid paralysis seen with West Nile virus infections usually presents as a limb weakness that progresses markedly over a 48-hour period. There is an absence of pain, but paresthesia, areflexia or hyporeflexia, and asymmetry are commonly seen. About one-half of the patients hospitalized with severe disease in the United States experience a significant degree of weakness, and approximately 10% of the New York patients had acute flaccid paralysis, including several patients who developed a paralysis that resembled Guillain-Barré syndrome without the usual nerve conduction findings [66].

There is still no firm data regarding the long-term effects of West Nile virus infections. In the New York outbreak in 2000, over one-half of those hospitalized had not returned to their functional level by discharge, and only one-third were fully ambulatory. The most persistent long-term symptoms included fatigue, memory loss, difficulty walking, weakness, and depression [56,64,65,66].

Diagnosis

A high index of suspicion based on symptoms, time of year, history, and the presence of other known cases is paramount in diagnosing West Nile fever. Other arboviral diseases, such as St. Louis encephalitis, Kunjin virus, or other diseases caused by flaviviruses can have a similar initial presentation [36,57]. Fortunately, there is a specific neutralizing antibody to West Nile virus that can be used in serologic tests to help make the diagnosis. A fourfold rise in titer between acute and convalescent samples, determined by plaque-reduction neutralization assay, is confirmatory. A useful serologic test on serum or CSF is the assay for IgM using the antibody-capture ELISA procedure [36,57]. The finding of IgM in the CSF is a very good indication of meningoencephalitis if found within eight days of the onset of symptoms [36,56,67]. Some IFA tests have also been suggested as being helpful in the diagnosis.

Peripheral blood samples are usually not helpful because the leukocyte count is often normal, although it can be elevated in some cases [67]. There can be a lymphocytopenia or even anemia. The CSF will frequently have an increase in cell count, with a predominance of lymphocytes and increased protein. CSF glucose is usually normal [67].

Imaging studies may be helpful after the development of meningoencephalitis to exclude other etiologies [67]. Computed tomography (CT) scans usually do not show evidence of acute disease, but about one-third of the magnetic resonance imaging (MRI) studies revealed changes in the leptomeninges or periventricular areas. MRI studies have also shown lesions in the basal ganglia and thalamus [56].

Culture of the organism is difficult, but an unambiguous diagnosis of West Nile fever can be made by virus isolation in cell culture, or in suckling mice by IFA analysis. In fatal encephalitis cases, the West Nile virus can be readily detected by immunohistochemistry or molecular amplification methods. Brain tissues at autopsy can be stained to show the viral antigens as well as the neuronal necrosis and microglial infiltrates caused by the disease.

Treatment and Prevention

The treatment of West Nile virus infections is supportive, with hospitalization of any patient who appears to have meningitis or encephalitis. Intravenous fluids and respiratory assistance are often required, and the prevention of secondary infections should be considered. Patients with severe neurologic findings will need a great deal of supportive care [36].

Interferon alpha-2b, IgG, and ribavirin in high doses have shown some activity against the virus in vitro, but there has been no confirming evidence of their usefulness in patients. Other possible medications being tested are steroids, antiseizure drugs, and antiosmotic agents [64,66,67].

The most prudent means of protection against West Nile virus is to avoid mosquito bites by wearing long-sleeved shirts and pants and being aware of the usual biting times of early morning and evening. This is often not practical, so using the proper insect repellent is the next best means of protection [36]. The CDC recommends that consumers use repellent products that have been registered by the Environmental Protection Agency (EPA). These products include DEET, with a concentration of 20% to 30%, picaridin (KBR 3023), oil of lemon eucalyptus or para-menthane-3,8-diol (PMD), and IR3535 applied to the clothing and skin [68]. Compounds containing permethrin may also be used and are highly effective in repelling and killing ticks, mosquitoes, and other arthropods but should only be applied to clothing, netting, and gear and not to the skin [68]. Permethrin retains effectiveness on clothing even after laundering.

A vaccine for humans is not available at this time; however, the National Institutes of Health sponsored a trial of an inactivated vaccine developed by scientists at the Oregon National Primate Research Center in Portland [69]. The phase I trial including 50 adults was completed December 2016, and as of April 2017, no results have been published [241]. In mice, the vaccine protected against a lethal dose of West Nile virus, successfully eliciting neutralizing antibody responses and CD8+ T cells, which attack infected cells [69].

ZIKA VIRUS

ZIKV is the latest in a series of related human arboviral pathogens that has migrated out of Africa and Asia into the Americas over the past two decades [251,252]. Like yellow fever, dengue, and chikungunya viruses, the vector for ZIKV is the Aedes mosquito, and epidemics within susceptible population groups are sustained by a mosquito-human-mosquito transmission cycle.

In the 2015–2017 outbreak within the United States, cases of ZIKV disease were primarily reported in returning travelers and in women having unprotected sex with men infected while traveling to regions with ongoing mosquito transmission. A total of 43,092 cases were reported between 2015 and 2018 in the United States and U.S. territories [256]. The potential for a localized or regional outbreak of ZIKV disease in the United States is significant given the level of travel exposure, opportunities for ZIKV migration, and the prevalence of A. aegypti mosquitoes along the southern and southeastern rim of the country [257].

In epidemic settings and endemic areas, ZIKV infection is primarily vector-borne, transmitted by the bite of an infected Aedes mosquito. In addition, other modes of transmission are now known to be important in human ZIKV disease. These include sexual transmission from an infected male to female and male partners; transplacental transmission from mother to fetus during pregnancy, leading to congenital ZIKV disease; and perinatal transmission from a viremic mother to her newborn infant [258,259]. There is theoretical concern that blood transfusion and tissue/organ transplantation could also serve as vehicles of transmission. Therefore, the FDA has recommended universal screening of donated whole blood and components for ZIKV in the United States and its territories [260].

All reported cases of sexual transmission have involved vaginal or anal sex with men shortly before, during, or shortly after a symptomatic illness consistent with ZIKV disease [261]. It is not known whether infected men who never develop symptoms can transmit ZIKV to their sex partners. For now, the CDC recommends that men who have been diagnosed with ZIKV consider using condoms or abstaining from sex for six months following infection [261]. Sexual transmission of ZIKV from infected women to their sex partners has not been reported. The consistent and correct use of latex condoms is known to reduce substantially the risk of acquiring sexually transmitted infections, including those caused by viruses.

In the course of acute infection during pregnancy, ZIKV can be transmitted across the placenta to the developing fetus. Evidence for intrauterine fetal infection includes demonstration of ZIKV in the placenta and products of conception following spontaneous abortion, identification of ZIKV RNA in amniotic fluid by RT-PCR, and virologic and serologic studies of infants born with microcephaly. The true incidence and natural history of this phenomenon, including the importance of such factors as gestational age, level and duration of viremia, and immune enhancement by pre-existing heterologous anti-flavivirus antibodies, is currently unknown [262].

Two cases of intrapartum transmission of ZIKV from a newly infected, viremic mother to her newborn infant have been reported [263]. One infant was considered to be asymptomatic; the other child developed a rash and transient thrombocytopenia. Although ZIKV has been identified in breast milk, there have been no reports of transmission through breastfeeding.

Clinical Presentation and Diagnosis

In epidemic settings, the majority of primary ZIKV infections are asymptomatic, and those who do become ill usually experience a self-limited, mild febrile illness with rash, conjunctivitis, myalgia, and arthralgia lasting three to six days. The incubation period for ZIKV is not well defined; it is considered to be similar to that of other mosquito-borne flaviviruses—usually less than one week and in the range of 3 to 10 days.

During the period from September 2015 through February 2016, 72 of 88 women enrolled in a study tested positive for acute ZIKV infection by RT-PCR on blood, urine, or both. All women had rash, as this was an inclusion criterion; the prevailing pattern was a descending macular or maculopapular exanthem accompanied by pruritus in 94% of patients. Arthralgia was reported in 65% of ZIKV-positive women, conjunctival injection was seen in 58%, and lymphadenopathy (generalized or regional) was present in 41%. Fever was documented in only one-third of patients and, when present, was low-grade and of short duration. Nausea and vomiting were reported in 21%, and respiratory findings were evident in 7% [264].

From these observations there emerges a distinctive, though nonspecific, clinical ZIKV syndrome: an acute onset descending maculopapular rash (often with pruritus), conjunctival injection, arthralgia, myalgia, and transient low-grade fever. Lymphadenopathy may be present, but respiratory symptoms and signs are conspicuously uncommon. ZIKV disease should be considered in patients with any combination of these symptoms who have traveled to areas with ongoing transmission in the two weeks preceding onset of illness. Rare manifestations of acute ZIKV infection, based on isolated case reports, include meningoencephalitis, myelitis, thrombocytopenic purpura, and ocular complications [263,265,266].

Because dengue and chikungunya viruses have the same vector of transmission and share a similar geographic distribution and clinical profile with ZIKV, patients with suspected ZIKV disease should be evaluated and managed for these possibilities as well. Other considerations in the differential diagnosis include malaria, rubella, measles, parvovirus, adenovirus, enterovirus, leptospirosis, rickettsiosis, and group A streptococcal infections [267].

The possibility of ZIKV disease should be considered in the patient with a compatible clinical syndrome (e.g., febrile rash illness with arthralgia and conjunctivitis) and epidemiologic risk factors, such as residence in or travel to an area of active ZIKV transmission within the previous two weeks, or sexual contact with a person known or suspected of recent ZIKV infection. Laboratory confirmation relies on molecular detection of the viral genome (via RT-PCR) in blood or body fluids and serologic assay for acute-phase ZIKV-specific IgM antibody.

The FDA has issued an emergency use authorization for two diagnostic tools for ZIKV: the Triplex Real-Time RT-PCR assay and the Zika MAC-ELISA for anti-ZIKV IgM [255]. These have been distributed to qualified laboratories that are certified to perform high-complexity tests in the United States. Clinicians should contact local and state health departments to facilitate diagnostic testing. The CDC provides updated guidance for the selection and timing of ZIKV diagnostic testing at https://www.cdc.gov/zika/hc-providers/testing-for-zika-virus.html.

Treatment and Prevention

There is no effective antiviral therapy for ZIKV infection; treatment is supportive and directed toward relief of symptoms. When the diagnosis is uncertain and dengue, or co-infection with dengue, is a possibility, the patient should be managed expectantly for each. In consideration of dengue, aspirin and NSAIDs should be avoided and the patient should be monitored for signs of progression to hemorrhagic fever or shock [254]. In managing ZIKV disease, patient education and secondary prevention are important, especially in regard to sexual transmission and risk reduction in pregnancy. All pregnant women with molecular or serologic evidence of recent ZIKV infection should be evaluated and managed (monitored) for adverse pregnancy outcomes.

Pregnant women who report symptoms or signs consistent with acute ZIKV disease and who have traveled to or who live in areas with active ZIKV transmission or who have had potential sexual exposure (i.e., sexual contact without barrier/condom method with a person who lives in or has traveled to an area with ZIKV) should be tested for ZIKV infection. Serum and urine RT-PCR tests are recommended for those seeking care less than two weeks after onset of symptoms [253]. A positive RT-PCR result confirms the diagnosis of recent maternal ZIKV infection. Patients with a negative RT-PCR test result should receive ZIKV IgM and dengue virus IgM antibody testing. Symptomatic pregnant women who seek care 2 to 12 weeks after symptom onset should first receive ZIKV and dengue virus antibody testing. If the ZIKV antibody test is positive or equivocal, reflex RT-PCR should be automatically performed on the serum sample to determine whether ZIKV RNA is present.

DENGUE FEVER

Dengue fever is caused by one of four similar flaviviruses (dengue viruses 1 through 4) that are transmitted via mosquito in tropical and subtropical regions [135,162]. The WHO estimates that there may be 390 million dengue infections worldwide each year, of which 97 million have clinically significant symptoms, including 500,000 cases of dengue hemorrhagic fever and more than 12,500 deaths, mainly among children [135]. Although dengue is relatively rare in the United States, it is endemic in many parts of the world, including Africa, the Eastern Mediterranean, Southeast Asia, the Americas, and the Western Pacific, with the Americas, Asia, and the Western Pacific being the most severely affected.

The incidence of dengue has been increasing rapidly in the last several decades, particularly since 1981 [135,162]. The disease is both appearing in new areas and increasing in numbers of infections per year. Almost all cases of dengue fever in the continental United States have been acquired through travel to endemic regions [162]. However, there have been limited local outbreaks in Texas, Florida, Arizona, and Hawaii. More importantly, dengue is endemic to Puerto Rico, the U.S. Virgin Islands, Guam, and Samoa, and citizens in these regions are at increased risk for infection [135,162]. Although the geographic distribution of dengue is similar to that seen with malaria, it is more common in urban and more populated areas rather than more rural areas [135]. Infection rates for travelers to endemic regions range from 2.9% to 8% [163].

The principle vector for dengue is the mosquito Aedes aegypti, a species that originated in Africa but is now commonly found in most tropical and subtropical areas [164]. The Aedes albopictus mosquito, which is native to Asia, has also been implicated in the spread of dengue. World travel of the mosquitoes in cargo is a likely culprit [164]. Direct person-to-person transmission has not been documented, but there have been cases linked to dengue-infected blood, organs, or other tissues from blood transfusions; solid organ or bone marrow transplants; needlestick injuries; and mucous membrane contact with dengue-infected blood [163].

Clinical Presentation

The first signs and symptoms of dengue infection typically develop within 4 to 7 days of the infectious mosquito bite and last for 3 to 10 days [162]. The characteristic presentation of classic dengue fever includes a high fever (up to 105 degrees F), severe headache, retro-orbital pain, severe joint and muscle pain, nausea and vomiting, rash, hemorrhagic manifestation, and/or leukopenia [163,165]. The characteristic rash is macular or maculopapular and generalized and usually develops as the fever subsides. An estimated 50% of patients may remain asymptomatic, while about 1% of patients will develop dengue hemorrhagic fever [163].

The most clinically relevant sign of dengue hemorrhagic fever is vascular leakage, with all of the following criteria necessary for diagnosis: fever or recent history of fever, any hemorrhagic manifestation, thrombocytopenia (i.e., platelet count <100,000/mm^3), and evidence of increased vascular permeability [163]. In a few patients, most commonly children experiencing their second dengue infection, dengue shock syndrome will develop [165]. Dengue shock syndrome is characterized by the presence of all of the criteria for dengue hemorrhagic fever with the addition of hypotension, narrow pulse pressure (≤20 mm Hg), or shock [163].

Diagnosis

Clinicians should obtain a complete personal and travel history for all patients suspected of having dengue fever or hemorrhagic fever [166]. Cases can be laboratory confirmed with the use of RT-PCR, anti-dengue IgM or IgG antibody titer, or immunofluorescence or immunohistochemical analysis of autopsy tissue [162]. In conjunction with a thorough history indicating recent febrile illness and travel to an endemic area, a positive test suggests probable infection. However, it is important to note that a positive antibody test will only indicate that the patient has ever been infected; it does not necessarily confirm recent illness. Furthermore, there is some cross-reactivity with other flaviviruses, including West Nile virus and yellow fever [163].

Treatment and Prevention

There are no approved treatments available for dengue, although a vaccine was approved for endemic areas (i.e., American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands) in 2019 [132,135,163,236]. Supportive care, in the form of bed rest and adequate fluids to maintain hydration, is recommended [135,163]. In more severe cases, maintaining the patient's circulatory volume will be key. Antipyretics may be necessary to reduce fever, and the CDC recommends the use of acetaminophen [163]. Narcotics may be used to treat severe pain. Aspirin (and other salicylates) and NSAIDs should be avoided due to the risk of hemorrhage and, in children, Reye syndrome [163].

As with many zoonotic diseases, the best treatment for dengue fever is prevention. This includes vaccination (if indicated) and all measures necessary to prevent being bitten by an Aedes mosquito, such as bed nets, use of DEET-containing insect repellants, and wearing long-sleeved shirts and long pants [135,163,165]. Travelers should be advised to choose accommodations with air conditioning and window and door screens [163]. Because mosquitoes breed in standing water, eliminating these habitats (e.g., earthenware jars, metal drums, concrete cisterns used for domestic water storage, discarded plastic food containers, used automobile tires) in urban or residential areas has become a priority [135].

RABIES

Rabies is caused by the rabies virus, an RNA rhabdovirus belonging to the genus Lyssavirus, which under electron microscopy has a distinctive "bullet" shape [70]. Its genome and the various types of viral antigens particular to individual types of animals in given regions have been elucidated.

The disease, in animals and humans, has been known since ancient times. The name dates to about 3000 B.C.E. and means "to do violence" in Sanskrit. Detailed investigation of rabies began in the latter part of the 19th century, and Louis Pasteur discovered a vaccine for rabies in 1885. The development of a vaccine for animals, particularly the widespread vaccination of dogs and cats in the United States begun in the 1940s and the oral vaccination program for raccoons begun in the 2000s, has markedly decreased the number of human cases in the United States in the past century [71]. Additionally, effective human rabies immune globulin and human rabies vaccines have been developed. However, many thousands of human cases still occur worldwide each year, with 34 documented cases in the United States between 2003 and 2014 (10 of which were contracted outside of the United States and its territories) [74,77]. At the present time, approximately 5,000 animal rabies cases are reported to the CDC each year, of which more than 90% are in wildlife. The most commonly identified rabies hosts in the United States are bats, raccoons, skunks, and foxes.

The number of human fatalities associated with rabies in the United States has decreased from 100 or more each year in the early 1900s to just one or two per year today. From 1960 to 2018, a total of 125 human rabies cases were reported in the United States, about 25% of which resulted from dog bites sustained during international travel [71]. Of infections acquired in this country, 70% were attributed to bats. Deaths are primarily due to failure to seek medical assistance, usually because the individual is unaware of exposure, as is common with bat bites. In addition to animal bites, cases have also been documented from corneal and organ transplants [71,73]. It is estimated that about 55,000 people worldwide die from the disease every year, mostly in developing countries where preventive measures are not adequate [77].

Rabies is present in essentially every country in the world and in every state in the United States, except for Hawaii. During 2017, 49 states and Puerto Rico reported 4,454 animal cases and 2 human cases [71]. Historically, human deaths have occurred in all regions where animal cases are present. In the United States, domestic animals accounted for 9% of all rabid animals reported in 2017 [71]. All mammals can contract rabies, but interestingly, birds do not get or carry the disease. Of the common wild animals in the United States, raccoons are the most infected in the East; skunks are the most infected animals in the Midwest and California; foxes and coyotes are most afflicted in Texas, the Southwest, and Alaska; and mongoose are most affected in Puerto Rico [74].

Rabies is the infectious disease with the highest known case-fatality rate in the world [75,76]. It is an acute, progressive encephalitis that almost always leads to the death of the patient if they do not begin to receive the vaccine series soon after exposure. The disease occurs when the virus enters the body, most commonly by the bite from an infected animal. Infection can also occur from contact with contaminated animal body parts, saliva, or other body fluids, especially when it involves penetration through mucous membranes or broken skin [70]. Fortunately, case reports have shown this type of transmission is much less likely to happen. There does not appear to be human-to-human transmission of rabies, except via infected transplanted tissues or organs [72,73]. After entering the body, the virus particles pass via the peripheral nervous system to lodge and replicate in the central nervous system. The rabies virus becomes distributed throughout the brain and is also disseminated to the salivary glands and other organs.

The incubation period is usually about two weeks but can be as long as several months. Shorter incubation periods appear to be associated with inoculations closer to the head [76]. If untreated, rabies is almost 100% fatal [8,70]. The only existing treatment for non-vaccinated humans is injection with rabies immune globulin and rabies vaccine within days after exposure; therefore, timely diagnosis of the disease is extremely important.

Clinical Presentation and Diagnosis

The clinical presentation often begins with a feeling of fatigue, malaise, and possible paresthesias near the site of inoculation. Most patients have a low-grade fever, but some remain afebrile in the early stages prior to developing a fever over the next few days. Nausea and vomiting can be present as well as lethargy and anorexia. The signs and symptoms of a central nervous system disease and encephalitis usually follow rapidly. Diplopia or other visual defects, unsteady gait, cranial nerve palsies, cognitive changes, photophobia, phonophobia, restlessness, and limb weakness are common findings. The neurologic condition of the patient rapidly declines, with increasing confusion, disorientation, tremors, twitching or myoclonic muscle movements, seizures, and increased pain sensations. Some patients develop laryngospasm when attempting to drink. Many patients eventually have pulmonary problems, leading to poor ventilation and respiratory failure. Autonomic system collapse and coma ensue, with death following regardless of supportive measures [70,76].

There are descriptions of two possible forms of disease presentation. One is called the paralytic form, whereby an ascending paralysis similar to Guillain-Barré syndrome predominates. The other, which is more common, is the encephalitic or "furious" form described above [75,76,78].

It is imperative to make the diagnosis of a rabies-prone exposure during the period prior to the development of symptoms. A delay in diagnosis and treatment can mean almost certain death for the patient [76]. Therefore, a history of suspicious animal bite or contact with a victim of the disease, especially the saliva of a victim, must lead to the performance of diagnostic tests.

Several tests are necessary to diagnose rabies in humans; no single test is sufficient [70]. Fortunately, there are several very good diagnostic procedures that can be performed fairly quickly on serum, saliva, CSF, or skin biopsies taken from the nuchal region of the neck. Antibody analysis can be performed on serum or CSF, and skin biopsy samples can be examined for rabies antigen in the cutaneous nerves at the base of the hair follicles [70]. Other laboratory tests include electron microscopy, virus culture, and immunohistochemistry. Laboratory analysis also allows for the determination of the type of animal involved and, in many cases, the locality from which the infection originated. There are many public health and other designated facilities available to perform these procedures. Neuroimaging procedures, including CT scans and MRIs, are usually normal initially but show signs of cerebral edema and other features of encephalitis as the disease progresses.

If possible, the suspected animal should be tested for rabies antigen. Tests on animals may require samples of their brain tissue [70]. Because of its high sensitivity and specificity, the direct fluorescent antibody (DFA) test is considered the gold-standard diagnostic method for rabies determination in animals in the United States [70]. The presence of Negri bodies, characteristic intracytoplasmic inclusion nodules within neurons, is confirmatory evidence of the disease. The rapid determination of whether an animal is rabid can save a potential victim from psychologic trauma and an expensive treatment regimen [70].

Treatment and Prevention

Any wound from an animal should be intensively cleaned with soap and water. Antiviral compounds (e.g., povidone iodine) should be used if available; thorough wound cleansing has been shown to markedly decrease the risk of bacterial infection [242]. As discussed, postexposure treatment can prevent the disease if given early and prior to the onset of symptoms.

