CVD193S • Global Health Special Offer

Table of Contents

CVD193S • Global Health Special Offer

How to Receive Credit

NetCE 5 Hour Course #91763 • Bioterrorism: An Update for Healthcare Professionals

91763 • Bioterrorism: An Update for Healthcare Professionals

1. INTRODUCTION

2. UNDERSTANDING AND RESPONDING TO BIOTERRORISM

3. BIOTERRORISM IN RECENT HISTORY

4. TYPES OF AGENTS

5. BACTERIAL AGENTS

6. VIRUSES

7. TOXINS

8. DETECTING AND MANAGING A BIOLOGIC ATTACK

9. APIC BIOTERRORISM READINESS PLAN

10. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

11. RESOURCES

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 5 Hour Course #97790 • Domestic and Sexual Violence

97790 • Domestic and Sexual Violence

1. INTRODUCTION

2. AN OVERVIEW OF THE ISSUE