In non-immunized individuals, treatment consists of the use of immune globulins and vaccine [242]. A human rabies immunoglobulin (HRIG) is available in the United States and most other developed countries. Historically, equine rabies immunoglobulin (ERIG) was used and regimens included a series of painful and sometimes dangerous injections. The currently available ERIG is highly purified and is considered "quite safe" by the WHO [79]. A skin test should always be performed before using ERIG. The safer HRIG is expensive, but requires only an intragluteal injection, usually with a dose of 20 IU/kg [79]. The WHO advises that HRIG, like ERIG, also be administered in the vicinity of the bite wound [79].

In addition, rabies vaccine must also be started. According to the CDC Advisory Committee on Immunization Practices (ACIP), the vaccine should be injected IM at a site distant from the HRIG injection site, possibly the deltoid. The ACIP recommends giving four doses of human diploid cell vaccine or purified chick embryo cell vaccine, 1.0 mL (at days 0, 3, 7, and 14) for immunocompetent individuals and the usual five-dose regimen for immunocompromised individuals [80,242].

When symptoms appear, diligent supportive measures are required, including induced coma for patients with involuntary muscle movements and severe pain [76,82]. Additional treatment regimens have included IV ribavirin and other antiviral agents under investigative drug protocols; however, there are very few reports of recovery [76,81]. The experimental Milwaukee protocol is associated with significantly longer survival than conventional treatments for symptomatic rabies, but has been tested on an exceedingly small number of patients and "excellent and adaptive medical intensive care and careful avoidance of mistakes and complications of intensive care may prove to be essential to positive outcomes" with this treatment regimen [82]. The probability of treatment failure, even with this protocol, is extremely high [76].

Individuals who had been previously adequately vaccinated for rabies are treated differently. The ACIP suggests that these patients receive rabies vaccine IM as soon as practical with a second injection three days later [83,242]. The recommended site is the deltoid muscle. They do not advise giving HRIG to previously immunized patients [72,81,242].

In the United States, every state has some type of requirement that household dogs and cats be vaccinated for rabies. Although the vaccine is commercially available, almost all vaccinations of domestic animals are performed by veterinarians. Some states or municipalities also impose quarantines of varying periods to help reduce the possible spread of rabies [84].

The CDC and the WHO suggest that individuals who might have a higher risk of coming in contact with a rabid animal be vaccinated. This pre-exposure prophylaxis includes occupations such as veterinarians, laboratory workers, animal control officers, and animal handlers. The recommended vaccine is a cell culture vaccine (CCV) [85]. It is also recommended that the production and use of nerve-cell vaccines cease.

The WHO suggests that an intradermal administration of CCV 0.1 mL be used in three doses at day 0, 7, and then between 21 and 28 days or, alternately, intramuscular administration of 0.5 to 1 mL, depending on the type of vaccine, on the same three-day schedule [85]. However, rabies vaccine adsorbed is no longer available in the United States and therefore intradermal administration is no longer recommended [83]. Intramuscular vaccinations should be administered in the deltoid area of the arm for adults and the anterolateral area of the thigh for children younger than 2 years of age; the vaccine should not be administered in the gluteal area. Serologic analyses should be performed every six months for those at high risk and every two years for those at lower risk; a booster injection is not recommended unless rabies-virus neutralizing antibody titers fall below 0.5 IU/mL [85]. Booster injections are not recommended for individuals travelling to high-risk areas if they have previously completed pre-exposure or post-exposure prophylaxis.

AVIAN INFLUENZA

The influenza viruses that are carried by birds, both domesticated and wild, rarely have infected humans. This is partly due to the fact that avian influenza (AI) viruses attach to receptors found on bird cells but not found on human cells. Human viruses prefer the receptors found in the human respiratory tract. Pigs have receptors used by avian, swine, and human influenza viruses and have traditionally been the link between avian and human influenza viruses. Because pigs acquire all three types of viruses, reassortment/antigenic shift of the hemagglutinin and neuraminidase proteins occurs in the pig host, which then transmits the new strain to humans or other pigs [86,87].

However, there now exists evidence that avian influenza can spread directly to humans [87]. In 2004, areas of Asia experienced large-scale outbreaks of avian influenza, specifically the H5N1 virus, in poultry. The virus went on to infect humans, with a high mortality rate. The number of countries, people, and animals affected by the virus reached unprecedented levels. In 2006, the CDC summarized the H5N1 outbreak. Wild birds and poultry had been infected in Asia, parts of Europe, the Middle East, and Africa. Human infections continued to be reported in China, Egypt, Indonesia, Azerbaijan, Cambodia, and Djibouti. There were some probable human-to-human transmissions of H5N1, but these were rare. As of June 2016, the WHO reported 850 human cases of H5N1, with a fatality rate of approximately 53% [88]. In January 2014, the first case of a human infection with H5N1 in the Americas was reported in Canada; the patient, who died, had recently travelled to Beijing, China [243]. Both the CDC and the WHO have reported that there is a strong threat of a future pandemic of avian influenza and that preparedness is vital [90,91,92]. In August 2012, the Indonesian Ministry of Health announced another H5N1 death of a man infected either from birds he kept in his home or from exposure to H5N1 near his home, which is about 50 meters from a poultry slaughterhouse. This brings the total of confirmed cases of H5N1 in Indonesia to 191 with 159 deaths, a fatality rate of 83% [93].

Although influenza A viruses can infect all birds, domestic poultry flocks are more vulnerable to infections that can reach epidemic proportions. Generally, domesticated fowl transmit the virus in saliva, nasal secretions, and feces. However, it is thought that the fecal-oral route is the common way the virus is spread among flocks. Wild birds rarely become sick but are a source of infection through their droppings because they carry the virus in their intestines. Free-roaming domestic fowl are at more risk from wild bird droppings than housed flocks. Both food and water supplies can be contaminated by droppings or sharing with wild birds. At first it was thought that wild birds spread the virus from farm to farm, but further study indicated that people and equipment probably spread the virus to domesticated flocks [94,95].

AI viruses are classified as low pathogenic and high pathogenic based on their genetic sequence and the resulting illness in birds. Low pathogenic AI has been detected in wild birds, mostly ducks, geese, and gulls, since 1975 [94,96]. Low pathogenic AI virus causes only ruffled feathers and a reduction in egg production. Fortunately, most AI viruses are low pathogenic; however, in six to nine months, they can mutate to high pathogenic. High pathogenic AI viruses, first noted in 1878 in Italy, are highly contagious, spread rapidly, and are almost 100% fatal. Fowl can die the same day that they first exhibit symptoms [96,97,98].

Whenever an AI virus infects a human directly, there is much concern. Humans rarely have any immunity to AI viruses. Medical resources around the world quickly mobilize when there is a case of AI that skips reassortment in swine and directly infects a human. Fowl within a 2-mile (3-kilometer) radius of the source bird/flock are killed in order to contain the virus. An AI virus in humans usually produces upper respiratory disease and conjunctivitis. The infected humans and their contacts are watched closely for secondary transmission. For a pandemic to follow, these factors are needed:

- Humans do not have immunity to the virus

- Direct transmission from bird to human

- Sustainable transmission from human to human

- Movement of infected/contagious individuals to other geographic locations

Once a new pandemic influenza virus emerges, it generally circulates for many years [94,97]. Researchers at the University of Wisconsin, Madison, have been combining H5N1 with a seasonal flu strain (H3N2). As a result, they have found such reassortment flu viruses are highly pathogenic; 22 were more pathogenic for mice than the original H5N1, and 3 caused extremely severe disease [99].

Avian Influenza Viruses

The hemagglutinin antigens that historically have caused human influenza are H1, H2, and H3. Although all known hemagglutinin subtypes occur in birds, H5, H7, and H9 have been implicated more in recent outbreaks. Various combinations with the neuraminidase antigens occur. All of these AI viruses are type A, as B and C do not infect birds. Some of the cases focused on in the past two decades have included the following [90,100,101]:

- H5N1 – Hong Kong, 1997, first documented human infection-18 hospitalized, 6 deaths, 1.5 million chickens culled

- H9N2 – Hong Kong, 1999, 2 mild cases in children, several in mainland China

- H7N2 – Virginia, 2002, 4.7 million chickens and turkeys culled

- H7N7 – Netherlands, 2003, 80 poultry workers, 3 family members infected (79 eye infections, 6 influenza-like), 1 veterinarian death due to acute respiratory distress syndrome and complications

- H5N1 – Hong Kong/China, 2003, 2 ill, 1 death

- H9N2 – Hong Kong, 2003, 1 case confirmed in a child

- H5N1 – Asia, 2004–2005 (H5N1 had been found in Asian chickens April, 2003), 112 confirmed cases, 57 deaths; too widespread to cull all fowl

- H7N3 – British Columbia, 2004

- H5N2 – Taiwan, 2004, low pathogenic, no human illness

- H7N2 – Delaware, 2004, no human illness

- H5N2 – Texas, 2004, no human illness

- H5N1 – Russia/Romania/Turkey/Azerbaijan, 2006, some human illness, unknown deaths

- H5 Outbreaks – 21 U.S. states and Canada, 2014–2015, highly pathogenic, found in backyard and commercial flocks and wild birds, no human illness

- H7N8 – Indiana, 2016, highly and low pathogenic virus detected in nine commercial turkey flocks, all culled, no human illness

- H7N9 – China, 2013–2017 (ongoing), contact with poultry at farms and live markets, 1,347 laboratory-confirmed human infections (as of April 2017)

Fortunately, although in some of these outbreaks bird-to-human transmission did occur, human-to-human transmission has been extremely rare. Limited transmission possibly did occur between humans in the Netherlands, but no sustainable transmission occurred, so an epidemic or pandemic did not follow. There were 14 cases and 12 deaths (11 children) from H5N1 virus in Vietnam. The viruses isolated from those who expired in Vietnam were mostly resistant to amantadine and rimantadine. Studies are continuing as to the effectiveness of oseltamivir and zanamivir against H5N1 viruses. There is some evidence that H5N1 is sensitive to oseltamivir; however, some evidence of resistance to oseltamivir has been reported in highly pathogenic avian influenza H5N1 viruses isolated from human cases [94,95,97,101,102,103]. Most of the H5N1 outbreaks were controlled by veterinarian officials or spontaneously died out. However, H1N1 continues to fulminate in poultry in Egypt [104].

Avian Influenza and Humans

Most cases of AI in humans have resulted from contact with infected poultry or contaminated surfaces. It is also possible for the virus to become aerosolized and then land on exposed surfaces of the mouth, nose, or eyes. Aerosolized virus could also be inhaled directly into the lungs. Eating poultry products has not been associated with the development of AI. Influenza viruses are destroyed by adequate heat.

Some patients might become concerned about contaminated poultry products from other countries entering our food supply. Some countries will not permit poultry to be imported from countries in which there were confirmed human cases of AI, such as China's ban of U.S. chicken in 2015. However, the risk of AI spreading through the global chicken industry is low because most chickens on the international market are killed and frozen or chilled. All documented transmission to date has been from live birds [101,105].

Humans have no immunity to AI viruses, so illness tends to be severe and the fatality rate is high. Prevention is difficult because the viruses tend to be highly contagious. Because of the mobile nature of people and efficient, rapid transport, any virus can spread quickly around the world. The current manufacturing process of influenza vaccine requires several months. The elements are all in place for a pandemic.

In August 2007, a team of scientists at the National Institute of Allergy and Infectious Diseases reported that it had developed a way to generate vaccines and therapeutic antibodies that could target constantly mutating influenza viruses, such as H5N1. The team focused on mutations that enable H5N1 hemagglutinin protein to better recognize and enter human cells and those mutations that will elicit antibodies. This information will enable researchers to consider how to design potential vaccines that will protect people from future emerging AI virus mutants, possibly helping to contain a pandemic in its early stages [106].

In order to understand how influenza viruses mutate, researchers have been working to synthesize the hemagglutinin responsible for the 1918 influenza ("Spanish flu") pandemic. The success of this endeavor was reported in 2004, and scientists have since discovered how subtle alterations enabled the virus to move from birds to people [107].

The H5N2 avian influenza virus continues to be monitored around the world by scientists. It is highly virulent but has not been transmitted person-to-person yet [92,108]. In 2015, H5N2 avian influenza virus (along with H5N8 and H5N1) were found in more than 200 bird samples, indicating the likelihood that 40 million farm and backyard birds have been infected in 20 states [245].

Clinical Presentation and Diagnosis

As noted, humans have no immunity to avian influenza A viruses, so illness tends to be severe and the fatality rate is high. The symptom complex can range from the typical influenza findings of fever, headache, myalgia, sore throat, and cough to severe respiratory distress. Many humans develop conjunctivitis, which can be the initial complaint. This usually includes red, itching, and tearing eyes with associated photophobia and purulent discharge. The severe form progresses to pneumonia, which can be fulminant and followed by multiorgan failure and death. Although the very young and very old are most at risk for the viral pneumonia, fatalities have occurred among previously healthy adults [89].

Laboratory testing is required to diagnose avian viral disease; it cannot be determined by clinical signs and symptoms alone [89]. Diagnosis is initially based on the history from a patient with the symptoms of influenza who has had contact with birds, poultry, or an endemic area. A complaint of eye irritation, which on examination appears to be conjunctivitis, is another clue to the presence of the disease. The available laboratory tests include viral culture and reverse transcriptase PCR (RT-PCR). These can be performed on samples of eye exudate, tears, or throat swabs. Analyses are most useful if obtained within four days of the onset of symptoms, and eye swabs are more likely to be positive than throat culture [109].

Treatment and Prevention

As in other viral diseases, supportive treatment is a mainstay in avian viral infections. Over the past few years, several regimens have been attempted in the treatment of avian viral disease. The antiviral medications amantadine, rimantadine, oseltamivir, and zanamivir have been used in cases of human influenza in the United States. However, amantadine and rimantadine were shown to be ineffective against the H5N1 strain of avian influenza in humans during the outbreaks in Asia in 2004 and 2005 [110]. The CDC and the WHO recommend oseltamivir, peramivir, or zanamivir for treatment and prevention of human infection with avian influenza A viruses; however, as noted, some evidence of resistance to oseltamivir has been reported in viruses isolated from some human cases [89]. The suggested adult dose for the treatment of influenza is 75 mg twice per day, starting within two days of symptoms and continuing for five days. Results are best if the drug is started within two days after contact with an infected individual or fowl. For prophylaxis, the dose is also 75 mg twice a day, but taken for 10 days [46].

A major step to limiting disease and transmission among domesticated fowl is to destroy all diseased birds and their flock mates. Because the virus appears to be carried by people and machines, possibly on shoes and tires to surrounding areas, the recommendation is that all fowl in a 2-mile (3-kilometer) radius of the diseased flock be culled. Obviously, no shipping of live poultry from the infected areas should occur.

During the outbreaks of avian influenza in poultry in Asia during 2003–2004, people were not restricted from traveling to outbreak areas because of the limited transmission to humans. However, the following recommendations were sent to embassies and Americans living abroad [111]:

- Practice frequent and careful handwashing with soap and water or with a hand cleanser if soap and water are unavailable.

- Avoid bird markets and poultry yards where avian influenza is most likely to be transmitted.

- All poultry and eggs should be cooked well, as influenza virus is destroyed by heat.

- Protect pets by keeping them inside to avoid exposure to birds that may be sick, refraining from feeding them raw meat or poultry, and avoiding all contact with stray cats or dogs.

- Masks and other personal protective equipment in public areas are not recommended.

- Travelers should be immunized with the current influenza vaccine against human influenza strains before traveling and should be reminded that winter (flu season) occurs in the Southern Hemisphere when the Northern Hemisphere is experiencing summer.

The CDC has also developed guidelines for airline personnel dealing with a suspected case of avian influenza on board an international flight originating in an area in which avian influenza has been reported [112]:

- As much as possible, airline staffs are to keep the sick person separated from close contact with others.

- A surgical or procedural mask should be provided to limit the amount of droplets coughed into the air. If the passenger cannot wear the mask, anyone assisting him/her should be masked.

- The passenger should be taught cough etiquette if it is not being practiced.

- Disposable gloves are to be worn for any contact with body fluids, and hands are to be washed well when gloves are removed.

- The captain is to report the illness to the nearest U.S. Quarantine Station if the aircraft is coming to the United States. The Quarantine Station will coordinate appropriate medical assistance when the plane lands and will notify the appropriate CDC staff.

Influenza viruses are destroyed by adequate heat. Because the pathogen is found in poultry, all individuals should be reminded to cook poultry, including eggs, thoroughly. Chicken should be cooked until the internal temperature reaches 180 degrees F. All utensils and surfaces that have come in contact with raw poultry should be washed well with soap and water immediately following use. A separate cutting board should be used to cut raw poultry. In order to retard bacterial or viral replication, all poultry products should be defrosted in the refrigerator, not at room temperature.

Some patients might become concerned about contaminated poultry products from other countries entering our food supply. Some countries will not permit imported poultry from countries in which there were confirmed human cases of avian influenza. However, the risk of avian influenza spreading through the global chicken industry is low because most chickens on the international market are killed and frozen or well chilled. All documented transmission to date has been from live birds [105].

Vaccine Development

As with the development of all vaccines, the first step is to isolate the organism. In the case of AI, various research centers and companies around the world are working to make a vaccine. The first step is to isolate the virus (e.g., the H5N1 influenza A virus in 2004). Next, the virus is dismantled so the most virulent elements can be excluded. Then the virus is reassembled without those virulent elements, and attempts are made to produce it [105]. As noted, the virus has been isolated and the virulent elements have been identified to allow vaccine development to proceed. In 2006, a new recombinant H5N1 virus became available for distribution to companies interested in pandemic vaccine development [114]. In 2007, GlaxoSmithKline received a contract from the U.S. Department of Health and Human Services to manufacture 22.5 million doses of AI vaccine in addition to the 5 million doses ordered in 2006 [115]. Research to find novel media or methods (rather than using eggs) is ongoing [116].

In April 2007, the FDA approved the first human vaccine for the AI virus H5N1 [117]. This vaccine is intended for individuals 18 to 64 years of age who could be at an increased risk of exposure to the H5N1 influenza virus. The vaccine is not available commercially, but rather has been purchased by the federal government to be distributed if necessary. The vaccine consists of two 90-mcg IM doses given 28 days apart. There is thimerosal, a preservative, in this vaccine [46,117]. Because this vaccine has been approved by the FDA and found to be safe and effective, it is no longer considered experimental. Therefore, it can be used during a pandemic without the time-consuming protocol and signed informed consent necessary for an experimental drug or vaccine [117]. Data from trials being conducted on ACAM-FLU-A show that the vaccine generates a robust antibody response against H5N1 avian influenza [118].

SWINE INFLUENZA

As discussed, pigs represent an important link in the interspecies transmission of influenza and in the creation of new virus types. In addition, swine influenza has the potential to cause significant disease in humans, although it is difficult to predict the potential impact of swine influenza in humans. Because most individuals, with the possible exception of those with regular contact with pigs, do not have immunity to these viruses, the potential for pandemic exists.

Swine influenza is usually caused by the H1N1 subtype, but other swine influenza A viruses do occur, including H1N2, H3N1, and H3N2 [119]. Although swine flu viruses do not typically infect humans, sporadic human infections have occurred. When this occurs, these viruses are called "variant viruses" and are denoted by adding the letter "v" to the virus subtype designation. Human infections with H1N1v, H3N2v, and H1N2v viruses have been detected in the United States [119,120]. Pigs may become infected with more than one virus subtype simultaneously; in these cases, genes from the viruses may mix and create a new "reassortment" virus [121]. The main swine influenza viruses circulating in U.S. pigs in the past decade include triple reassortant (tr) H1N1, trH3N2, and trH1N2 [119,120].

Among pigs, swine influenza is a highly contagious acute respiratory disease. In many countries, including the United States, swine populations are routinely vaccinated against the prevalent subtypes. Vaccination of pigs, while not sufficient to produce sterilizing immunity, can reduce the levels of virus shed by the animals and reduce the potential for human exposure and infection [121].

In 2009, an outbreak of H1N1 influenza A (hereafter referred to as 2009 H1N1), popularly referred to as the "swine flu," occurred. Tests showed this virus was similar to influenza viruses normally occurring in pigs in North America. However, with more extensive testing scientists learned that there were two genes present that typically occur in pigs in Europe and Asia. In addition, there were also avian and human genes. A quadruple reassortment virus was the result [122].

It should be noted that the so-called Spanish Influenza of 1918–1919 was also an H1N1 virus. The hemagglutinin gene in 2009 H1N1 influenza apparently descended from the avian-origin 1918 pandemic influenza virus. The 2009 H1N1 virus is not a new subtype, but many humans had no pre-existing antibody to it (especially those younger than 65 years of age) and widespread transmission resulted. This led to the first pandemic since 1968. The virus quickly spread worldwide, and on June 11, 2009, the WHO declared it a worldwide pandemic. In the United States the virus was first detected in humans in April 2009. By September more than 99% of the circulating viruses were 2009 H1N1. It remained the predominant circulating virus for the entire 2009–2010 influenza season [122,123]. On June 23, 2010, the public health emergency for 2009 H1N1 expired in the United States, and the WHO declared the pandemic over on August 10, 2010 [124].

Data from past pandemics show that influenza activity occurs in waves. A second wave of 2009 H1N1 occurred in the fall of 2010 and peaked in the first three weeks of October [125]. Experts believe that 2009 H1N1 will continue to circulate for some time, perhaps as a typical winter flu. As noted, it was included in the formulation of the 2016–2017 vaccine [131].

Transmission

Like all flu viruses, 2009 H1N1 is mainly spread among people by coughing, sneezing, talking, and occasionally via fomites. It is not spread by food or by eating pork or pork products. There have been no cases acquired from influenza-contaminated drinking water. Chlorine treatment of drinking water has been shown to inactivate the highly pathogenic H5N1 virus, and H1N1 would be similarly affected. A documented case of influenza from any water exposure (drinking or recreational) has not occurred.

Pets, such as dogs, cats, and ferrets, can be infected with H1N1 from close contact with a sick human. All available information indicates that H1N1-infected dogs, cats, and ferrets do not transmit the illness to humans. So far, there is no H1N1 vaccine for animals. Most recover with supportive care [122].

When a swine influenza virus does become a source of widespread human illness, the transmission patterns change. Instead of being mainly limited to swine contact, the virus will spread by human-to-human contact. According to the CDC, available data indicate that the 2009 H1N1 virus is transmitted in ways similar to other influenza viruses, primarily large-particle respiratory droplet transmission [126]. Because humans have little to no immunity to influenza viruses of swine origin, transmission may be common.

H1N1 survives on surfaces, including kitchen counters, door knobs, desk tops, and other fomites, for two to eight hours. Individuals can pick up the virus when they touch contaminated objects and unconsciously then touch their eyes, mouth, or nose. Thus it is vital for people to learn to keep their hands away from their mouths, eyes, and nose and to frequently wash their hands well with soap and water or use an alcohol-based hand sanitizer. An alcohol-based product, bleach solution, or hot, soapy water can be used to clean surfaces [127]. One positive result of the H1N1 pandemic, as indicated in a study conducted in Hong Kong, is that people are washing their hands more frequently and wearing face masks when having influenza-like illness or when in public areas [128].

A major transmission concern with 2009 H1N1 was regarding newborns whose mothers had the virus. The CDC and State Health Departments strongly recommended the 2009 H1N1 vaccine for this population because of demonstrated risks to both infants and pregnant women. However, many disregarded the recommendation. It was then decided that infant and mother should be separated until the mother had been on antivirals for at least 48 hours, was afebrile for 24 hours without antipyretics, and could control her cough and respiratory secretions. Before visiting the infant, the mother was instructed to clean her hands well with soap and water or an alcohol-based hand sanitizer, wear a face mask, and observe respiratory/cough etiquette. If her gown had been contaminated with byproducts of coughing or sneezing, she was instructed to change to a fresh gown. Following these guidelines, the mother was then permitted to hold, feed, and care for the infant [125].

Prevention

Like seasonal influenza, vaccination is the most important preventive measure. Other common sense preventive steps (e.g., appropriate cough cover, correct disposal of used tissues, adequate rest, good fluid intake, staying home when ill) should be practiced.

Vaccine

The CDC identified five groups who were given first priority 2009 H1N1 vaccination [129]:

- Pregnant women

- Persons who live with or provide care for infants younger than 6 months of age

- Healthcare and emergency medical services personnel

- Children and young adults 6 months to 24 years of age

- Persons 25 to 64 years of age at higher risk for influenza-related complications

These patients were vaccinated as soon as the vaccine was available. As with seasonal influenza vaccine, it is also important to note that two doses of the vaccine are necessary for previously unvaccinated children younger than 9 years of age, as they typically have had limited exposure to influenza viruses and are not immunologically primed [129,131]. For the 2016–2017 flu season, the ACIP recommended that children 6 months through 8 years of age not previously immunized be given two doses at least four weeks apart [131]. At least one study has shown that a single injection is adequate when vaccinating pregnant women [131].

Symptoms and Diagnosis

Similar to seasonal flu, H1N1 symptoms include chills, fever, myalgia, fatigue, headache, cough, sore throat, and rhinitis. But unlike seasonal flu, there may be vomiting and diarrhea in some people. Others may have respiratory symptoms without fever [122,127].

Unless it becomes a pandemic, swine influenza infection in humans generally goes undistinguished from typical human influenza as a result of the overlapping flu seasons and the relatively mild clinical presentation. The disease is diagnosed by analysis of a sputum sample collected in the first four to five days of illness, when an individual is most likely to be shedding the virus [119]. A new test for 2009 H1N1 was authorized by the FDA in June 2010 to be used on upper or lower respiratory secretions. The CDC Influenza 2009 A (H1N1) pdm Real-Time RT-PCR panel (IVD) replaces the test authorized in April 2009 [133].

In the case of the 2009 H1N1 virus, the CDC recommended that clinicians test persons for the virus if they had an acute febrile respiratory illness or sepsis-like syndrome [126]. Patients who require hospitalization or who are at high risk for severe disease should be tested and treated first.

It was believed that persons at greater risk for complications of seasonal influenza would also be at greater risk for complications associated with 2009 H1N1 flu. This included [126]:

- Pregnant women

- Children younger than 5 years of age

- Persons 65 years of age or older

- Adults and children who have chronic illnesses

- Adults and children who have immunosuppression

- Children and adolescents who are receiving long-term aspirin therapy

However, as the epidemic progressed it became apparent that those younger than 65 years of age were at great risk (Table 5) [125].

Table 5: DISTRIBUTION OF 2009 H1N1 AND SEASONAL INFLUENZA BY AGE GROUP

Influenza Type

0 to 17 Years

18 to 64 Years

0 to 64 Years

65 Years and Older

Cases

2009 H1N1

33%

57%

90%

10%

Seasonal

--

--

<10%

90%

Hospitalizations

2009 H1N1

32%

58%

90%

10%

Seasonal

--

--

40%

60%

Deaths

2009 H1N1

10%

77%

87%

13%

Seasonal

--

--

10%

90%

Source: [125,134]

Treatment

While most swine influenza cases were sufficiently mild to resolve spontaneously, antiviral medications were used if treatment was indicated. The specifically recommended agents were determined based on clinical and epidemiologic assessment of the virus. For example, in the case of the 2009 H1N1 outbreak in North America, the virus's susceptibility profile indicated that the preferred antivirals would be oseltamivir or zanamivir (or peramivir in case of severe illness requiring hospitalization) [119,121].

During the 2009 H1N1 pandemic, the CDC recommended antiviral treatment for all persons with suspected or confirmed influenza requiring hospitalization [123]. In addition, early empiric treatment with oseltamivir or zanamivir was considered for persons with suspected or confirmed influenza who were at higher risk for complications, including [123]:

- Children younger than 2 years of age

- Persons 65 years of age or older

- Pregnant women and women up to two weeks postpartum (including following pregnancy loss)

- Persons of any age with certain chronic medical or immunosuppressive conditions

- Persons younger than 19 years of age who are receiving long-term aspirin therapy

The recommended treatment for adult and adolescent patients is either 75 mg oseltamivir twice per day for five days, 10 mg (two 5-mg inhalations) of zanamivir twice daily for five days, or a single 600 mg IV infusion of peramivir over 15 to 30 minutes [46,119,123]. Children 7 years of age and older may be treated with the adult dose of zanamivir. However, calculating oseltamivir doses for children is more complicated and has been the source of medical errors [136]. It is important to note that while healthcare providers in the United States generally write prescriptions for liquid medications in milliliters, oseltamivir is dosed in milligrams [136]. For children younger than 1 year of age, the oseltamivir dose is based on age. Infants younger than 3 months of age should be given 12 mg twice daily; infants 3 to 5 months of age should receive a dose of 20 mg twice daily [46]. Infants 6 to 11 months of age should receive a dose of 25 mg twice per day. For children between 1 and 12 years of age, dosage is based on weight [46,123]:

- <15 kg (<33 lbs): 30 mg twice daily

- >15 kg to 23 kg (>34 lbs to 51 lbs): 45 mg twice daily

- >23 kg to 40 kg (>51 lbs to 88 lbs): 60 mg twice daily

- >40 kg (>88 lbs): 75 mg twice daily

Treatment should continue for five days in most cases, but longer treatment should be considered for patients that remain ill after five days [46,123]. Pregnancy is not considered a contraindication to the use of oseltamivir or zanamivir.

As of December 2012, 2009 H1N1 was susceptible to both oseltamivir and zanamivir, with a few exceptions. Those resistant to oseltamivir have been sensitive to zanamivir. Sporadic oseltamivir-resistant 2009 H1N1 virus infections have been identified, but the public health impact has been limited [137]. As of October 2012, no evidence existed of ongoing transmission of oseltamivir-resistant 2009 H1N1 virus strains worldwide [137].

Investigational Drugs

A study at Utah State University examined the use of oseltamivir combined with T-705 (favipiravir), an antiviral in late-stage development, on mice. This combination was effective against H1N1, N3N2, and H5N1 influenzas. The study indicated that two antivirals may be a better strategy for treatment of humans with influenza [138].

Because there were no FDA-approved intravenous drugs to treat influenza at the time of the 2009 pandemic, a new investigational antiviral drug, peramivir (approved 2014), was used with patients hospitalized with H1N1 under an Influenza Emergency Use Authorization (EUA) and special permission [139]. Peramivir acts by inhibiting the neuraminidase enzyme that affects the release of viral particles, which results in less virus in the body. The EUA permitted the use of the IV drug only for those hospitalized with a severe suspected or laboratory-confirmed case of 2009 H1N1 who were not responding to inhaled or oral antiviral therapy or for whom the approved antivirals were not acceptable [139]. It was not to be used for seasonal or uncomplicated flu. A creatinine clearance test was required before administration to assure that the patient did not have renal insufficiency. Peramivir is contraindicated for any patients with allergies to zanamivir, oseltamivir, or any component in peramivir. Children, birth through 17 years of age, are not permitted to receive peramivir; because safety and efficacy in this population has not been established, this use is investigational [140].

Peramivir is available in a 200 mg/20 mL single-use vial, which is stored at 59 to 86 degrees F (15 to 30 degrees C). After dilution, it should be given immediately or refrigerated and administered within 24 hours. Some patients on peramivir experienced diarrhea, nausea/vomiting, or neutropenia. Less common side effects included nervousness/agitation, hypertension, headache, depression, dizziness, cystitis, anorexia, hematuria, hyperbilirubinemia, hyperglycemia, somnolence, insomnia, electrocardiogram abnormalities, and nightmares [140].

HANTAVIRUS SYNDROMES

In 1993, there was a series of mysterious deaths due to pulmonary failure in healthy young adults in the four corners region of the American Southwest [141,142]. Considerable research into the problem resulted in the identification of a virus, harbored in local mice, as the cause of the illness. The virus identified was an RNA Hantavirus, a group related to the Bunyaviridae family that causes hemorrhagic fever with renal syndrome (HFRS) in Asia and hantavirus pulmonary syndrome (HPS) in the Americas.

Although many thought that HPS was a new entity, the local Navajo inhabitants described a similar disease that they had known about for many years. Between 1993 and January 2017, 728 cases were reported in the United States, with a 36% fatality rate [141,142]. HPS has been documented in 35 states, with 96% occurring in states west of the Mississippi river and more than half of the confirmed cases reported outside the Four Corners area. In 2017, an outbreak of HPS was linked to home-based rat-breeding facilities in Wisconsin and Illinois; infected rats may have also been distributed or received in Colorado, Delaware, Georgia, Idaho, Iowa, Minnesota, Missouri, New Jersey, Pennsylvania, South Carolina, Tennessee, and Utah [237]. There have also been reported cases in Central and South America [142,143].

The main host for HPS is the deer mouse (Peromyscus maniculatus), but other mice and rodents have been found to carry the organism. There have been other documented hantavirus infections in the United States, with some having specific rodent carriers. The Bayou virus caused disease in Louisiana, and the New York-1 virus was isolated after producing illness in a patient in the Northeast. The causative agent for the 1993 outbreak and subsequent HPS cases has become known as the Sin Nombre virus. In the United States and Canada, the Sin Nombre hantavirus is responsible for the majority of cases of HPS [142].

HPS virus particles are shed by the rodents in their saliva, urine, and feces. They do not seem to have any signs of illness while carrying the virus. Although the disease can be contracted by the bite from a rodent or by contamination of foodstuffs, the most common means of spread is from aerosols. The dried excrement of the animals is easily swept or blown into the air, where it is inhaled into the lungs [142,144]. Most patients who contract the disease remember cleaning rodent excrement or dead mice from an enclosed area in or around their home. Human-to-human spread does not occur [142,143,144].

Clinical Presentation and Diagnosis

The incubation time from contact with the virus until the onset of symptoms is thought to be about one to five weeks. Almost everyone who develops the disease will have fatigue, fever greater than 38.3 degrees C, and myalgia, usually in the large muscles of the back, thighs, and shoulders. There is usually hypotension, tachypnea, and tachycardia. About one-half of patients experience nausea and vomiting, headache, dizziness, and abdominal pain [142,144]. After 4 to 10 days, the late symptoms of HPS appear with the onset of coughing, shortness of breath, increasing pulmonary distress, and pulmonary edema [142]. HPS appears to resemble acute respiratory distress syndrome in patients with advanced disease. In some patients, renal impairment may also develop, but this is more common in illness caused by hantaviruses other than the Sin Nombre virus.

Chest x-ray shows bilateral interstitial edema, which becomes progressively worse and develops into alveolar edema as the patient deteriorates. Differentiation from acute respiratory distress syndrome can usually be made based on clinical findings; however, good laboratory tests are also available. Laboratory diagnosis can be made by the detection of hantavirus-specific IgM or rising titers of hantavirus-specific IgG. PCR analysis of clinical specimens is also useful. In addition, blood samples can be analyzed for hantavirus antigen by immunochemistry. Patients with HPS often have a left-shifted increase in neutrophils, which helps to differentiate the early symptoms from other viral infections [142,143,144].

Treatment and Prevention

No treatment has proven to be useful for HPS, with the exception of supportive care. Ribavirin, which has helped in some hantavirus infections in Europe, has not proven to be of use in patients with HPS [130,144]. In most cases, admission to an intensive care unit is necessary, and oxygen is required as the patient becomes hypoxic. Broad-spectrum antibiotics are suggested to help combat secondary bacterial infections. Analgesics and antipyretics provide comfort, but fluids should be carefully monitored due to possible capillary leakage [130,144]. Mechanical ventilation and cardiopulmonary support should be available in the event of a sudden onset of pulmonary failure.

As noted, even with treatment, about 36% of patients have died from the disease [142]. This makes prevention an important factor in decreasing the morbidity and mortality associated with HPS. Educating the public in the proper handling of rodents and their excrement is the primary method of prevention. Avoiding contact with rodents is an obvious rule, but this is not always possible. Using latex or other protective gloves is suggested if contact with a dead rodent or its excrement is necessary. Because aerosolizing of the excretory products is documented to cause the disease, it is advised to "wet down" dead rodents or any areas where rodents have been present before attempting to clean the region. An enclosed area should be left open to air out before entry, if possible [142,144].

Attempt to rodent-proof the home and outbuildings by sealing off the possible points of entry and removing foodstuffs from kitchen counters and tables, especially at night. Garbage cans and other refuse containers should have tight lids. Trapping rodents or using traps and baits to decrease their numbers has been shown to reduce the number of cases in a local area [142,144]. The virus is inactivated by alcohol and chlorine preparations, which can be used as disinfectants in indoor and outdoor areas. Complete drenching with a 10% bleach solution is recommended [142]. Sunlight can also kill the virus. The use of respirators is only suggested for workers in regions of high rodent population or where the disease is known to be present but is a sensible precaution when working in enclosed areas with limited ventilation [142,144].

LYMPHOCYTIC CHORIOMENINGITIS (LCM)

Lymphocytic choriomeningitis (LCM) has the house mouse (Mus musculus Linnaeus) as its reservoir species. The disease is primarily a mild one, though probably underdiagnosed in individuals with normal immune systems [145]. Transmission is through contaminated food ingestion, aerosols, and bites from infected rodents. The house mouse is a very common rodent throughout the world and is sold in many places as a pet. LCM virus can also be spread by hamsters and guinea pigs if they have contact with infected mice. The CDC has maintained contact with retail stores, and some have stopped selling these rodents during periods of outbreaks [146]. This is not an uncommon disease. The prevalence of LCMV antibodies in urban human populations is 2% to 5%, and its distribution is worldwide.

Clinical Presentation and Diagnosis

Rodents infected with LCM virus show little sign of illness. Serologic testing of the rodents has not been very reliable, and the animals can shed virus for the duration of their lives without appearing to be ill [146]. In humans, LCM is characterized by a flu-like illness lasting only a few days. A few cases will relapse afterward, and these rare cases may develop meningeal inflammation signs, beginning with nuchal rigidity, headache, fever, malaise, and muscular pain. A limited number of cases progress to meningoencephalitis with paralysis and coma. Most will recover, although severe cases may have a protracted recovery time [146,147]. If a pregnant woman contracts the disease in the first or second trimester, there can be serious consequences for the fetus. Case fatalities are rare, except in immunocompromised patients. LCM can be isolated from the blood of febrile patients or from CSF in patients with meningitis; however, laboratory diagnosis in a patient suspected of having LCM is usually made by CSF PCR or by serologic studies (IgM and IgG antibody titers) on acute and convalescent serum.

Treatment and Prevention

Treatment of LCM is based on symptom management. Prevention of the disease involves care in cleaning and disinfecting cages and regions of wild mouse activity. Pregnant women should avoid handling possibly infected rodents. Wholesale and retail merchants should be aware of outbreaks and keep groups of rodents isolated from each other to prevent cross contamination [146].

BOVINE SPONGIFORM ENCEPHALITIS (BSE)

Bovine spongiform encephalitis (BSE), commonly known as mad cow disease, has received a considerable amount of attention in the medical and lay press since the first reported outbreaks in 1986 [148]. The human disease is called variant Creutzfeldt-Jakob disease (vCJD) and is different from the naturally occurring Creutzfeldt-Jakob disease (CJD) seen mostly in older patients; both are degenerative, progressive, and fatal brain disorders with no known cure [148]. While CJD occurs spontaneously, vCJD has only been seen where there was a connection to ingestion of diseased animal tissue. As of February 2020, there were a total of 231 cases of vCJD reported throughout the world [148]. Most cases were in the United Kingdom (178) and France (28); however, cases have been reported by many countries, including Spain (5), the United States (4), Ireland (4), the Netherlands (3), Italy (3), Portugal (2), Canada (2), Japan (1), Saudi Arabia (1), and Taiwan (1) [148]. Several cases of the disease being diagnosed in the United States and other countries (excluding France) occurred in individuals who had contracted the disease in the United Kingdom [148]. There have been three possible bloodborne transmissions of vCJD through transfusion, but there has never been a documented case of human-to-human transmission [148].

In 1986, BSE was first identified in cattle in England, and in 1989, it was officially listed as a zoonosis. By 1996, the disease seemed to jump the species barrier to humans, presenting as a new variant of CJD [148,149]. This new strain was linked to BSE, possibly through eating meat from BSE-infected cattle. BSE and vCJD are together called transmissible spongiform encephalopathies (TSEs) because they reduce the brain to the same spongy appearance, with gaps appearing within the tissue. TSEs present in sheep as scrapie, in cows as BSE, and in humans as vCJD.

By the end of 2004, millions of cattle throughout the world, but predominately in the United Kingdom, had been slaughtered as part of a plan to control the disease [149,150]. Some researchers believe the disease has peaked already (during 2006–2008), while others point to the disease's long incubation period and suggest that thousands may be affected in the future. The number of new cases does appear to be decreasing annually [151].

Understanding the history of BSE and vCJD makes this complex zoonosis much easier to put into perspective. While sheep, cows, and humans were part of the outbreak in the 1990s and 2000s, heightened awareness as a result of this outbreak led to the knowledge that deer, elk, mink, and cats have related diseases as well [152]. Other species can be experimentally infected, but they do not appear to propagate the illness [152].

Part of the difficulty in making the connection between the species during the initial investigative stages was the lack of identification of a causative agent. Depending on the source, the agents are either prions, virions, or not named at all and merely referred to as TSEs. Most authorities now use the term prions, an acronym for proteinaceous infectious particles. Closely related to viruses, but not a virus, they have no DNA or RNA. Prions make their way into the brain and incorporate themselves into brain cells as proteinase-resistant fibrils. In cows, only the brain has measurable amounts of these fibrils. In sheep, the fibrils can be isolated from a number of different locations, including placental tissue.

In the final stage of the disease, brain tissue becomes sponge-like and the cows become "mad" or "maniacal" before dying. In sheep, advanced disease makes the animals scratch and bite at themselves until they scrape off their coats and excoriate their skin. The brain lesions found in scrapie are identical to that in BSE [152].

The initial recorded BSE outbreak in the 1980s coincided with changes in rendering sheep and an increase in the sheep population in the United Kingdom. The outbreak began after the winters of 1981 and 1982, when cattle were fed with meat and bone meal products contaminated by rendered brain parts from sheep infected with scrapie [152]. A ban on using ruminant rendered products in animal feeds was enacted in 1988 in the United Kingdom and was followed by most developed countries. The initial 1997 feed bans in the United States and Canada have since been replaced with enhanced feed bans in 2009 and 2007, respectively, to eliminate high-risk animal byproducts from all animal feeds, pet foods, and fertilizers, rather than from cattle feed alone [148]. These enhanced bans were implemented to mitigate the recognized limitations of the original bans [148].

The slaughter of possibly infected animals became mandated following the first death attributed to vCJD. It was determined that because of the possibility that the disease could be transmitted to humans in the same way as to animals, ruminant byproducts that might include the brain should be banned to prevent the possibility of transmission. A large number of products in the United Kingdom used ruminant byproducts, leading to public panic. Articles such as lipstick, which might have used rendered material, became objects of concern. This may have been warranted, but the slow release of information contributed to the public uneasiness. It was not until November 1998 that the European ban was lifted on beef from the United Kingdom. In cows, only brain tissue appears capable of transmitting disease [149,153].

No direct transmission has been documented between cows; however, vertical (placental) transmission has been reported [154]. Sheep pass the disease vertically, and it has been theorized that transmission through ingestion of placental tissue from infected animals that give birth in the field is possible.

Kuru, another human disease characterized by a spongy appearance and gaps in the brain, is also contracted through ingestion of animal products infected with TSEs. The brain lesions in vCJD and kuru are identical to those seen in sheep with scrapie. As in vCJD, kuru causes the death of brain cells, with such symptoms as unsteadiness, insomnia, memory loss, and dementia. The Fore people of Papua New Guinea practiced ritualistic consumption of the brains of their deceased relatives as a sign of respect, thus propagating the disease [153]. Variant CJD is not transmitted like kuru. Proof that it is transmitted through ingestion of infected brains is quite difficult due to the long and somewhat unknown length of time from infection to first signs of disease. Injecting neuronal tissue from cows infected with BSE into mice will induce disease, as will brain tissue from infected sheep injected into monkeys. However, it is not possible to draw conclusions about human transmission from this research [155].

In 2007, a new neurologic disorder originating in pigs was reported in a group of slaughterhouse workers processing severed heads [156]. This new condition, referred to as progressive inflammatory neuropathy or immune polyradiculoneuropathy, is believed to be caused by inhalation of brain tissue that is aerosolized by the use of compressed air guns to harvest the organ. The condition is characterized by an enlarged spinal root, pain, weakness, fatigue, and numbness or tingling in the extremities [156,157]. The condition is not believed to be infectious or foodborne, although investigations are ongoing. At this time, it is not believed to be directly related to spongiform encephalitis.

Clinical Presentation and Diagnosis

It is difficult to document the disease agent when it is non-antigenic, as the body does not mount any immune response, making tests such as standard antibody titers useless. Diagnosis of vCJD therefore tends to be based on signs and symptoms with confirmation by examining brain tissue.

This makes the differentiation of vCJD from other progressive, neurodegenerative processes difficult, especially in older patients. The diagnosis is also hampered by the very long incubation period of vCJD, which can be many years between contact with the organism and the development of symptoms [158]. Usual symptoms can include progressive dementia, myoclonus, visual changes, cerebellar dysfunction, pyramidal or extrapyramidal signs, and akinetic mutism. Pain is experienced by about one-half of the patients [159].

Evidence Based Practice Recommendation

The American College of Radiology notes diffusion-weighted imaging can help identify and characterize Creutzfeldt-Jakob disease.

https://acsearch.acr.org/docs/69477/Narrative

Last Accessed: April 17, 2020

Level of Evidence: Expert Opinion/Consensus Statement

When the more common causes are eliminated and a spongiform encephalopathy is suspected, there are several ways to distinguish between "classic" CJD and vCJD. The most obvious is age; classic CJD causes death at a mean age of 68 years following a rapid course with a duration of illness of only four to five months [148]. Variant CJD is a disease of young people, with death at a mean age of 28 years following a more prolonged course, usually over a year. Classic CJD presents with early neurologic signs and dementia, but patients with vCJD often have early behavioral or psychiatric symptoms and painful dysesthesias, with delayed neurologic findings [158].

MRI has been used successfully to diagnose vCJD. An unusual appearance of the thalamus or a specific increase in intensity in the posterior portion of the thalamus, the pulvinar region, has been found in neurologically confirmed cases of vCJD [158]. This finding, called "the pulvinar sign" has not been observed in classic CJD [159].

As noted, the firm diagnosis of vCJD is made with either a brain biopsy during life or examining pathology material at autopsy; however, Western blot analysis of lymph node specimens has shown the presence of prion material in patients with the disease. Florid plaques have been described in brain sections of patients with vCJD but not in those with classic CJD. The vacuolation (spongiform change) has been seen in many portions of examined brains, with most disease found in the occipital cortex and cerebellum [149,160].

Prevention and Treatment

There is no treatment for this disease in any species mentioned. This makes prevention and radical public health measures essential to control BSE, vCJD, and scrapie. All are reportable diseases. Compulsory slaughter has been practiced to eradicate herds with BSE-positive cattle; this was obviously done at huge costs to the public, farmer, and government. The United States has a scrapie eradication program to eliminate scrapie from the sheep herds in the country. The United States and other countries have barred blood donations from people who have lived in the United Kingdom or continental Europe for a cumulative three months or more between the years 1980 to 1996 as a precautionary measure against the spread of vCJD [246].

The best way to protect ourselves and educate patients is to have the correct information and to practice safe consumption. Due to the nature of the prion proteinase resistance and probably its small size, the agent is not destroyed with ultraviolet light, freezing or thawing, boiling for 30 minutes, or formaldehyde. In other words, there is no way to safely cook the agent out of a brain or render a tissue absolutely free of the agent. In 2006, the European Union ban on British beef was lifted due to enhanced BSE testing and control measures (e.g., the banning of feeding cow proteins, including brains, to other cows) [160]. Travelers to the United Kingdom, Ireland, or certain other European countries (France, Greece, and Poland) should be advised that if they are concerned about contracting vCJD, avoiding beef products altogether is the only certain option, but that eating whole muscle meat, rather than ground meat or foods made with brains, carries an "exceedingly low risk" of infection [160,247]. Aside from the European countries listed above, the risk posed by BSE in other European countries is similar to that from U.S. beef. The risk status of Canadian beef is an estimated 18 to 48 times higher than that of U.S. beef and is considered to have similar risk as United Kingdom beef. Cow milk and milk products from all countries are believed to be safe [160].

Because there is no cure or vaccine for the TSEs, treatment is generally confined to supportive measures and symptomatic therapies. It has been suggested that phenothiazines may inhibit prion production, but this has not been confirmed in a series of studies [161]. Anticonvulsants are used to manage seizures and violent outbursts [158]. Experimental therapies include the antimalarial quinacrine and the antipsychotic chlorpromazine to prevent abnormal prion protein conversion. One patient has been treated with pentosan polysulphate and had no evidence of disease progression for 23 months [158]. The agent inhibits prion protein production, replication, and cell toxicity associated with vCJD. Unfortunately, the treatment must be initiated soon after infection to prevent disease onset, which, outside of experiments, is likely impractical.

7. PROTOZOAL ZOONOTIC DISEASES

The common zoonotic diseases caused by protozoa include toxoplasmosis, giardiasis, babesiosis, cryptosporidiosis, malaria and balantidiasis. Toxoplasmosis and giardiasis are seen fairly often in North America.

TOXOPLASMOSIS

The agent of toxoplasmosis is Toxoplasma gondii (phylum Apicomplexa). T. gondii is one of the most widely disseminated parasites known in the world [167]. It has a two-host lifecycle, present in both predator and prey. The intermediate hosts are humans, swine, goats, sheep, dogs, rodents, cattle, and cats. Cats are the definitive host but can be intermediate hosts as well. All members of the cat family can carry the organism, but domestic cats are clearly the source of zoonosis in most people, resulting from fecal-oral transmission [15,167,168]. Studies of cat populations show 16% to 80% of cats in the United States have been infected; the estimated worldwide prevalence in domestic cats is 30% to 40% [169].

Cats become infected with toxoplasmosis when they ingest tissue infected with the bradyzoite phase of T. gondii, which is encysted in the muscle tissue of their prey. When shedding oocysts, a cat can excrete up to 20 million organisms per day. The cyst opens in the gastrointestinal tract, and the bradyzoites are released to enter the enteroepithelial cells in the cat's small intestine. They then shed eggs (oocysts) sporadically into the feces for 7 to 21 days after ingestion [167]. Antibody titers in the cat will not start to rise until after the first round of shedding has stopped. Immunity will last in the cat unless major re-exposure occurs or if high-dose steroid therapy is initiated. Some authorities believe that direct transmission from cats to humans is uncommon and that the organisms are more likely transmitted from contaminated soils or undercooked foods [170]. Kittens, rather than adult cats, have been identified as a cause of direct transmission to humans [167]. It has been reported that 8% of beef, 20% of pork, and 20% of lamb is infected with toxoplasma [170]. In the United States, an estimated 11% of the population 6 years of age and older has been infected with toxoplasma and are chronic, asymptomatic carriers of the parasite; some places in the world have shown infection rates as high as 95% [167].

When an intermediate host becomes infected or consumes meat with encysted toxoplasma, the bradyzoites enter the enteroepithelial cells of the host but do not remain there, as in the definitive host. In the intermediate host, they penetrate the lymphatics of the gastrointestinal tract and from there disseminate throughout other tissues, including the placenta and fetal tissue. Congenital toxoplasmosis is seen in children of mothers who may not realize that they are carrying the organism. In general, the infection must occur during the pregnancy for the disease to be transmitted to the fetus [167,170,171].

Immunocompromised individuals, especially acquired immunodeficiency syndrome (AIDS) patients, can suffer severe complications and should be advised to consult their healthcare providers to determine whether they have been infected with toxoplasma [167,169,170]. It is important to note that immunocompromised individuals have the same rate of infection regardless of whether they are cat owners or not [170]. Contaminated meat or contact with soil contaminated with cat feces is a more common transmission method than poor handling of a litter box. Nevertheless, the CDC advises pregnant women to avoid changing cat litter [167].

Clinical Presentation and Diagnosis

The clinical manifestations of infection in humans are similar to the flu or mononucleosis. As noted, the concern is greatest for pregnant women and HIV-positive individuals. In the first trimester of pregnancy, spontaneous abortions, retinochoroiditis, hydrocephalus, microencephaly, and psychomotor retardation of the fetus are the most common sequelae to exposure [167,171]. In an immunocompromised host, toxoplasmosis can be life-threatening. These individuals are more prone to a disseminating version that can lead to hemorrhagic lesions in the brain. Myocarditis, hepatitis, meningoencephalitis, chorioretinitis, and internal organ involvement have also been reported [171].

Diagnosis of toxoplasmosis is usually made with serologic testing. Indirect IFAs of IgG and IgM are positive within a few days after infection [167]. Imaging studies and PCR analysis of CSF are useful in immunocompromised patients with signs of encephalitis or focal mass lesions within the brain. In such patients, a brain biopsy may be considered for definitive diagnosis and to exclude other diagnostic possibilities (e.g., brain abscess, lymphoma, metastatic carcinoma). In many cases, the history of the consumption of undercooked or raw meat aids in making the diagnosis [170].

Treatment and Prevention

Treatment is rarely necessary in people with normal immune systems as most recover without treatment. Suspected cases in persons who are ill may be treated with the combination of pyrimethamine and sulfadiazine, plus folinic acid (leucovorin) for a period of three to four weeks. Clindamycin may be substituted for sulfadiazine in patients sensitive to sulfa drugs [167]. For encephalitis, the treatment is continued for four to six weeks. Patients with HIV/AIDS who are toxoplasma-seropositive and who have CD4 counts <100 cells/mcL should receive prophylaxis against toxoplasmosis. This can be accomplished with trimethoprim/sulfamethoxazole (TMP-SMX) double-strength daily dose or alternately, TMP-SMX double-strength three times weekly [172]. The recommended therapy for acquired toxoplasmosis in HIV-infected children is sulfadiazine plus pyrimethamine and leucovorin [173].

Evidence Based Practice Recommendation

In order to prevent Toxoplasma gondii infection, the American Academy of Pediatrics recommends that pregnant women avoid contact with material/soil potentially contaminated with cat feces, especially handling of cat litters or gardening.

https://pediatrics.aappublications.org/content/pediatrics/early/2017/01/26/peds.2016-3860.full.pdf

Last Accessed: April 17, 2020

Level of Evidence: Expert Opinion/Consensus Statement

It is very important to educate immunocompromised individuals and pregnant women in prevention techniques. All meat should be thoroughly cooked. Not coming in contact with cat feces or contaminated soil is very important, as is handwashing after gardening or yard work. If there is a sandbox in the backyard, it should be covered. If possible, limit a household cat's ability to consume rodents, which would best be accomplished by keeping the cat indoors, and only feed commercial pet food [167]. Oocysts hatch about 24 hours after being shed in the feces and are not infective before hatching. If the litter box is changed daily, exposure risk will be reduced. Encourage others in the household to participate in the cat's care, and ask them to change the litter box to protect the family members who are at risk. If the at-risk person must change the box, gloves, dust mask (to prevent swallowing or inhaling oocysts), and diligent emptying of the box daily are recommended. If you are working with a woman in early prenatal screening who owns a cat or who comes in contact with them, recommend having a titer if exposure must be documented and explain the importance of handwashing after handling cats or raw meat. Because of the potential seriousness of this zoonosis for certain populations, research is being conducted on a vaccine. At this time, there is no approved vaccine available [167].

GIARDIASIS

Giardiasis is one of the most common diarrheal diseases in the world, and nearly 33% of people in developing countries have had giardiasis [174]. The causative organism, Giardia lamblia (also known as G. intestinalis or G. duodenalis), is found in food, soil, water, and surfaces that have been contaminated with feces. It is now the most commonly identified parasite in the United States [174]. The symptoms of giardiasis usually appear about a week or two after the Giardia cysts are ingested. Very few organisms are required for infection, with only about 10 cysts causing an infection rate of 100% [174].

The cysts produce trophozoites, which colonize the upper portion of the small bowel. They generally cause a significant non-bloody diarrhea in the human or animal victim, which can then be transmitted by the fecal-oral route. Contaminated water is the most common source of infection, but venereal transmission has also been reported [174].

Morbidity is moderate and primarily involves gastrointestinal symptoms. Mortality from giardiasis is unlikely, unless associated with extreme dehydration [15,175].

Clinical Presentation and Diagnosis

The majority of patients present with an insidious onset of diarrhea. This usually consists of frequent loose stools that do not contain blood or mucus. Watery diarrhea and malodorous soft or greasy stools can be interspersed with episodes of constipation. The gastrointestinal symptoms are often exacerbated by eating and may be associated with mid abdominal pain and cramping. Nausea, gastroesophageal reflux, malaise, fatigue, lactose intolerance, and weight loss are common. Adult patients with long-term disease may develop malabsorption syndrome, while children can demonstrate the findings of failure to thrive [174,176].

Physical examination is usually normal, with the exception of possible abdominal tenderness upon palpation. In extreme cases, there may be dehydration and wasting. Laboratory studies should include stool examination with at least three samples taken at two-day intervals [174,177]. Because antibiotics, laxatives, or barium may mask the presence of the organism in the stool, the samples may need to be obtained after a 5- to 10-day hiatus. There are ELISA and IFA tests available for stool samples that have excellent sensitivity and specificity [177]. Cultures are useful primarily to detect other causes of diarrhea, because Giardia is not easily grown from stool samples. The most useful serum study is IgM analysis, but only for the determination of acute versus chronic infections [177]. Endoscopy, with duodenal aspiration or biopsy, may also be used to obtain a diagnosis.

Treatment and Prevention

Evidence Based Practice Recommendation

The World Gastroenterology Organisation asserts that nitazoxanide is an effective antiprotozoal in the treatment of diarrhea caused by Giardia intestinalis.

https://www.worldgastroenterology.org/guidelines/global-guidelines/acute-diarrhea/acute-diarrhea-english

Last Accessed: April 17, 2020

Level of Evidence: Expert Opinion/Consensus Statement

For many years, the first-line treatment in the United States has been metronidazole [178,179]. The usual adult dose is 500 mg orally twice daily for five to seven days [46]. Tinidazole is a newer drug, approved in the United States, that can be administered in a single oral dose of 2 grams, taken with food. For children older than 3 years of age, the recommended dose is 50 mg/kg [46]. For women in the first trimester of pregnancy, for whom metronidazole and tinidazole are contraindicated, paromomycin 25–35 mg/kg/day in three divided doses should be used for 5 to 10 days [46]. Quinacrine is commonly used outside of the United States. Other antibiotics and antiparasitic agents, such as nitazoxanide, have also been used to effectively treat the disease [46,174]. Some authorities feel that asymptomatic cases of diagnosed giardiasis infection, especially in children, should be left untreated. However, if untreated, an individual can shed the organisms for weeks to months. In rare cases, hospitalization is required for fluid and nutritional replacement, but most cases will resolve with minimal treatment.

Prevention includes the avoidance of potentially contaminated water and foodstuffs. Drinking water from a stream, shallow well, or other unfiltered source can lead to ingestion of the cysts. The cysts can live for extended periods of time in an outdoor environment. However, they are inactivated by chlorine and can be eliminated from a water source by filters of less than 1 micron (e.g., National Safety Foundation [NSF] Standard 53 or NSF Standard 58 for cyst and oocyst reduction) [174].

Giardiasis cannot be transmitted by blood products, but any possible fecal contact can be a source of infection, which includes accidentally swallowing water in a recreational pool or pond. Peeling or washing fruits and vegetables in clean water is also recommended [15,174]. When traveling to countries with an unsafe water supply, only drink water that has been boiled for more than one minute or bottled water labeled as reverse osmosis treated, distilled, filtered through an absolute 1 micron or smaller filter, or "1 micron absolute" [174,180]. Additionally, ice should not be used [174].

MALARIA

Malaria is a mosquito-borne parasite most common in sub-Saharan Africa. However, the disease is also apparent in Southeast Asia, the Middle East, Latin America, and areas of Europe [181]. It is mainly found in tropical and subtropical areas that allow for the growth and survival of the Anopheles mosquito and the malarial parasites. Because temperatures colder than 68 degrees F will halt the parasites' life cycles, transmission is seasonal in some areas [181]. In equatorial countries, malaria transmission is continual and more intense; these are considered malaria-endemic or malaria-stable countries [182].

Approximately 50% of the world's population is at risk for malaria and each year about 212 million people contract and become ill due to the disease [181,182]. In 2018, an estimated 405,000 people died of malaria-related illness, most of them young children in sub-Saharan Africa [182]. Although malaria has been considered eradicated in the United States since the 1950s, about 1,500 to 2,000 cases of the disease are diagnosed and treated each year [184]. The CDC has also reported a total of 63 local outbreaks in the United States since 1953, all of which originated from a person who contracted the disease in a malaria-endemic country. Because the vector for malaria transmission (Anopheles mosquito) is present in the United States, there is a risk that the disease will be reintroduced.

The four protozoan species known to cause malaria in humans, Plasmodium falciparum, P. vivax, P. malariae, and P. ovale, are transmitted from person to person via infected mosquitoes. The most common are the P. falciparum and P. vivax species; P. falciparum also results in the most significant morbidity and mortality [181]. Although, as noted, the female Anopheles mosquito is the natural vector for malaria, in rare cases, direct transmission from mother to child, blood transfusion, organ transplant, or shared needles has been documented. Between 1963 and 2015, there were 97 reported cases of transfusion-transmitted malaria in the United States [184]. In areas of high transmission, it is children who are at risk of severe malaria and death, whereas in areas of low or unstable transmission, all age groups are at risk [185]. Pregnant women also have higher susceptibility to P. falciparum malaria, which increases infant mortality [184].

Clinical Presentation and Diagnosis

Prompt and accurate diagnosis of malaria is a cornerstone of the treatment process. Identification not only of the presence of the disease but also of the causative agent is necessary in order to implement appropriate and effective treatment. This can be difficult, as the initial signs and symptoms of malaria are nonspecific and may be confused for other systemic viral infections. After infection, there is typically a 7- to 30-day incubation period, or longer if antiviral medications have been taken prophylactically. The classically described malaria attack (cold, hot, and sweating stages) is rarely observed [186]. More often, the first symptoms are a combination of headache, weakness, fatigue, abdominal discomfort, and/or muscle and joint aches, followed by fever, chills, perspiration, anorexia, vomiting, and/or worsening malaise [185,186]. Possible signs include elevated temperature, enlarged spleen, and perspiration. If the disease is limited to this stage, it is considered uncomplicated, and treatment is often successful. Relapse of malaria can occur after two to four symptom-free years in persons infected with P. vivax and P. ovale species [184].

If the disease is caused by the P. falciparum species, it can progress to severe malaria. Severe malaria is complicated by serious organ failures or abnormalities in the patient's blood or metabolism. Advanced severe malaria can result in [186]:

- Cerebral malaria, with abnormal behavior, impairment of consciousness, seizures, coma, or other neurologic abnormalities

- Severe anemia

- Hemoglobinuria

- Pulmonary edema or acute respiratory distress syndrome, which may occur even after the parasite counts have decreased in response to treatment

- Abnormalities in blood coagulation and thrombocytopenia

- Cardiovascular collapse and shock

Other conditions that should raise concern in malarial patients are acute kidney failure, hyperparasitemia, metabolic acidosis, and hypoglycemia [186]. In patients for whom the malaria infection reaches the severe stage, the mortality rate is 15% to 20% [185].

In addition to the clinical diagnosis, there are three main tests used in the parasitologic confirmation of the diagnosis of malaria: light microscopy, rapid diagnostic tests, and PCR. Light microscopy remains the standard test for detection of malarial parasites [113]. The test is conducted by staining a blood smear, usually with the Giemsa stain, and examining the specimen by microscope. There are also several rapid tests available that utilize antigen detection. These tests provide results quickly (within 2 to 15 minutes), but their use is restricted by limited accuracy and higher costs [113]. When they are used, it is usually as an adjunct to microscopy or as the main test if microscopic analysis is not available, particularly because early treatment is so vital for positive clinical outcomes. The limitations of the rapid tests have shifted attention to PCR-based molecular diagnosis. Although the PCR tests available for malaria are more accurate than either the microscopy or antigen detection systems, the prohibitive costs and need for specialized equipment have made this option less useful [113,187]. IFA and ELISA tests are available to test for past exposure to the disease [113].

Treatment and Prevention

Treatment for uncomplicated malaria varies based on the region in which the disease was acquired and the infective species (Table 6 and Table 7). Some areas have been particularly identified as sensitive to chloroquine, the traditional drug of choice for malaria. Because resistance to chloroquine has increased significantly, it is now generally used only for malaria known to originate from Central America (west of the Panama Canal), Haiti, the Dominican Republic, and most of the Middle East [188]. In all other areas, the organisms are considered to be resistant to the drug, and other agents are used. It is also recommended that, when possible, in vivo assessment of therapeutic efficacy, in vitro studies of parasite susceptibility to drugs in culture, or molecular genotyping be used to establish sensitivity of the parasite to the drug regimen [185].

Table 6: TREATMENT RECOMMENDATIONS FOR UNCOMPLICATED MALARIA

Plasmodium species

Drug

Dosing

Comments

P. falciparum or "species not identified" in areas without chloroquine-resistant strains

Chloroquine

Initial oral dose: 600 mg base (1,000 mg salt), followed with 300 mg base (500 mg salt) at 6, 24, and 48 hours

Maximum dose: 1,500 mg base (2,500 mg salt)

Use adult dosing in pregnancy.

Adjust pediatric dosing by patient weight; do not exceed recommended adult dosing.

Consider atovaquone-proguanil (preferred) or mefloquine if quinine is unavailable.

Quinine and atovaquone-proguanil are recommended for use in children 8 years of age and younger.

Hydroxychloroquine

(2nd-line alternative)

Initial oral dose: 620 mg base (800 mg salt), given immediately, followed with 310 mg base (400 mg salt) at 6, 24, and 48 hours

Maximum dose: 1,550 mg base (2,000 mg salt)

P. falciparum or "species not identified" in areas with chloroquine-resistant strains

Atovaquone/

proguanil

1 g/400 mg as a single dose, once daily for three days

These are fixed dose combination medicines that may be used for nonpregnant adult and pediatric patients. Both have been found to be very effective.

Artemether/

lumefantrine

Patients 25 to <35 kg: Three tablets at hour 0 and hour 8 on the first day, then three tablets twice daily on days 2 and 3

Patients >35 kg: Four tablets at hour 0 and hour 8 on the first day, then four tablets twice daily on days 2 and 3

Quinine sulfate plus doxycycline, tetracycline, or clindamycin

648 mg every eight hours for three to seven days

Quinine sulfate plus either doxycycline or tetracycline generally preferred. Treatment duration depends on area of acquisition. Quinine sulfate/clindamycin is recommended during pregnancy. Quinine dosing duration depends on area of acquisition; clindamycin dosing should continue for 7 days regardless of area of acquisition.

Mefloquine

5 tablets (1,250 mg) as a single dose daily

Associated with severe neuropsychiatric reactions; recommended only when other options cannot be used. If clinical improvement is not seen within 48 to 72 hours, an alternative therapy should be used for retreatment.

P. malariae

Chloroquine

Same as for P. falciparum

There is little evidence of chloroquine resistance in P. malariae. May be used during pregnancy.

Hydroxychloroquine

(2nd-line alternative)

Same as for P. falciparum

P. vivax acquired in all areas except Papua New Guinea or Indonesia

Chloroquine

Same as for P. falciparum

If patient is nonresponsive, change treatment to one of the three options listed for treatment of P. vivax malaria acquired in Papua New Guinea and notify state health department and CDC.

Hydroxychloroquine

(2nd-line alternative)

Same as for P. falciparum

P. vivax acquired in Papua New Guinea or Indonesia

Quinine sulfate plus doxycycline or tetracycline

648 mg every eight hours for three to seven days

High possibility of chloroquine-resistant strains. Options are equally recommended. During pregnancy, treat with quinine for seven days, regardless of area of acquisition. Risk/benefit of adding doxycycline or tetracycline (pregnancy category D) to quinine should be carefully evaluated. Risk/benefit of using atovaquone-proguanil or mefloquine (both pregnancy category C) should be carefully evaluated.

Atovaquone/

proguanil

1 g/400 mg as a single dose, once daily for three consecutive days

Mefloquine

5 tablets (1,250 mg) as a single dose daily

P. ovale

Chloroquine

Same as for P. falciparum

May be used during pregnancy

Hydroxychloroquine

(2nd-line alternative)

Same as for P. falciparum

P. knowlesi

Atovaquone/

proguanil

250 mg/100 mg, four times per day for three days

There is little evidence comparing various medications for the treatment of this relatively new strain.

Source: [46,189,190]

Table 7: TREATMENT RECOMMENDATIONS FOR SEVERE MALARIAa

Drug

Dosing

Comments

Quinidine gluconate

IV loading dose: 6.25 mg base/kg (10 mg salt/kg) over one to two hours. Follow with continuous IV infusion 0.0125 mg base/kg/min (0.02 mg salt/kg/min).

Alternative regimen: IV loading dose: 15 mg base/kg (24 mg salt/kg) over four hours. Eight hours after loading dose, follow with 7.5 mg base/kg (12 mg/kg salt) over four hours, every eight hours.

At least 24 hours of infusion are recommended.

When parasite density is <1% and patient is able to take oral medication, complete treatment course with oral quinine per recommendations for uncomplicated malaria.

Reduce maintenance dose by one-third to one-half on the third treatment day in patients with no clinical improvement or in patients with renal failure that persists.

Doxycycline

IV: 100 mg every 12 hours

Oral: 100 mg every 12 hours for seven days

Tetracycline

Oral: 250 mg every six hours for seven days

Clindamycin

IV: 5 mg base/kg IV every eight hours

Oral: 20 mg base/kg/day divided three times/day for seven days

aThe regimen for the treatment of severe malaria in the United States consists of quinidine plus either doxycycline, tetracycline, or clindamycin.

Source: [189]

CDC clinicians are on call at the Malaria Hotline 24 hours per day, seven days per week, to provide advice to healthcare providers on the diagnosis and treatment of malaria. They may reached during business hours 9 a.m. to 5 p.m. Monday through Friday) at (770) 488-7788 or (885) 856-4713. During off hours, weekends, and federal holidays, call (770) 488-7100 and ask to have the malaria clinician on call paged.

Individuals that are known to be traveling to malaria-endemic areas, and areas of resistance in particular, should be counseled regarding antimosquito measures and malarial symptoms prior to departure [191]. Chemoprophylaxis with the most appropriate antimalarial agents should be provided.

8. BACTERIAL ZOONOTIC DISEASES

Animal products often contain several types of bacteria. The bacteria may be the animal's own flora that contaminates the meat in the process of being slaughtered and prepared for market. Bacterial contamination can also occur from an environmental source during poor handling, either before or after purchase for consumption. Only if the bacterial pathogen originated from the animal is it truly zoonotic. Factory workers who accidentally contaminate a product with a disease they are carrying, as has happened with E. coli, can create a public health problem. Because it does not originate from an animal, it is not considered a zoonotic infection in the true sense of the definition. In this section, anthrax, cholera, botulism, the diseases caused by Salmonella spp., and brucellosis will be discussed.

ANTHRAX

Anthrax can be transmitted by ingestion of meat from an infected animal, usually a ruminant. The agent of disease is Bacillus anthracis. Three forms of anthrax occur in humans, with manifestations depending upon how the organism is contacted; they are cutaneous, gastrointestinal, and inhalation anthrax. The diseases are distinct; however, infection with one form presents a risk for developing the others.

Most cases of anthrax are cutaneous in humans. The pulmonary and gastrointestinal forms are less common. If untreated, the pulmonary (inhalation) form has an 86% to 89% case fatality rate, intestinal 25% to 60%, and the cutaneous form 20% [192].

Cutaneous anthrax is the most common naturally occurring form, with an estimated 2,000 human cases reported annually [193]. The disease typically follows exposure to animals that are infected with anthrax. Cutaneous infections occur when the bacterium or spores enter a cut or abrasion on the skin, such as when handling contaminated wool, hides, or leather.

Gastrointestinal anthrax is not commonly seen; however, outbreaks have occurred in Africa and Asia [193]. GI anthrax follows the ingestion of insufficiently cooked contaminated meat.

Inhalation anthrax is the most lethal form of the disease, but it occurs less frequently as a naturally occurring disease than either the cutaneous or gastrointestinal forms. However, the dissemination of spores could cause widespread disease, and therefore, this is the most likely form of anthrax to be used as a biologic weapon. Prior to the bioterror-related cases in 2001, inhalation anthrax had not been reported in the United States since 1976 [192,193]. This makes even a single case a cause for alarm today.

The natural incidence of anthrax is rare in the United States, but infection is an occupational hazard among veterinarians, farmers, and individuals who handle animal wool, hair, hides, or bone meal products. It is endemic in Africa and Asia, despite vaccination programs, and is not uncommon in the Middle East, the Indian subcontinent, and Latin America [194]. Most cases are seen after heavy rains, which release the spores and bring them to the surface. Drought also can trigger anthrax spore germination, while flies and vultures spread the spores [194]. The spores produced by the bacteria are extremely resistant in the environment; they have been documented to survive 22 years in a dry culture [193]. They tolerate freezing and will not be killed by most disinfectants at regular strength concentrations. Methods for sterilizing or inactivating spores on contaminated materials include steam sterilization or ethylene oxide gas sterilization, boiling or using dry heat, or treating with formaldehyde, glutaraldehyde, or hypochlorite for specified periods of time and exposure concentrations; air drying does not destroy the spores [192]. Inhalation of spores is the most common way for the pulmonary form of the disease to be transmitted. When contaminated meat is cut, the spores can be released into the immediate area of the source. This could be in the field or in the kitchen of those who raise their own meat or consume wild ruminant meat, such as deer or elk. Anthrax is a mandatory reportable disease whenever a case is identified in an animal or human.

Clinical Presentation and Diagnosis

Cutaneous anthrax skin infection begins as a raised pruritic lesion or papule that resembles an insect bite. Within one to two days, the lesion develops into a fluid-filled vesicle, which ruptures to form a painless ulcer 1–3 cm in diameter with a necrotic area in the center. Pronounced edema is often associated with the lesions because of the release of an edema-producing toxin by the bacteria. The lymph nodes in the area may become involved and enlarged.

The incubation period in humans is usually 1 to 10 days but can be prolonged to almost two weeks [193,195]. To describe the lesion in more detail, picture a painless macular eruption that appears within two to five days, most commonly on an exposed portion of the body. The lesion progresses from a red macule to a pruritic papule, then to a single or ring of vesicles. This is followed by a depressed ulcer and finally a black necrotic eschar that falls off within 7 to 10 days. There is edema associated with the eschar but usually no permanent scarring of the affected area. The symptoms of purely cutaneous anthrax infection can include fever, headache, regional lymph node involvement, and myalgia. The cutaneous form of anthrax may progress to systemic disease, with a fatality rate of up to 20% if untreated [196].

Gastrointestinal anthrax is characterized by an acute inflammation of the intestinal tract. Initial signs of nausea, loss of appetite, vomiting, and fever are followed by abdominal pain, vomiting of blood, and severe diarrhea [192,193].

The first sign of inhalation anthrax is the acute onset of a flu-like illness. If inhalation anthrax progresses to the pneumonic form, the initial symptoms are often followed by a short period of improvement. Next, there is an abrupt development of severe respiratory distress with dyspnea, diaphoresis, stridor, and cyanosis. Shock and death usually occur within 24 to 36 hours after the onset of respiratory distress [195]. In the later stages, mortality approaches 100% despite aggressive treatment. Physical findings can be nonspecific. The chest x-ray is usually disease-specific, revealing a widened mediastinum with pleural effusions, but typically without infiltrates [192]. Thoracic trauma can have similar signs, but often with infiltrates. A hemorrhagic mediastinitis often develops.

Laboratory tests of blood products are usually normal if the disease is not disseminated. The B. anthracis organism can be obtained for culture or gram stain; however, analysis beyond simple cultures should only be performed in a specialized laboratory environment [196]. On gram stain, the organism can be recognized as a large, rod-shaped, gram-positive, spore-forming bacillus [194]. More positive identification requires lysis by gamma phage and dFA, or most positively by immunohistochemical staining. There is an ELISA test available, but generally only at reference laboratories. A negative culture does not rule out cutaneous anthrax, especially if obtained after antibiotics are started [194].

Treatment and Prevention

Most B. anthracis strains are sensitive to a broad range of antibiotics. Either ciprofloxacin or doxycycline is usually recommended for the treatment of anthrax. In the past, penicillin was a first-line treatment, but due to concerns regarding resistance, it is no longer recommended by the CDC or the U.S. military. To be truly effective, antibiotic treatment should be initiated as early as possible. If left untreated, the disease is highly fatal. Immediate prophylaxis with ciprofloxacin 500 mg or doxycycline 100 mg orally twice daily is commonly recommended for cutaneous anthrax [197,198]. Treatment should continue for 60 days or longer; if the source in known to be from livestock or its products, a 7- to 10-day course is sufficient. If an individual has not been previously vaccinated, a three-dose series of vaccine should also be given subcutaneously at diagnosis and two and four weeks later [192,198]. For inhalation anthrax treatment in adults, intravenous medications are suggested as the initial treatment and should be combined with one or two other effective agents [196,198].

In some cases, other antibiotics may be considered, such as the other fluoroquinolones, including levofloxacin, clindamycin, and moxifloxacin; however, use of clindamycin and moxifloxacin are not currently approved for this use by the FDA [197]. Rifampin and linezolid have been suggested as an adjunct treatment, and high-dose penicillins (e.g., amoxicillin, penicillin VK) may be tried if no other antibacterials are available and the strain is susceptible. In general, the cephalosporins are not useful in treating anthrax because the organism produces an enzyme that neutralizes them [197]. Supportive therapy for shock, fluid volume deficit, and adequacy of the airway may be needed.

In 2013, a new antibiotic with significant activity against B. anthracis, anthracimycin, was discovered [199]. Although it is not yet FDA-approved, it may have a place in the treatment of anthrax in the future.

Human-derived anthrax immune globulin (AIG) was used to successfully treat a naturally occurring inhalation anthrax case in Pennsylvania in 2006 [233]. In 2015, the FDA approved AIG for the treatment of inhalation anthrax [234]. Immune globulin administration may be considered in combination with appropriate antibiotics when multiple organ systems are involved or following lack of response to standard therapy.

Vaccination for anthrax can prevent the disease if given prior to contact with the bacillus. However, it can also be used postexposure to help minimize the patient's reaction to the organism. Anthrax Vaccine Adsorbed (AVA) is the only licensed human anthrax vaccine in the United States [192]. The vaccination schedule consists of three injections of 0.5 mL of the vaccine administered subcutaneously in the deltoid region. After the first injection, the follow-up doses are given two and four weeks later. The vaccine is approved only for healthy, nonpregnant adults. There is an adverse reaction incidence of approximately 6% for local inflammation and 2% to 3% for systemic symptoms [46].

There is no data to suggest patient-to-patient transmission of anthrax; therefore, only standard barrier isolation precautions are recommended for hospitalized patients with all forms of anthrax [198]. There is no need to immunize or provide prophylaxis to patient contacts unless a determination is made that they, like the patient, were exposed to the organism. Standard disinfectants used for hospital infection control are effective in cleaning surfaces contaminated with infected bodily fluids [193].

Proper burial or cremation of humans and animals that have died because of anthrax infection is essential to prevent further transmission of the disease. Serious consideration must be given to cremation. Embalming of bodies could be associated with special risks.

VIBRIO AND CHOLERA

Raw food has a potential for serious zoonotic diseases. Bacteria of the Vibrio genus exist in most fish and shellfish habitats. All members of this genus can produce gastrointestinal signs in varying degrees of severity. Raw oysters are one of the more prevalent shellfish to carry Vibrio spp. [200]. Ingesting the food items can produce the disease, but handling fish or shellfish contaminated with Vibrio can also lead to infection through chapped hands or finger cuts [200].

Cholera, the most well-known of the diseases caused by the Vibrio organisms, is caused by V. cholerae. Although Vibrio infections are much more common in developing countries, outbreaks and individual cases can occur in Europe and North America. Two serogroups of V. cholerae cause outbreaks: V. cholerae 0139 and V. cholerae 01 biotype El Tor. V. cholerae 0139 was first identified in Bangladesh in 1992 and is confined to Southeast Asia. V. cholerae 01 biotype El Tor has spread rapidly around the world and may be seen in patients returning from foreign countries [201].

Cholera is rarely spread from person to person without the contamination of food or water by animals or people. The organism can live in or on foodstuffs for up to five days at ambient temperatures and for 10 days at 5 to 10 degrees C. Most cases in endemic areas are in young children [201].

Clinical Presentation and Diagnosis

Some cases of cholera are asymptomatic or only produce a mild diarrhea. A major Vibrio infection is characterized by a sudden onset of severe enteritis with diarrhea, vomiting, and leg cramps. The usual incubation period is 0.5 to 5 days [201]. Marked dehydration can occur, especially in the instance where reinfection is occurring from a point source. There may be accompanying fever. If the bacteria infect a wound, the site can become necrotic and cellulitis can spread until the infection is no longer localized. Once septicemia occurs, the case fatality rate can be as high as 50%; it may be as high as 25% in wound infection cases [15]. Laboratory diagnosis can be made with gram stain or by culture of the organism.

Treatment and Prevention

The gastroenteritis form of Vibrio infection can usually be managed supportively in previously healthy individuals with intravenous followed by oral fluid and electrolyte replacement. It is the very young, the elderly, and patients with chronic disease, who may have a harder time dealing with vibriosis and require antibiotics. Antibiotic use for moderately and severely ill patients has been shown to reduce the volume of stool output, the duration of diarrhea, and the duration of positive stool cultures [202]. Doxycycline is recommended for adults, and azithromycin is recommended as first-line treatment for children and pregnant women.

Care must be taken with cooked shellfish to ensure that handling does not recontaminate the food product just before consumption. As noted, Vibrio spp. are relatively tolerant of wide temperature ranges and, consequently, can exist on a food preparation surface for a considerable time.

In 2016, the FDA approved the first cholera vaccine, Vaxchora. This one-dose oral vaccine is approved for adults 18 to 64 years of age traveling to cholera-affected areas [203]. Other preventative measures recommended by the CDC include only drinking safe water, frequently washing hands with soap (or scrubbing hands with ash or sand) and safe water, cooking all foods and eating them hot, and only consuming raw fruits and vegetables that have been peeled recently by oneself.

BOTULISM

Botulinum toxins have gained widespread recognition as a result of the introduction of botulinum type A (Botox) into the field of cosmetology. The toxins have been important medically for many years due to the serious and often fatal consequences of ingesting improperly canned or bottled foods. However, the disease can also be caused by contact with, or ingestion of, contaminated fish and herbivores.

Botulinum toxins are proteins produced by the anaerobic bacterium Clostridium botulinum and consist of seven separate but related neurotoxins, denoted A through G. All of the strains produce similar effects when ingested or inhaled. They are among the most toxic compounds known, with an estimated toxic dose of only 0.001 mcg/kg of body weight [204]. These neurotoxins act by binding at the presynaptic nerve terminals and the cholinergic autonomic sites. They also block acetylcholine transmission, causing skeletal muscle weakness and paralysis as well as bulbar palsies [204].

Human disease is caused by strains A, B, E, and rarely, F [205]. In the United States, toxin A is found predominantly west of the Mississippi River, while toxin B is found most commonly in the East. Toxin E is found in northern latitudes, such as the Pacific Northwest, the Great Lakes region, and Alaska. The frequency of botulism in native Alaskans is among the highest in the world, as toxin E outbreaks are frequently associated with fish products [204]. The disease can also be caused by wounds infected with C. botulinum and is known as "wound botulism." An intestinal form has been reported in infants when the organism is ingested and germinates in the gastrointestinal tract. There is no person-to-person transmission of botulism, and airborne transmission of botulism does not occur naturally [204].

In 2015, potato salad prepared with home-canned potatoes sickened 29 people after it was eaten at a church potluck in Ohio. The coordinated effort by the area hospitals, county and state health departments, and the CDC, which sent 50 doses of botulinum antitoxin from the Strategic National Stockpile, is credited with saving the lives of 28 of the patients and vastly reducing their illness severity and length of hospital stay. The potatoes were bottled using a boiling water canner rather than a pressure canner, which is recommended and able to effectively deactivate spores. This was the largest outbreak of botulism in the United States in nearly 40 years [249].

Clinical Presentation and Diagnosis

Following an incubation period of 2 hours to 8 days, depending on the dose (typically 12 to 72 hours), the early signs and symptoms of diplopia, blurred vision, dry mouth, ptosis, and photophobia appear. This is followed by skeletal muscle weakness and paralysis, which is typified by a descending, symmetrical pattern, ending in respiratory difficulty and eventually respiratory failure. Interestingly, the patient usually remains alert and afebrile, although there may be dysarthria, dysphagia, and dysphonia. The pupils may be dilated and fixed, the gag reflex may be absent, and deep tendon reflexes are diminished or absent. The patient may develop hypotension, cyanosis, and evidence of carbon dioxide retention. In foodborne botulism, all of these findings may be evident in patients within 24 hours of the ingestion of the tainted items [204,206].

Some cases of botulism may be confused with disorders such as Guillain-Barré syndrome or myasthenia gravis (MG). It has been suggested that the edrophonium (Tensilon) test may be used to differentiate it from MG, but because it may be transiently positive in botulism, its actual usefulness is in doubt [205]. The edrophonium test requires that the patient have a sign, such as ptosis, that can be reversed with an intravenous injection of a cholinesterase agent like edrophonium.

Very limited information can be obtained from laboratory tests. Survivors usually do not develop an antibody response to the toxin because of the subimmunogenic amount of material required to produce major symptoms. In cases of ingested botulinum toxin, culture of the serum or stool may be useful [204]. An ELISA test might possibly detect the toxin on nasal mucous membranes for 24 hours in cases of inhalation.

The recommended test for confirmation of botulism is the mouse neutralization bioassay [204,206]. This assay can detect as little as 0.03 ng of botulinum toxin within one to four days after exposure.

Treatment and Prevention

There are good antitoxins available; however, they only halt the progression of future symptoms and do not reverse the existing clinical presentation. A licensed heptavalent antitoxin for all known types of botulinum (A, B, C, D, E, F, and G) has been approved by the FDA and is recommended for all cases of botulism in patients other than infants [204,207]. The antitoxin is of equine origin, which means that skin testing must be performed to help prevent serum sickness or anaphylaxis in susceptible individuals [208]. Intravenous human botulism immune globulin (BIG-IV, BabyBIG) is available for the treatment of patients younger than 1 year of age with infant botulism caused by toxin type A or B. In cases of suspected infant botulism, for consultation, and to obtain BabyBIG, physicians should call (510) 231-7600 [248]. Antibiotics (i.e., penicillin G, chloramphenicol, clindamycin) are useful in wound botulism, but not in foodborne botulism [204].

For patients with symptoms of botulism, the prompt administration of botulinum antitoxin and supportive care can markedly reduce the mortality rate. Supportive care may include ventilatory assistance for several weeks or even months. Treatment is the same for children and adults [204].

Botulism poisoning is not an infection. It is not transmitted from person to person, and only standard precautions are required to control its spread. Because botulism poisoning is not transmittable, patients do not need to be isolated. The CDC recommends that contaminated objects or surfaces be cleaned with 0.1% hypochlorite bleach solution if they cannot be avoided for the hours to days required for natural degradation [209].

SALMONELLOSIS

The diseases caused by this group of organisms are well known in animals and in humans. Salmonellosis is caused by Salmonella spp., of which there are more than 2,500 serotypes. The species is divided into six subgroups or subspecies based on pathogenicity, DNA similarity, common host, and other factors. The classification system is complex, and the diseases that are expressed are quite diverse. Most pathogenic Salmonella spp. become localized in the body within the victim's cells [210,211]. Consequently, after ingestion they are taken up by macrophages, which facilitate their spread through the lymphatic system.

It is from an animal host in the asymptomatic carrier state that many Salmonella diseases are transmitted to humans [213]. Domestic and wild animals can be reservoirs for these zoonoses, including domestic and wild reptiles, farm animals, chickens and other poultry (especially ducks), and small mammals. All transmissions to humans are from ingestion [211]. Most transmissions occur from meat, poultry, raw eggs, and milk products, but any food, including vegetables, may become contaminated. It can also be transmitted directly by the fecal-oral route [211]. Infected water sources can also transmit disease, and infected food handlers have been noted to cause sporadic outbreaks. Freezing does not destroy the agent.

Salmonellosis diseases fall into three categories in humans: gastroenteritis, septicemia, and enteric fever. Animal cases are more chronic, and an asymptomatic carrier state is seen in many species after the disease runs its course [213]. The carrier state is also common in humans, with typhoid fever being the most familiar. Inappropriate use of antibiotics can prolong the carrier state. Other examples of diseases seen in humans caused by Salmonella include paratyphoid fever and the many forms of gastroenteritis. The case fatality rate is less than 1% and is primarily seen in the young or elderly [211].

Clinical Presentation and Diagnosis

The common presentation of salmonellosis is gastroenteritis with fever, abdominal cramping, vomiting, diarrhea that is often bloody, chills, and weight loss [210,211]. There is often a history of ingesting a possibly contaminated food product within the past few days, but in many cases a full epidemiologic investigation is necessary to find the source of infection. The symptoms usually appear within 12 to 72 hours after ingestion of the infective organism.

Serum is useful in testing for the enteric fever form S. typhi only. Culturing the feces is usually needed to verify the disease [214]. The samples can be serotyped, in most cases, to help identify the exact source of an infection.

Treatment and Prevention

Antimicrobial therapy is not recommended for the usual case of uncomplicated salmonella gastroenteritis, as this tends to be self-limited, lasting about four to seven days; antibiotic treatment does not shorten the duration and may prolong the carrier state, which could have adverse public health consequences if the patient is in close contact with others or is a food handler [211,214]. Patients with enteric fever presentation or signs of disseminated foci of salmonella infection do require antibiotic treatment. Careful attention to antimicrobial sensitivity testing of the infecting strain is important, as some salmonella strains are multidrug-resistant [212,214]. Choices for antibiotic therapy for severe infections include fluoroquinolones, third-generation cephalosporins, and ampicillin (for susceptible infections) [214]. Third-generation cephalosporins, which must be given by injection, are widely used in children with serious infections because the quinolones are not generally recommended for this age group. The drugs commonly used in the past, chloramphenicol, ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole, are occasionally used as alternatives [211]. For cases in which a carrier state is identified, it is important to treat the individual who is the carrier. It is also especially important to identify sources of drug-resistant strains to avoid outbreaks similar to those in northern California during spring 1997 related to the home production of Mexican-style cheese [215].

Evidence Based Practice Recommendation

According to the World Gastroenterology Organisation, two typhoid vaccines (with limited cost-efficiency) are approved for clinical use to prevent diarrhea associated with Salmonella typhi infection.

https://www.worldgastroenterology.org/guidelines/global-guidelines/acute-diarrhea/acute-diarrhea-english

Last Accessed: April 17, 2020

Level of Evidence: Expert Opinion/Consensus Statement

In managing clusters of salmonellosis among livestock, fecal samples should be tested and the animal cleared of carrier status only after a series of samples are determined to be free of the bacteria. In the case of infection coming from a food handler, tracking the source will be hastened if the initial case is reported in a timely fashion to allow public health officials to investigate as quickly as possible.

Common sense (e.g., hand washing after handling raw foods or animals/animal feces) prevails in the prevention of these diseases. Avoiding raw eggs, unpasteurized dairy products, and other questionable food products will prevent most cases, as will proper cooking of poultry and meats [210,213,214].

BRUCELLOSIS

Brucellosis, also known as undulant fever, is a zoonotic disease caused by infection with a species of Brucella. The most common are B. abortus (cattle), B. melitensis (sheep), and B. suis (swine), with rare cases reported due to infection with B. canis (canine). B. melitensis is thought to be the most virulent, the most prevalent, and the cause of the most severe and acute cases of brucellosis worldwide; it is also the source of most human cases of brucellosis in the United States [216]. According to the USDA, the only known focus of B. abortus infection in the United States is among bison and elk in and around Yellowstone National Park [217]. Brucellosis is highly endemic in countries such as Peru, Mexico, Spain, Greece, Iraq, Iran, Jordan, and Kuwait. It is considered a rare disease in the United States, where an average of approximately 100 cases are reported per year, mostly from Florida, California, Virginia, and Texas [218]. Ingesting non-pasteurized milk or cheese is a likely cause for many of these cases [218,219].

Clinical Presentation and Diagnosis

The brucellae are a group of gram-negative cocci bacillary organisms. The most common way to become infected is by drinking or eating unpasteurized milk or cheese products derived from sheep, goats, or cows. Meat packing and laboratory worker infections suggest that Brucella is highly infectious via direct contact with carcasses or by inhalation aerosol route [219]. It is estimated that inhalation of only 10–100 bacteria is sufficient to cause disease in humans. The incubation period is 5 to 60 days, and many infections are asymptomatic under natural conditions. Large aerosol doses may shorten the incubation period and increase the clinical attack rate. Brucellosis infection has a low mortality rate (2% to 5% of untreated cases), with most deaths caused by endocarditis or meningitis. It is an incapacitating disease in its natural form [198,219].

Acute brucellosis presents as a flu-like illness, with fever, headache, joint pain, sweats, chills, and general weakness as common complaints. Cough and pleuritic chest pain may be present, but may not correlate with radiographic results. Chest x-rays may show lung abscesses, single or miliary nodules, and pleural effusions. Gastrointestinal symptoms, such as anorexia, nausea, vomiting, diarrhea, and constipation, colitis, or an infiltrative hepatitis occur in up to 70% of adult cases and less frequently in children. Hepatomegaly and splenomegaly can occur in as many as 45% to 63% of cases. Peripheral joint involvement may vary from pain on range of motion to joint immobility and effusion, usually involving the hips and sacroiliac joints [219]. Meningitis occurs in less than 5% of brucellosis cases and may be an acute presenting illness of a chronic syndrome, occurring late in the course of a persistent infection [219]. Behavioral disturbances in children and psychoses may occur in the meningoencephalitic form of the disease.

Laboratory studies for Brucella spp. are most productive if accomplished early in the course of the disease. The organism is slow-growing and should be incubated for about three weeks before a negative result can be reported. Cultures can be obtained from blood, urine, CSF, or even bone marrow. Serologic testing is the most common diagnostic procedure, with rising titers or an agglutination titer of more than 1:100 being a good indication that brucellosis is the diagnosis [218].

Many other procedures have been utilized, including IFA, ELISA, and counter immunoelectrophoresis. The micro-agglutination test is still considered to be the gold standard test. This test allows for the differentiation of an acute (predominately IgM) infection versus a relapse (predominately IgG). Identification is made by culturing Brucella spp. from blood or bone marrow [198,218].

Treatment and Prevention

Brucellosis is treatable with antibiotics, but due to the intracellular nature of the infectious process, treatment usually requires combination therapy over a long duration. Optimal antibiotic therapy for brucellosis has been studied; however, recommendations differ [218]. Doxycycline (200 mg daily) plus rifampin (600–1,200 mg daily) for six weeks may be appropriate for uncomplicated disease in adults [12,218]. Fluoroquinolones (e.g., ciprofloxacin) have been used as monotherapy but carry a high relapse rate; adding these agents to doxycycline offers no specific advantages over other combination regimens but may be preferred in areas where resistance to rifampin is high [218]. The WHO guidelines for treatment of acute brucellosis recommend [218]:

- Doxycycline (100 mg) twice daily plus rifampin (600–900 mg/day) given orally for six weeks. This regimen is more convenient but may increase the risk of relapse.

- Doxycycline (100 mg) orally twice daily for six weeks and streptomycin (1 g/day IM) for two to three weeks. This regimen is believed to be more effective, mainly in preventing relapse. Gentamicin can be used as a substitute for streptomycin and has shown equal efficacy.

- Ciprofloxacin-based regimens have shown efficacy equal to that of doxycycline-based regimens.

A 2012 Cochrane review found that a regimen consisting of doxycycline for six weeks plus streptomycin for two to three weeks was more effective than one consisting of doxycycline plus rifampicin for six weeks [220]. The investigators also found that a regimen consisting of a fluoroquinolone plus rifampicin for six weeks was as effective overall as doxycycline plus rifampin (based on low-quality evidence) and was slightly better tolerated.

Limited data are available regarding the treatment of brucellosis in pregnant women. TMP-SMZ has been effective, either as monotherapy or in combination with rifampin or gentamicin [218].

For children younger than 8 years of age, a regimen of rifampin and TMP-SMZ for six weeks is the therapy of choice. Relapses occur in about 5% of patients and are due to sequestered rather than resistant organisms [221,222]. Arthritis may occur in recurrent cases. For complications, such as endocarditis or meningoencephalitis, triple therapy including rifampin, a tetracycline, and an aminoglycoside has been recommended [12,218].

Prevention is largely limited to those occupations for which brucellosis is a risk, as naturally occurring forms of the disease have been drastically limited in the United States through the use of animal vaccines. However, food and animal products imported from other countries can pose a risk. Avoidance of high-risk food products, particularly unpasteurized dairy products, is an important step in avoiding the disease [219]. For those in direct contact with Brucella spp. cultures, prophylaxis may be considered [223].

9. PARASITIC ZOONOTIC DISEASES

Parasitic zoonoses may be the most widespread in the world [224]. Although they generally produce a much greater morbidity than mortality, these diseases have an enormous impact on economic and social well-being in many countries. Fortunately, most of the diseases are endemic in areas outside North America and only involve travelers or immigrants in the United States and Canada.

There are multitudes of parasitic organisms that affect animals, many of which can then be transmitted to humans. Trichinosis, tapeworm infestation, and anisakiasis will be discussed as examples due to their similar morphology.

TRICHINOSIS

Trichinosis, also known as trichinellosis, is caused by the nematode Trichinella spiralis. It is common in Europe and the United States and is a reportable disease [225]. Several other Trichinella spp. are found around the world in carnivorous mammals and birds. The typical hosts of the worm in North America are pigs, rats, and bears. Less commonly, humans, dogs, cats, wolves, and horses can also be hosts. In the host, the adult organism typically lives in the intestine. There, it produces larvae, which penetrate the intestinal wall and migrate into skeletal muscle, where they encyst.

Infection occurs when infected meat of a host is consumed. The common source in this country is undercooked pork, especially from small farm operations that feed uncooked meat scraps to the animals or from pig cannibalism [225]. People have been infected from consumption of horse and bear meat as well.

Clinical Presentation and Diagnosis

The symptoms of infection are initially diarrhea, vomiting, fever, and abdominal distress. This is followed by flu-like symptoms from the muscle infection. In this stage, patients may have headaches, chills, cough, arthralgia, and myalgia. In severe infections, there can be myocarditis, paresis, central nervous system involvement, and respiratory distress. There have been fatalities from the disease [225].

The initial symptoms usually appear one to two days after ingesting the contaminated food product, with the later signs and symptoms showing up after about two to eight weeks. A detailed patient history is very helpful in identifying this zoonosis, and cases frequently present in an isolated small group or family.

Some of the Trichinella larvae may be passed in the feces, which can assist in diagnosis. Laboratory analysis includes antibody detection, muscle biopsy, and microscopy. The patient may have a pronounced eosinophilia [225].

Treatment and Prevention

Treatment should begin as soon as possible once the diagnosis is suggested. The CDC suggests the anthelmintics mebendazole and albendazole as possible therapeutic medications, although they are not FDA approved for this purpose. Steroids may be required for severe symptoms [46,225,226].

Adequate cooking of meat products will kill the organisms. This usually means obtaining an internal temperature of 170 degrees F. Pork can also be frozen for 20 days at 5 degrees F (if less than 6 inches thick) to assure safety. Thorough cooking of wild game meats will provide protection, but the freezing regimen is not always effective. In addition, curing by salting, smoking, or drying does not always kill the nematodes or cysts. Interestingly, microwaving does not consistently inactivate the organism, but ionizing irradiation has been used successfully to provide protection [225].

TAPEWORMS

The cestodes that produce the common human tapeworm infestation belong to the Taeniidae family. The most frequently seen in the United States are Taenia saginata, or beef tapeworm, and Taenia solium, the pork tapeworm. Taenia asiatica is limited to Asia and seen mostly in the Republic of Korea, China, Taiwan, Indonesia, and Thailand. T. solium can also cause cysticercosis [14]. Dipylidium caninum is found in dogs and cats and produces the disease dipylidiasis, most frequently seen in children younger than 8 years of age [227]. Humans are the only definitive hosts for T. saginata and T. solium, with pigs and cattle being common sources of the infestation.

All tapeworm organisms cause the disease process after being ingested by the victim in food or by direct contact, in the case of dipylidiasis. In addition, D. caninum can also be transmitted by ingesting infected fleas [227].

The lifecycle begins with egg packets within proglottids being released into the environment by a carrier. The eggs can survive for months on the ground or on most surfaces [14]. Once ingested, the organisms invade the intestinal wall of the victim and migrate to striated muscle, where they become cysticerci. The cysticerci can persist for years in an animal and cause significant morbidity. In humans, an adult tapeworm develops over a period of about two months. It attaches to the small intestine, where it can reside and excrete multitudes of proglottids for many years.

Clinical Presentation and Diagnosis

The symptoms of infestation with T. saginata are minimal, with mild abdominal pain being the most common finding. The clinical presentation of T. solium is even more minimal. It is usually the discovery of proglottids in the stool that signals the presence of the infestation [14]. Infrequently, the pork tapeworm progresses to cysticercosis, which can cause central nervous system symptoms if it invades the brain.

Dipylidiasis is typically asymptomatic; however, a severe worm burden can cause local pruritus, abdominal pain, allergic manifestations, and intestinal obstruction. The disease is often identified by the parent noting "rice stools" in a child's diaper [14,228].

Microscopic identification of the eggs and proglottids in the feces is diagnostic. This may not be possible until three months after infection because the adult tapeworm must first be present. Repeated examinations may be necessary to find the organisms, especially in light infestations. Antibody detection methods can be useful in the early stages of the disease, before the presence of proglottids in the stool. The differentiation of the species of Taenia requires more detailed analysis, with examination of the gravid proglottids or the scolex of the organism [14,228].

Treatment and Prevention

Treatment with antiparasitic medication is usually very effective. The CDC recommends praziquantel, although it is not yet approved for this use by the FDA [14,46]. The usual anthelmintics (i.e., albendazole or praziquantel) have been used for the treatment of neurocysticercosis [229]. Treatment of dipylidiasis in adults and children can be with praziquantel or albendazole (off-label use) [46].

Prevention of dipylidiasis in pets and humans is aided by the control of fleas with pet medications or flea collars. Good hygiene and refraining from sleeping with or kissing the animal will also help prevent the infestation. Good sanitary practices are also the best way to prevent taeniasis [227].

ANISAKIASIS

There are many fish-borne zoonotic diseases, including ciguatera poisoning, tetrodotoxin poisoning from pufferfish, and infestations of Diphyllobothrium tapeworms. Because of the increasing consumption of uncooked fish in North America, there has been an increased awareness of anisakiasis. Anisakis simplex is a nematode (roundworm) found in several types of ocean fish and marine animals. It has been known in Japan for centuries, but it was first described in detail in the Netherlands in 1960 [230].

The adult nematodes reside in the intestines of marine mammals such as dolphins and sea lions. These mammals excrete the eggs, which are ingested by crustaceans. Fish then eat the crustaceans and become intermediate hosts, as the larvae imbed themselves in their flesh. Commonly affected fish include mackerel, salmon, squid, rockfish, anchovies, sardines, hake, and herring [230,231]. After ingestion by humans, the larvae attach themselves to the gastric mucosa or penetrate the stomach or intestinal wall. This can lead to abscess formation or eosinophilic granulomatosis. A severe allergic reaction often occurs, which causes more morbidity than the local effects of the adult nematodes [231].

Clinical Presentation and Diagnosis

Patients may suffer a marked allergic response, including urticaria, angioedema, bronchospasm, and anaphylaxis, within 24 hours of eating raw or undercooked fish [232]. The latency of the reaction ranges from 15 minutes to 26 hours, with 5 hours after consumption being the mean [231]. Gastrointestinal symptoms of abdominal pain, diarrhea, fullness, nausea, and vomiting are often mild, although the vomiting may be violent enough to expel some of the larvae [232]. If the organisms lodge in the bowel, they can produce a granulomatous response, mimicking Crohn disease, after about one to two weeks [231]. They can also be found in organs or areas outside the gastrointestinal tract, such as the peritoneum and liver [230].

Diagnosis can be made by endoscopy, during which the 2-cm larvae can be seen and removed. The organisms can also be seen on biopsy specimens obtained during the endoscopic procedure or surgery [232].

Treatment and Prevention

The treatment of choice is removal of the organisms during fiberoptic endoscopy or surgery [231,232]. Successful treatment of anisakiasis with albendazole 400 mg orally twice daily for 6 to 21 days has been reported in cases with a strong presumptive diagnosis based on history and/or serology [232]. Prevention is almost absolute if raw or uncooked fish is avoided. However, this is not practical in many parts of the world, including the United States. Fortunately, most chefs trained in handling and preparing raw fish can spot tainted fish. Freezing at negative 4 degrees F for at least seven days will kill the larvae, as will "blast-freezing" at negative 31 degrees F for 15 hours [232]. Irradiation of fish can also kill the organisms as will the cooking of thawed or fresh fish. Salting, in high concentration, and smoking may provide some prevention but not enough to assure a safe product [250]. When smoking, the flesh must reach 65 degrees C to kill the parasites.

10. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

Obtaining a detailed patient history is a vital aspect of diagnosing many zoonotic diseases, particularly those that are rare or that display similar signs and symptoms to other conditions. Furthermore, communication with patients regarding diagnostic procedures, treatment regimens, and prevention of zoonotic diseases depends on clear communication between the patient and clinician. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. The interpreter should be considered an active agent in the diagnosis and/or treatment processes, negotiating between two cultures and assisting in promoting culturally competent communication and practice [50]. This is particularly an issue for zoonotic diseases that commonly originate in countries outside the United States, for which English will be a second language for some or many of the patients.

In the increasingly multicultural landscape of the United States, interpreters are a valuable resource to help bridge the communication and cultural gap between patients or caregivers and practitioners. Interpreters are more than passive agents who translate and transmit information from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. When interacting with patients for whom English is a second language, the consideration of the use of an interpreter and/or patient education materials in their native language may improve understanding and outcomes.

11. CONCLUSION

The zoonotic diseases, in their many forms, have produced widespread morbidity and mortality. From the very old zoonoses, such as plague and rabies, to the relatively new diseases, like avian influenza and West Nile encephalitis, these diseases can be expected to cause disease in humans well into the future.

This course presented a spectrum of the more common zoonoses and briefly reviewed the background, clinical presentation, diagnostic procedures, treatment, and preventive measures associated with the individual diseases. It is vital for medical professionals to have a working knowledge of the zoonoses that they may encounter. Particularly considering the globalization of commerce and travel, early diagnosis and effective treatment can protect against potential outbreaks and pandemics.

Works Cited

1. Blancou J, Meslin FX. Brief review of the history of zoonoses. Rev Sci Tech. 2000;19(1):15-22.

2. Uppsala Universitet. Systema Naturae: An Epoch-Making Book. Available at http://www2.linnaeus.uu.se/online/animal/1_1.html. Last accessed April 8, 2020.

3. Berger D. A brief history of medical diagnosis and the birth of the clinical laboratory. Part 1: ancient times through the 19th century. MLO Med Lab Obs. 1999;31(7):28-30, 32, 34-40.

4. Medicine Net. Definition of Koch's Postulates. Available at https://www.medicinenet.com/script/main/art.asp?articlekey=7105. Last accessed April 8, 2020.

5. Berger D. A brief history of medical diagnosis and the birth of the clinical laboratory. Part 2: laboratory science and professional certification in the 20th century. MLO Med Lab Obs. 1999;31(8):32-34, 36, 38.

6. Centers for Disease Control and Prevention. Eastern equine encephalitis—Florida, eastern United States, 1991. MMWR. 1991;40(31):533-535.

7. Burroughs T, Knobler S, Lederberg J (eds). The Emergence of Zoonotic Diseases: Understanding the Impact on Animal and Human Health. Washington, DC: National Academy Press; 2002.

8. Gilbert AT, Petersen BW, Recuenco S, et al. Evidence of rabies virus exposure among humans in the Peruvian Amazon. Am J Trop Med Hyg. 2012;87(2):206-215.

9. Sanchez A, Ksiazek TG, Rollin PE, et al. Reemergence of Ebola virus in Africa. Emerg Infect Dis. 1995;1(3):96-97.

10. Centers for Disease Control and Prevention. About Parasites. Available at https://www.cdc.gov/parasites/about.html. Last accessed April 8, 2020.

11. Horton HH, Misrahi JJ, Matthews GW, Kocher PL. Critical biological agents: disease reporting as a tool for determining bioterrorism preparedness. J Law Med Ethics. 2002;30(2):262-266.

12. Heymann DL (ed). Control of Communicable Diseases Manual. 20th ed. Washington, DC: World Health Organization/American Public Health Association; 2014.

13. Koehsler M, Walochnik J, Georgopoulos M, et al. Linguatula serrata tongue worm in human eye, Austria. Emerg Infect Dis. 2011;17(5).

14. Centers for Disease Control and Prevention. Laboratory Identification of Parasitic Diseases of Public Health Concern: Taeniasis. Available at https://www.cdc.gov/dpdx/taeniasis/index.html. Last accessed April 8, 2020.

15. Hugh-Jones ME, Hubbert WT, Hagstad HV. Zoonoses: Recognition, Control and Prevention. Ames, IA: University of Iowa Press; 1995.

16. Huff JL, Eberle R, Capitanio J, Zhou SS, Barry PA. Differential detection of B virus and rhesus cytomegalovirus in rhesus macaques. J Gen Virol. 2003;84(Pt 1):83-92.

17. National Institute of Allergy and Infectious Diseases. A History of Lyme Disease, Symptoms, Diagnosis, Treatment, and Prevention. Available at https://www.niaid.nih.gov/diseases-conditions/lyme-disease. Last accessed April 6, 2020.

18. Centers for Disease Control and Prevention. Lyme Disease Data. Available at https://www.cdc.gov/lyme/stats/index.html. Last accessed April 6, 2020.

19. Grier T. Will There Ever Be An Accurate Test for Lyme Disease? Available at https://owndoc.com/pdf/when-accurate-lyme-tests.pdf. Last accessed April 8, 2020.

20. Lin T, Oliver JH Jr, Gao L, Kollars TM Jr, Clark KL. Genetic heterogeneity of Borrelia burgdorferi sensu lato in the southern United States based on restriction fragment length polymorphism and sequence analysis. J Clin Microbiol. 2001;39(7):2500-2507.

21. Humane Society of the United States. Lyme Disease. Available at https://www.humanesociety.org/resources/lyme-disease. Last accessed April 8, 2020.

22. Godin AJ. Wild Mammals of New England. Baltimore, MD: Johns Hopkins University Press; 1977.

23. Steere AC. A 58-year old man with a diagnosis of chronic Lyme disease. JAMA. 2002;288(8):1002-1010.

24. Spielman A. Host Abundance and Transmission of Ixodes-Borne Zoonoses. Cambridge, MA: Harvard University Press; 1994.

25. Steere AC, Coburn J, Glickstein L. The emergence of Lyme disease. J Clin Invest. 2004;113(8):1093-1101.

26. Depietropaolo DL, Powers JH, Gill JM. Diagnosis of Lyme disease. Am Fam Physician. 2005;72(2):297-304.

27. Steere AC, McHugh G, Suarez C, Hoitt J, Damle N, Sikland VK. Prospective study of coinfection in patients with erythema migrans. Clin Infect Dis. 2003;36(8):1078-1081.

28. Centers for Disease Control and Prevention. Ehrlichiosis. Available at https://www.cdc.gov/ehrlichiosis. Last accessed April 6, 2020.

29. Telford SR 3rd, Pollack RJ, Spielman A. Emerging vector-borne infections. Infect Dis Clin North Am. 1991;5(1):7-17.

30. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease: dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med. 1988;319(22):1441-1446.

31. IgeneX, Inc. Reference Laboratory Manual. Palo Alto, CA: IgeneX, Inc.; 1998: 1-17.

32. Centers for Disease Control and Prevention. Notice to readers: recommendations for test performance and interpretation from the second national conference on serologic diagnosis of Lyme disease. MMWR. 1995;44(31):590-591.

33. Centers for Disease Control and Prevention. Notice to readers: caution regarding testing for Lyme disease. MMWR. 2005;54(5):125.

34. Meyerhoff JO. Lyme Disease. Available at https://emedicine.medscape.com/article/330178-overview. Last accessed April 8, 2020.

35. Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect Ther. 2014;12(9): 1103-1135.

36. Centers for Disease Control and Prevention. West Nile Virus. Available at https://www.cdc.gov/westnile/index.html. Last accessed April 8, 2020.

37. Centers for Disease Control and Prevention. Lyme Disease Vaccination. Available at https://www.cdc.gov/lyme/prev/vaccine.html. Last accessed April 6, 2020.

38. Dennis DT, Inglesby TV, Henderson DA, et al. Tularemia as a biological weapon: medical and public health management. JAMA. 2001;285(21):2763-2773.

39. Centers for Disease Control and Prevention. Key Facts about Tularemia. Available at https://emergency.cdc.gov/agent/tularemia/facts.asp. Last accessed April 8, 2020.

40. Bratton RL, Corey R. Tick-borne disease. Am Fam Physician. 2005;71(12):2323-2330.

41. Cleveland KO. Tularemia. Available at https://emedicine.medscape.com/article/230923-overview. Last accessed April 8, 2020.

42. New York City Department of Health and Mental Hygiene. Tularemia. Available at https://www.health.ny.gov/diseases/communicable/tularemia/fact_sheet.htm. Last accessed A.

43. Centers for Disease Control and Prevention. Tularemia associated with a hamster bite—Colorado, 2004. MMWR. 2005;53(51):1202-1203.

44. Yuen JC, Malotky MV. Francisella tularensis osteomyelitis of the hand following a cat bite: a case of clinical suspicion. Plast Reconstr Surg. 2011;128(1):37e-39e.

45. Weinstein RA, Singh K. Laboratory-acquired infections. Clin Infect Dis. 2009;49(1):142-147.

46. LexiComp Online. Available at https://online.lexi.com. Last accessed April 8, 2020.

47. Reed DS, Smith LP, Cole KS, Santiago AE, Mann BJ, Barry EM. Live attenuated mutants of Francisella tularensis protect rabbits against aerosol challenge with a virulent type A strain. Am Soc Microbiol. 2014;82(5):2098-2105.

48. Centers for Disease Control and Prevention. Rocky Mountain Spotted Fever (RMSF). Available at https://www.cdc.gov/rmsf/ index.html. Last accessed April 6, 2020.

49. Demma LJ, Traeger MS, Nicholson WL, et al. Rocky Mountain spotted fever from an unexpected tick vector in Arizona. N Engl J Med. 2005;353(6):587-594.

50. Hwa-Froelich DA, Westby CE. Considerations when working with interpreters. Commun Disord Q. 2003;24(2):78-85.

51. Western KA, Benson GD, Gleason NN, Healy GR, Schultz MG. Babesiosis in a Massachusetts resident. N Engl J Med. 1970;283(16):854-856.

52. Centers for Disease Control and Prevention. Parasites: Babesiosis. Available at https://www.cdc.gov/parasites/babesiosis/health_professionals/index.html Last accessed April 6, 2020.

53. Pritt BS, Sloan LM, Hoang DK, et al. Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota, 2009. N Engl J Med. 2011;365(5):422-429.

54. New York State Department of Health. Anaplasmosis and Ehrlichiosis: Tick-Borne Bacterial Infections. Available at https:// www.health.ny.gov/diseases/communicable/ehrlichiosis/fact_sheet.htm. Last accessed April 8, 2020.

55. Pastula DM, Turabelidze G, Yates KF. Notes from the field: Heartland virus disease—United States, 2012–2013. MMWR. 2014;63(12):270-271.

56. Petersen LR, Marfin AA, Gubler DJ. West Nile virus. JAMA. 2003;290(4):524-528.

57. Centers for Disease Control and Prevention. West Nile Virus in the United States: Guidelines for Surveillance, Prevention, and Control. Available at https://www.cdc.gov/westnile/resources/pdfs/wnvGuidelines.pdf. Last accessed April 6, 2020.

58. Centers for Disease Control and Prevention. West Nile Virus: Final Annual Maps and Data for 1999–2015. Available at https://www.cdc.gov/westnile/statsmaps/finalmapsdata/index.html. Last accessed April 6, 2020.

59. Scherret JH, Poidinger M, Mackenzie JS, et al. The relationships between West Nile and Kunjin viruses. Emerg Infect Dis. 2001;7(4):697-705.

60. Centers for Disease Control and Prevention. West Nile virus activity: Eastern United States, 2001. MMWR. 2001;50(29):617-619.

61. Campbell GL, Marfin AA, Lanciotti RS, Gubler DJ. West Nile virus. Lancet Infect Dis. 2002;2(9):519-529.

62. Klenk K, Snow J, Morgan K, et al. Alligators as West Nile virus amplifiers. Emerg Infect Dis. 2004;10(12):2150-2155.

63. Centers for Disease Control and Prevention. Update: West Nile virus activity—Northeastern United States, 2000. MMWR. 2000;49(36):820-822.

64. Petersen LR, Marfin AA. West Nile virus: a primer for the clinician. Ann Intern Med. 2002;137(3):173-179.

65. Sejvar JJ, Haddad MB, Tierney BC, et al. Neurologic manifestations and outcome of West Nile virus infection. JAMA. 2003;290(4):511-515.

66. Hayes EB, Sejvar JJ, Zaki SR, Lanciotti RS, Bode AV, Campbell GL. Virology, pathology, and clinical manifestations of West Nile virus disease. Emerg Infect Dis. 2005;11(8):1174-1179.

67. Salinas JD Jr. West Nile Virus. Available at https://emedicine.medscape.com/article/312210-overview. Last accessed April 8, 2020.

68. Nasci RS, Wirtz RA, Brogdon WG. Protection against mosquitoes, ticks, and other insects and arthropods. In: CDC's Health Information for International Travel: 2016 (Yellow Book). New York, NY: Oxford University Press; 2015.

69. National Institutes for Health. NIH-Funded Vaccine for West Nile Virus Enters Human Clinical Trials. Available at https://www.nih.gov/news-events/news-releases/nih-funded-vaccine-west-nile-virus-enters-human-clinical-trials. Last accessed April 8, 2020.

70. Centers for Disease Control and Prevention. Rabies: Transmission. Available at https://www.cdc.gov/rabies/transmission/index.html. Last accessed April 6, 2020.

71. Centers for Disease Control and Prevention. Rabies in the U.S. Available at https://www.cdc.gov/rabies/location/usa/index.html Last accessed April 6, 2020.

72. Centers for Disease Control and Prevention. Human rabies prevention—United States, 1999. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 1999;48(RR-1):1-21.

73. Srinivasan A, Burton EC, Kuehnert MJ, et al. Transmission of rabies virus from an organ donor to four transplant recipients. N Engl J Med. 2005;352(11):1103-1111.

74. Monroe BP, Yager P, Blanton J, et al. Rabies surveillance in the United States during 2014. J Am Vet Med Assoc. 2016;248(7): 777-788.

75. Wilde H, Briggs DJ, Meslin FX, Hemachttdha T, Sitprija V. Rabies update for travel medicine advisors. Clin Infect Dis. 2003;37(1):96-100.

76. Jackson AC, Warrell MJ, Rupprecht CE, et al. Management of rabies in humans. Clin Infect Dis. 2003;36(1):60-63.

77. World Health Organization. Rabies. Available at https://www.who.int/health-topics/rabies. Last accessed April 8, 2020.

78. Centers for Disease Control and Prevention. Human death associated with bat rabies—California, 2003. MMWR. 2004;53(2): 33-35.

79. World Health Organization. WHO Guide for Rabies Pre- and Post-Exposure Prophylaxis in Humans. Available at https://www.who.int/rabies/PEP_Prophylaxis_guideline_15_12_2014.pdf. Last accessed April 8, 2020.

80. Rupprecht CE, Briggs D, Brown CM, et al. Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the Advisory Committee on Immunization Practices. MMWR. 2010;59(RR2):1-9.

81. Centers for Disease Control and Prevention. Recovery of a patient from clinical rabies—Wisconsin, 2004. MMWR. 2004;53(50):1171-1173.

82. Medical College of Wisconsin. Rabies Registry. Available at https://www.mcw.edu/departments/pediatrics/divisions/infectious-diseases/rabies-registry-website. Last accessed April 8, 2020.

83. Manning SE, Rupprecht CE, Fishbein D, et al. Human rabies prevention—United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR. 2008;57(RR3):1-26, 28.

84. Centers for Disease Control and Prevention. Compendium of animal rabies prevention and control, 2005. MMWR. 2005;54(RR03):1-8.

85. World Health Organization. Rabies vaccines: WHO position paper—recommendations. Vaccine. 2010;28(44):7140-7142.

86. Olsen CW. Influenza: pigs, people and public health. National Pork Board: Public Health Fact Sheet. 2004;2(6):1-3.

87. Centers for Disease Control and Prevention. Transmission of Influenza A Viruses between Animals and People. Available athttps://www.cdc.gov/flu/avianflu/virus-transmission.htm. Last accessed April 8, 2020.

88. World Health Organization. Cumulative Number of Confirmed Human Cases of Avian Influenza A(H5N1) Reported to WHO, 2003–2016. Available at https://www.who.int/influenza/human_animal_interface/EN_GIP_20160404cumulativenumberH5N1cases.pdf. Last accessed April 8, 2020.

89. Centers for Disease Control and Prevention. Avian Influenza A Virus Infections in Humans. Available at https://www.cdc.gov/flu/avianflu/avian-in-humans.htm. Last accessed April 8, 2020.

90. World Health Organization. Avian Influenza A (H7N9) Virus. Available at https://www.who.int/influenza/human_animal_interface/influenza_h7n9/en. Last accessed April 8, 2020.

91. World Health Organization. Avian Influenza: Assessing the Pandemic Threat. Available at https://apps.who.int/iris/bitstream/handle/10665/68985/WHO_CDS_2005.29.pdf;jsessionid=254942D70AD25712A859C38DA6502FCB?sequence=1. Last accessed April 8, 2020.

92. Centers for Disease Control and Prevention. Public Health Threat of Highly Pathogenic Avian Influenza A (H5N1) Virus. Available at https://www.cdc.gov/flu/avianflu/h5n1-threat.htm. Last accessed April 8, 2020.

93. World Health Organization. Avian Influenza: Situation in Indonesia: Update. Available at https://www.who.int/csr/don/2012_08_10b/en. Last accessed April 8, 2020.

94. Centers for Disease Control and Prevention. Avian Influenza in Birds. Available at https://www.cdc.gov/flu/avianflu/avian-in-birds.htm. Last accessed April 8, 2020.

95. Hitt E. Avian Flu: What Clinicians Need to Know. Available at https://www.medscape.com/viewarticle/468007. Last accessed April 8, 2020.

96. U.S. Department of Agriculture. USDA Avian Influenza Face Sheet. Available at https://www.usda.gov/sites/default/files/documents/usda-avian-influenza-factsheet.pdf. Last accessed April 8, 2020.

97. World Health Organization. Frequently Asked Questions on Human Infection Caused by the Avian Influenza A(H7N9) Virus. Available at https://www.who.int/publications/m/item/frequently-asked-questions-on-human-infection-caused-by-the-avian-influenza-a(h7n9)-virus. Last accessed April 8, 2020.

98. Centers for Disease Control and Prevention. Update: influenza activity, U.S. 2003–2004 season. MMWR. 2004;53(13):284-287.

99. Li C, Hatta M, Nidom CA, et al. Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence. Proc Natl Acad Sci U S A. 2010;107(10):4687-4692.

100. World Health Organization. H5N1 Highly Pathogenic Avian Influenza: Timeline of Major Events. Available at https://www.who.int/influenza/human_animal_interface/H5N1_avian_influenza_update20141204.pdf. Last accessed April 8, 2020.

101. Centers for Disease Control and Prevention. Avian Influenza Current Situation Summary. Available at https://www.cdc.gov/flu/avianflu/avian-flu-summary.htm. Last accessed April 8, 2020.

102. Centers for Disease Control and Prevention. Influenza Type A Viruses. Available at https://www.cdc.gov/flu/avianflu/influenza-a-virus-subtypes.htm. Last accessed April 8, 2020.

103. Centers for Disease Control and Prevention. Prevention and Treatment of Avian Influenza A Viruses in People. Available at https://www.cdc.gov/flu/avianflu/prevention.htm. Last accessed April 8, 2020.

104. Kayali G, Kandeil A, El-Shesheny R, et al. Avian influenza A(H5N1) virus in Egypt. Emerg Infect Dis. 2016;22(3).

105. Crispin SW, Cohen M, Mapes T. Bird-flu outbreak revives concerns stirred by SARS. Wall St J. January 28, 2004:A1.

106. National Institutes of Health. NIH Scientists Target Future Pandemic Strains of H5N1 Avian Influenza. Available at https:// www.nih.gov/news-events/news-releases/nih-scientists-target-future-pandemic-strains-h5n1-avian-influenza. Last accessed April 8, 2020.

107. Gamblin SJ, Haire LF, Russell RJ, et al. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science. 2004;303(5665):1838-1842.

108. Centers for Disease Control and Prevention. Licensure of a high-dose inactivated influenza vaccine for persons aged ≥65 years (Fluzone high-dose) and guidance for use—United States, 2010. MMWR. 2010;59(16):485-486.

109. Koopmans M, Wilbrink B, Conyn M, et al. Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet. 2004;363(9409):587-593.

110. World Health Organization. WHO Rapid Advice Guidelines on Pharmacological Management of Humans Infected with Avian Influenza A (H5N1) Virus. Available at https://apps.who.int/iris/bitstream/handle/10665/69373/WHO_PSM_PAR_2006.6_eng.pdf?sequence=1. Last accessed April 8, 2020.

111. Centers for Disease Control and Prevention. Guidelines and Recommendations: Interim Guidance about Avian Influenza (H5N1) for U.S. Citizens Living Abroad. Available at https://wwwnc.cdc.gov/travel/diseases/avian-bird-flu. Last accessed April 8, 2020.

112. Centers for Disease Control and Prevention. Archived: Interim Guidance for Airline Flight Crews and Persons Meeting Passengers Arriving from Areas with Avian Influenza (Updated). Available at https://www.cdc.gov/h1n1flu/guidance/air-crew-dom-intl.htm. Last accessed April 8, 2020.

113. Centers for Disease Control and Prevention. Malaria Diagnosis (United States). Available at https://www.cdc.gov/malaria/diagnosis_treatment/diagnosis.html. Last accessed April 8, 2020.

114. World Health Organization. Availability of New Recombinant H5N1 Vaccine Virus. Available at https://www.who.int/influenza/vaccines/virus/H5N1virus26May/en. Last accessed April 8, 2020.

115. GlaxoKlineSmith. GlaxoSmithKline Receives New HHS Order for H5N1 Bulk Antigen. Available at https://www.infectioncontroltoday.com/guidelines/glaxosmithkline-receives-new-hhs-order-h5n1-bulk-antigen-first-clinical-trials-candidate. Last accessed April 8, 2020.

116. Wong SS, Webby RJ. Traditional and new influenza vaccines. Clin Microbiol Rev. 2013;26(3):476-492.

117. U.S. Food and Drug Administration. H5N1 Influenza Virus Vaccine, manufactured by Sanofi Pasteur, Inc. Questions and Answers. Available at https://www.fda.gov/vaccines-blood-biologics/vaccines/h5n1-influenza-virus-vaccine-manufactured-sanofi-pasteur-inc-questions-and-answers. Last accessed April 8, 2020.

118. Science Daily. Universal Influenza Vaccine Tested Successfully in Humans. Available at https://www.sciencedaily.com/releases/2008/01/080124185522.htm. Last accessed April 8, 2020.

119. Centers for Disease Control and Prevention. Information on Swine/Variant Influenza Viruses. Available at https://www.cdc.gov/ flu/swineflu. Last accessed April 8, 2020.

120. World Health Organization. Avian Influenza Update: Implications of H5N1 Infections in Pigs in China. Available at https:// www.who.int/csr/don/2004_08_25/en. Last accessed April 8, 2020.

121. World Health Organization. Pandemic (H1N1) 2009: Frequently Asked Questions. Available at https://www.who.int/csr/disease/swineflu/frequently_asked_questions/en. Last accessed April 8, 2020.

122. Centers for Disease Control and Prevention. 2009 H1N1 Flu ("Swine Flu") and You. Available at https://www.cdc.gov/h1n1flu/qa.htm. Last accessed April 8, 2020.

123. Centers for Disease Control and Prevention. Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009–2010 Season. Available at https://www.cdc.gov/h1n1flu/recommendations.htm. Last accessed April 8, 2020.

124. World Health Organization. H1N1 in Post-Pandemic Period. Available at https://www.who.int/mediacentre/news/statements/2010/h1n1_vpc_20100810/en. Last accessed April 8, 2020.

125. Fiore AE, Uyeki TM, Broder KM, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR. 2010;59(RR8):1-62.

126. Centers for Disease Control and Prevention. Interim Guidance on Infection Control Measures for 2009 H1N1 Influenza in Healthcare Settings, Including Protection of Healthcare Personnel. Available at https://www.cdc.gov/h1n1flu/guidelines_infection_control.htm. Last accessed April 8, 2020.

127. California Department of Public Health. Variant Influenza Fact Sheet. Available at https://www.cdph.ca.gov/Programs/CID/DCDC/CDPH%20Document%20Library/Immunization/VariantInfluenza-Quicksheet.pdf. Last accessed April 8, 2020.

128. Lau JTF, Griffiths S, Choi K-C, Lin C. Prevalence of preventive behaviors and associated factors during early phase of the H1N1 influenza epidemic. Am J Infect Control. 2010;38(5):374-380.

129. Centers for Disease Control and Prevention. Use of influenza A (H1N1) 2009 monovalent vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR. 2009;58(RR10):1-8.

130. American Lung Association. Hantavirus Pulmonary Syndrome: Symptoms and Diagnosis. Available at https://www.lung.org/lung-health-diseases/lung-disease-lookup/hantavirus-pulmonary-syndrome/symptoms-diagnosis. Last accessed April 8, 2020.

131. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines. MMWR Recomm Rep. 2016;65(5):1-54.

132. U.S. Food and Drug Administration. First FDA-Approved Vaccine for the Prevention of Dengue Disease in Endemic Regions. Available at https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-dengue-disease-endemic-regions. Last accessed April 8, 2020.

133. Fiore AE, Shay DK, Broder K, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices. MMWR. 2008;57(RR7):1-60.

134. Centers for Disease Control and Prevention. Updated CDC Estimates of 2009 H1N1 Influenza Cases, Hospitalizations and Deaths in the United States, April 2009–April 10, 2010. Available at https://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm. Last accessed April 8, 2020.

135. World Health Organization. Fact Sheet No. 117: Dengue and Severe Dengue. Available at https://www.who.int/en/news-room/fact-sheets/detail/dengue-and-severe-dengue. Last accessed April 8, 2020.

136. U.S. Food and Drug Administration. FDA Drug Safety Communication: Important Safety Changes to the Influenza Drug Tamiflu (Oseltamivir Phosphate) for Oral Suspensions. Available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-important-safety-changes-influenza-drug-tamiflu-oseltamivir-phosphate. Last accessed April 8, 2020.

137. Centers for Disease Control and Prevention. Antiviral Drug Resistance among Influenza Viruses. Available at https://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm. Last accessed April 8, 2020.

138. Smee DF, Hurst BL, Wong MH, et al. Effects of the combination of favipiravir (T-705) and oseltamivir on influenza A virus infections in mice. Antimicrob Agents Chemother. 2010;54(1):126-133.

139. U.S. Food and Drug Administration. Emergency Use Authorization of Peramivir IV: Fact Sheet for Health Care Providers. Available at https://www.fda.gov/media/77787/download. Last accessed April 8, 2020.

140. U.S. Food and Drug Administration. RIPAVAB (Peramivir Injection), for Intravenous Use. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206426lbl.pdf. Last accessed April 8, 2020.

141. Centers for Disease Control and Prevention. Reported Cases of HPS. Available at https://www.cdc.gov/hantavirus/surveillance/index.html. Last accessed April 6, 2020.

142. Centers for Disease Control and Prevention. Hantavirus. Available at https://www.cdc.gov/hantavirus. Last accessed April 6, 2020.

143. Centers for Disease Control and Prevention. Hantavirus pulmonary syndrome—Vermont, 2000. MMWR. 2001;50(28):603-605.

144. Centers for Disease Control and Prevention. Hantavirus: Technical/Clinical Information. Available at https://www.cdc.gov/hantavirus/technical/index.html. Last accessed April 8, 2020.

145. Centers for Disease Control and Prevention. Lymphocytic Choriomeningitis: Fact Sheet. Available at https://www.cdc.gov/vhf/ lcm/pdf/factsheet.pdf. Last accessed April 6, 2020.

146. Centers for Disease Control and Prevention. Update: interim guidance for minimizing risk for human lymphocytic choriomeningitis virus infection associated with pet rodents. MMWR. 2005;54(Dispatch):1-3.

147. Fischer SA, Graham MB, Kuehnert MJ, et al. Transmission of lymphocytic choriomeningitis virus by organ transplantation. N Engl J Med. 2006;354(21):2235-2249.

148. Centers for Disease Control and Prevention. Variant Creutzfeldt-Jakob Disease. Available at https://www.cdc.gov/prions/vcjd/index.html. Last accessed April 8, 2020.

149. Brown P, Will RG, Bradley R, Asher DM, Detwiler L. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution, and current concerns. Emerg Infect Dis. 2001;7(1):6-16.

150. Takemura K, Kahdre M, Joseph D, Yousef A, Sreevatsan S. An overview of transmissible spongiform encephalopathies. Anim Health Res Rev. 2004;5(2):103-124.

151. Centers for Disease Control and Prevention. BSE in North America. Available at https://www.cdc.gov/prions/bse/bse-north-america.html. Last accessed April 8, 2020.

152. George LW. Diseases of the nervous system. In: Smith BP (ed). Large Animal Internal Medicine. 5th ed. St. Louis, MO: Mosby-Year Book, Inc.; 2014.

153. Collinge J. Human prion diseases and bovine spongiform encephalopathy (BSE). Hum Mol Genet. 1997;6(10):1699-1705.

154. Wilesmith JW, Ryan JB, Atkinson MJ. Bovine spongiform encephalopathy: epidemiological studies on the origin. Veterinary Record. 1991;128:199-203.

155. Detwilder LA. Animal Transmissible Spongiform Encephalopathies (TSEs) and Their Impact on Animal and Human Health Worldwide. Yulee, FL: Proceedings of the American Association of Zoo Veterinarians; 1998.

156. Centers for Disease Control and Prevention. Investigation of progressive inflammatory neuropathy among swine slaughterhouse workers—Minnesota, 2007–2008. MMWR. 2008;57(5):1-3.

157. Lachance DH. Outbreak of immune polyradiculoneuropathy in workers exposed to porcine neural tissue. Abstract LBS.001. Academy of Neurology 60th Annual Meeting. Presented April 16, 2008.

158. Krause EZ. Variant Cruetzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy. Available at https://emedicine.medscape.com/article/1169688-overview. Last accessed April 8, 2020.

159. Collie DA, Summers DM, Sellar RJ, et al. Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases. Am J Neuroradiol. 2003;24(8):1560-1569.

160. Centers for Disease Control and Prevention. Variant Creutzfeldt-Jakob Disease: Risk for Travelers. Available at https://www.cdc.gov/prions/vcjd/risk-travelers.html. Last accessed April 8, 2020.

161. Amaral L, Kristiansen JE. Phenothiazines: potential management of Creutzfeldt-Jakob disease and its variant. Int J Antimicrob Agents. 2001;18(5):411-417.

162. Centers for Disease Control and Prevention. Dengue: Statistics and Maps. Available at https://www.cdc.gov/dengue/statistics-maps/index.html. Last accessed April 8, 2020.

163. Tomashek KM, Sharp TM, Margolis HS. Dengue. In: CDC's Health Information for International Travel: 2016 (Yellow Book). New York, NY: Oxford University Press; 2015.

164. Centers for Disease Control and Prevention. Dengue. Available at https://www.cdc.gov/dengue. Last accessed April 8, 2020.

165. Centers for Disease Control and Prevention. Dengue: Symptoms and Treatment. Available at https://www.cdc.gov/dengue/symptoms. Last accessed April 8, 2020.

166. Wiwanitkit V. The importance of accurate diagnosis of dengue fever. Future Virology. 2012;7(1):53-62.

167. Centers for Disease Control and Prevention. Toxoplasmosis (Toxoplasma Infection). Available at https://www.cdc.gov/parasites/toxoplasmosis. Last accessed April 6, 2020.

168. Foreyt WJ (ed). Veterinary Parasitology: Reference Manual. 5th ed. Ames, IA: Blackwell Publishing Professional; 2001.

169. Elmore SA, Jones JL, Conrad PA, Patton S, Lindsay DS, Dubey JP. Toxoplasma gondii: epidemiology, feline clinical aspects, and prevention. Trends Parasitol. 2010;26(4):190-196.

170. Kravetz JD, Federman DG. Cat-associated zoonoses. Arch Intern Med. 2002;162(17):1945-1952.

171. Dunn D, Wallon M, Peyron F, Petersen E, Peckham C, Gilbert R. Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counselling. Lancet. 1999;353(9167):1829-1833.

172. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR. 2009;58(RR-4):1-207.

173. Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children. MMWR. 2009;58(RR-11):1-166.

174. Centers for Disease Control and Prevention. Giardia. Available at https://www.cdc.gov/parasites/giardia. Last accessed April 6, 2020.

175. Adam RD. Biology of Giardia lamblia. Clin Microbiol Rev. 2001;14(3):447-475.

176. Buret AG. Mechanisms of epithelial dysfunction in giardiasis. Gut. 2007;56(3):316-317.

177. Nazer H. Giardiasis. Available at https://emedicine.medscape.com/article/176718-overview. Last accessed April 8, 2020.

178. Minvielle MC, Molina NB, Polverino D, Basualdo JA. First genotyping of Giardia lamblia from human and animal feces in Argentina, South America. Mem Inst Oswaldo Cruz. 2008;103(1):98-103.

179. Praesertbun R, Sukthana Y, Popruk S. Realtime PCR: benefits for detection of mild and symptomatic Giardia infections. Trop Med Health. 2012;40(2):31-35.

180. Centers for Disease Control and Prevention. Cryptosporidium (Also Known As "Crypto"): A Guide to Commercially-Bottled Water and Other Beverages. Available at https://www.cdc.gov/parasites/crypto/gen_info/bottled.html. Last accessed April 8, 2020.

181. World Health Organization. Fact Sheet No. 94: Malaria. Available at https://www.who.int/en/news-room/fact-sheets/detail/malaria. Last accessed April 8, 2020.

182. Centers for Disease Control and Prevention. Malaria's Impact Worldwide. Available at https://www.cdc.gov/malaria/malaria_worldwide/impact.html. Last accessed April 8, 2020.

183. World Health Organization. World Malaria Report, 2019. Available at https://www.who.int/malaria/publications/world-malaria-report-2019/en/. Last accessed April 8, 2020.

184. Centers for Disease Control and Prevention. Malaria Facts. Available at https://www.cdc.gov/globalhealth/newsroom/topics/malaria. Last accessed April 8, 2020.

185. World Health Organization. Guidelines for the Treatment of Malaria. 3rd ed. Geneva: World Health Organization; 2015.

186. Centers for Disease Control and Prevention. Malaria: Disease. Available at https://www.cdc.gov/malaria/about/disease.html. Last accessed April 6, 2020.

187. Rubio JM, Buhigas I, Subirats M, Baquero M, Puente S, Benito A. Limited level of accuracy provided by available rapid diagnosis tests for malaria enhances the need for PCR-based reference laboratories. J Clin Microbiology. 2001;39(7):2736-2737.

188. Centers for Disease Control and Prevention. Treatment of Malaria (Guidelines for Clinicians). Available at https://www.cdc.gov/malaria/resources/pdf/clinicalguidance.pdf. Last accessed April 6, 2020.

189. Centers for Disease Control and Prevention. Treatment of Malaria: Guidelines for Clinicians (United States). Available at https://www.cdc.gov/malaria/diagnosis_treatment/clinicians2.html. Last accessed April 6, 2020.

190. Figtree M, Lee R, Bain L, et al. Plasmodium knowlesi in human, Indonesian Borneo. Emerg Infect Dis. 2010;16(4):672-674.

191. Lo Re V III, Gluckman SJ. Prevention of malaria in travelers. Am Fam Phys. 2003;68(3):509-514.

192. Advisory Committee on Immunization Practices. Use of anthrax vaccine in the United States. MMWR. 2010;59(RR06):1-30.

193. Inglesby TV, O'Toole T, Henderson DA, et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002;287(17):2236-2252.

194. Cunha BA. Anthrax. Available at https://emedicine.medscape.com/article/212127-overview. Last accessed April 8, 2020.

195. Centers for Disease Control and Prevention. Anthrax: Guidelines and Recommendations. Available at https://www.cdc.gov/anthrax/specificgroups/health-care-providers/index.html. Last accessed April 6, 2020.

196. Shadomy SV, Traxler RM, Marston CK. Infectious diseases related to travel: anthrax. In: CDC's Health Information for International Travel: 2016 (Yellow Book). New York, NY: Oxford University Press; 2015.

197. Hendricks KA, Wright ME, Shadomy SV, et al. Centers for Disease Control and Prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis. 2014;20(2).

198. Withers MR (ed). Medical Management of Biological Casualties Handbook. 8th ed. Fort Detrick, MD: US Army Medical Research Institute of Infectious Diseases; 2014.

199. Jang KH, Nam S-J, Locke JB, et al. Anthracimycin, a potent anthrax antibiotic from a marine-derived actinomycete. Angew Chem Int Ed Engl. 2013;52(30):7822-7824.

200. U.S. Food and Drug Administration. Vibrio vulnificus Health Education Kit Fact Sheet. Available at https://www.fda.gov/food/health-educators/vibrio-vulnificus-health-education-kit-fact-sheet. Last accessed April 8, 2020.

201. World Health Organization. Cholera. Available at https://www.who.int/health-topics/cholera. Last accessed April 8, 2020.

202. Centers for Disease Control and Prevention. Vibrio cholerae Infection: Treatment. Available at https://www.cdc.gov/cholera/treatment/index.html. Last accessed April 6, 2020.

203. U.S. Food and Drug Administration. FDA Approves Vaccine to Prevent Cholera for Travelers. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-vaccine-prevent-cholera-travelers. Last accessed April 8, 2020.

204. Chan-Tack KM. Botulism. Available at https://emedicine.medscape.com/article/213311-overview. Last accessed April 8, 2020.

205. Centers for Disease Control and Prevention. Botulism. Available at https://www.cdc.gov/botulism. Last accessed April 8, 2020.

206. Shapiro RL, Hatheway C, Becher J, Swerdlow DL. Botulism surveillance and emergency response: a public health strategy for a global challenge. JAMA. 1997;278(5):433-435.

207. U.S. Food and Drug Administration. BAT (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) (Equine). Available at https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/bat-botulism-antitoxin-heptavalent-b-c-d-e-f-g-equine. Last accessed April 8, 2020.

208. Centers for Disease Control and Prevention. Investigational heptavalent botulinum antitoxin (HBAT) to replace licensed botulinum antitoxin AB and investigational botulinum antitoxin E. MMWR. 2010;59(10):299.

209. Centers for Disease Control and Prevention. Botulism in the United States, 1899–Handbook for Epidemiologists, Clinicians, and Laboratory Workers. Available at https://www.cdc.gov/botulism/pdf/bot-manual.pdf. Last accessed April 8, 2020.

210. World Health Organization. Fact Sheet No. 139: Salmonella (Non-Typhoidal). Available at https://www.who.int/en/news-room/fact-sheets/detail/salmonella-(non-typhoidal). Last accessed April 8, 2020.

211. Centers for Disease Control and Prevention. Salmonellosis: Technical Information. Available at https://www.cdc.gov/salmonella/general/technical.html. Last accessed April 8, 2020.

212. Onwuezobe IA, Oshun PO, Odigwe CC. Antimicrobials for treating symptomatic non-typhoidal Salmonella infection. Cochrane Database Syst Rev. 2012;11:CD001167.

213. Centers for Disease Control and Prevention. Healthy Pets, Healthy People: Salmonella Infection. Available at https://www.cdc.gov/healthypets/diseases/salmonella.html. Last accessed April 8, 2020.

214. Centers for Disease Control and Prevention. Salmonella: Questions and Answers. Available at https://www.cdc.gov/salmonella/general/index.html. Last accessed April 8, 2020.

215. Cody SH, Abbott SL, Marfin AA, et al. Two outbreaks of multidrug-resistant Salmonella serotype typhimurium DT104 infections linked to raw-milk cheese in Northern California. JAMA. 1999;281(19):1805-1810.

216. Bouza E, Sánchez-Carrillo C, Hernangómez S, González MJ. Laboratory-acquired brucellosis: a Spanish national survey. J Hosp Infect. Sep 2005;61(1):80-83.

217. U.S. Department of Agriculture. Brucellosis and Yellowstone Bison. Available at https://www.aphis.usda.gov/animal_health/animal_dis_spec/cattle/downloads/cattle-bison.pdf. Last accessed April 8, 2020.

218. Gerberding JL, Romero JM, Ferraro MJ. Case records of the Massachusetts General Hospital. Case 34-2008: a 58-year-old woman with neck pain and fever. N Engl J Med. 2008;359(18):1942-1949.

219. Centers for Disease Control and Prevention. Brucellosis. Available at https://www.cdc.gov/brucellosis. Last accessed April 6, 2020.

220. Yousefi-Nooraie R, Mortaz-Hejri S, Mehrani M, Sadeghipour P. Antibiotics for treating human brucellosis. Cochrane Database Syst Rev. 2012;10:CD007179.

221. Lubani MM, Dudin KI, Sharda DC, Ndhar DS, Araj GF, Hafez HA, et al. A multicenter therapeutic study of 1100 children with brucellosis. Pediatr Infect Dis J. 1989;8(2):75-78.

222. Roushan MR, Mohraz M, Janmohammadi N, Hajiahmadi M. Efficacy of cotrimoxazole and rifampin for 6 or 8 weeks of therapy in childhood brucellosis. Pediatr Infect Dis J. 2006;25(6):544-545.

223. Robichaud S, Libman M, Behr M, Rubin E. Prevention of laboratory-acquired brucellosis. Clin Infect Dis. 2004;38(12):e119-e122.

224. Northrop-Clewes CA, Shaw C. Parasites. Br Med Bull. 2000;56(1):193-208.

225. Centers for Disease Control and Prevention. Laboratory Identification of Parasitic Diseases of Public Health Concern: Trichinellosis. Available at https://www.cdc.gov/dpdx/trichinellosis/index.html. Last accessed April 6, 2020.

226. de Silva N, Guyatt H, Bundy D. Anthelmintics: a comparative review of their clinical pharmacology. Drugs. 1997;53(5):769-788.

227. Centers for Disease Control and Prevention. Dipylidium Infection (Also Known As Dog and Cat Flea Tapeworm). Available at https://www.cdc.gov/parasites/dipylidium. Last accessed April 8, 2020.

228. Sun M. Dipylidiasis. Available at https://web.stanford.edu/class/humbio103/ParaSites2003/Dipylidiasis/index.htm. Last accessed April 8, 2020.

229. Abba K, Ramaratnam S, Ranganathan LN. Anthelmintics for people with neurocysticercosis. Cochrane Database Syst Rev. 2010;(1):CD000215.

230. Tokyo Medical and Dental University. Anisakiasis. Available at http://www.tmd.ac.jp/med/mzoo/vlm/anisakiasis. Last accessed April 8, 2020.

231. Weir E. Sushi, nemotodes, and allergies. CMAJ. 2005;172(3):329.

232. Centers for Disease Control and Prevention. Anisakiasis. Available at https://www.cdc.gov/parasites/anisakiasis. Last accessed April 6, 2020.

233. Stern EJ, Uhde KB, Shadomy SV, Messonnier N. Conference report on public health and clinical guidelines for anthrax. Emerg Infect Dis. 2008;14(4).

234. U.S. Food and Drug Administration. FDA Approves Treatment for Inhalation Anthrax. Available at https://wayback.archive-it.org/7993/20170405005211/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm439752.htm. Last accessed April 8, 2020.

235. Centers for Disease Control and Prevention. New Lyme-Disease-Causing Bacteria Species Discovered. Available at https://www.cdc.gov/media/releases/2016/p0208-lyme-disease.html. Last accessed April 8, 2020.

236. Kirkpatrick BD, Whitehead SS, Pierce KK. The live attenuated dengue vaccine TV003 elicits complete protection against dengue in human challenge model. Sci Transl Med. 2016;8(330):330.

237. Centers for Disease Control and Prevention. Multi-State Outbreak of Seoul Virus. Available at https://www.cdc.gov/hantavirus/outbreaks/seoul-virus/index.html. Last accessed April 8, 2020.

238. Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2007;69(1):91-102.

239. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089-1134.

240. Centers for Disease Control and Prevention. Tularemia: Prevention. Available at https://www.cdc.gov/tularemia/prevention. Last accessed April 8, 2020.

241. ClinicalTrials.gov. Phase 1 Trial of Inactivated West Nile Virus Vaccine. Available at https://clinicaltrials.gov/ct2/show/NCT02337868. Last accessed April 8, 2020.

242. Centers for Disease Control and Prevention. Rabies Vaccine. Available at https://www.cdc.gov/rabies/medical_care/vaccine.html. Last accessed April 6, 2020.

243. Centers for Disease Control and Prevention. First Human Avian Influenza A (H5N1) Virus Infection Reported in Americas. Available at https://www.cdc.gov/flu/news/first-human-h5n1-americas.htm. Last accessed April 8, 2020.

244. World Health Organization. Human Infection with Avian Influenza A(H7N9) Virus—China. Available at https://www.who.int/csr/don/03-april-2017-ah7n9-china/en. Last accessed April 8, 2020.

245. Centers for Disease Control and Prevention. Bird Infections with Highly-Pathogenic Avian Influenza A (H5N2), (H5N8), and (H5N1) Viruses: Recommendations for Human Health Investigations and Response. Available at https://emergency.cdc.gov/han/han00378.asp. Last accessed April 8, 2020.

246. U.S. Food and Drug Administration. Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products. Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/revised-preventive-measures-reduce-possible-risk-transmission-creutzfeldt-jakob-disease-and-variant. Last accessed April 8, 2020.

247. World Organisation for Animal Health. Bovine Spongiform Encephalopathy (BSE): List of Bovine Spongiform Encephalopathy Risk Status of Member Countries. Available at https://www.oie.int/animal-health-in-the-world/official-disease-status/bse/list-of-bse-risk-status. Last accessed April 8, 2020.

248. California Department of Public Health. Infant Botulism Treatment and Prevention Program. Available at https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/IBTPP_International_Inquiries.aspx. Last accessed April 8, 2020.

249. McCarty CL, Angelo K, Beer KD, et al. Large outbreak of botulism associated with a church potluck meal—Ohio, 2015. MMWR. 2015;64(29):802-803.

250. John, DT, Petri WA. The intestinal nematodes. In: Markell and Voge's Medical Parasitology. 9th ed. St. Louis, MO: Saunders; 2013: 239-273.

251. Hayes EB. Zika virus outside Africa. Emerg Infect Dis. 2009;15(9):1347-1350.

252. Fauci AS, Morens DM. Zika virus in the Americas: yet another arbovirus threat. N Engl J Med. 2016;374(7):601-604.

253. Oduyebo T, Igbinosa I, Petersen EE, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure—United States, July 2016. MMWR. 2016;65(29):739-744.

254. Rabe IB, Staples JE, Villanueva J, et al. Interim guidance for interpretation of Zika virus antibody test results. MMWR. 2016;65(21):543-546.

255. Centers for Disease Control and Prevention. Testing for Zika Virus Infections. Available at https://www.cdc.gov/zika/laboratories/types-of-tests.html. Last accessed April 8, 2020.

256. Centers for Disease Control and Prevention. Zika Virus: Statistics and Maps. Available at https://www.cdc.gov/zika/reporting/index.html. Last accessed April 8, 2020.

257. Monaghan AJ, Morin CW, Steinhoff DF, et al. On the seasonal occurrence and abundance of the Zika virus vector mosquito Aedes aegypti in the contiguous United States. PLoS Curr. 2016;1.

258. Hills SL, Russell K, Hennessey M, et al. Transmission of Zika virus through sexual contact with travelers to areas of ongoing transmission—continental United States, 2016. MMWR. 2016;65(8):215-216.

259. European Centre for Disease Prevention and Control. Rapid Risk Assessment: Zika Virus Epidemic in the Americas: Potential Association with Microcephaly and Guillain-Barré Syndrome. Available at https://www.ecdc.europa.eu/en/publications-data/rapid-risk-assessment-zika-virus-disease-epidemic-potential-association-0. Last accessed April 8, 2020.

260. U.S. Food and Drug Administration. FDA Advises Testing for Zika Virus in All Donated Blood and Blood Components in the US. Available at https://www.fda.gov/news-events/press-announcements/fda-advises-testing-zika-virus-all-donated-blood-and-blood-components-us. Last accessed April 8, 2020.

261. Oster AM, Russell K, Stryker JE, et al. Update: interim guidance for prevention of sexual transmission of Zika virus—United States, 2016. MMWR. 2016;65(12):323-325.

262. Russell PK. The Zika pandemic: a perfect storm? PLoS Negl Trop Dis. 2016;10(3):e0004589.

263. Petersen LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. N Engl J Med. 2016;374(16):1552-1563.

264. Brasil P, Pereira JP Jr, Raja Gabaglia C, et al. Zika virus infection in pregnant women in Rio de Janeiro: preliminary report. Obstet Gynecol Surv. 2016;71(6):331-333.

265. Carteaux G, Maquart M, Bedet A, et al. Zika virus associated with meningoencephalitis. N Engl J Med. 2016;374(16):1595-1596.

266. Karimi O, Goorhuis A, Schinkel J, et al. Thrombocytopenia and subcutaneous bleedings in a patient with Zika virus infection. Lancet. 2016;387(10022):939-940.

267. Hennessey M, Fischer M, Staples JE. Zika virus spreads to new areas: region of the Americas, May 2015–January 2016. MMWR. 2016;65(3):55-58.

268. Romer Y, Adcock K, Wei Z, et al. Isolation of Heartland virus from lone star ticks, Georgia, USA, 2019. Emerg Infect Dis. 2022;28(4):786-792.

Evidence-Based Practice Recommendations Citations

1. Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect Ther. 2014;12(9):1103-1135. Available at https://www.tandfonline.com/doi/full/10.1586/14787210.2014.940900. Last accessed April 17, 2020.

2. American College of Radiology. ACR Appropriateness Criteria: Ataxia. Reston, VA: American College of Radiology; 2018. Available at https://acsearch.acr.org/docs/69477/Narrative. Last accessed April 17, 2020.

3. Maldonado YA, Read JS, Committee on Infectious Diseases. Diagnosis, treatment, and prevention of congenital toxoplasmosis in the United States. Pediatrics. 2017;139(2). Available at https://pediatrics.aappublications.org/content/pediatrics/early/2017/01/26/peds.2016-3860.full.pdf. Last accessed April 17, 2020.

4. World Gastroenterology Organisation. World Gastroenterology Organisation Global Guidelines: Acute Diarrhea in Adults and Children: A Global Perspective. Milwaukee, WI: World Gastroenterology Organisation; 2012. Available at https://www.worldgastroenterology.org/guidelines/global-guidelines/acute-diarrhea/acute-diarrhea-english. Last accessed April 17, 2020.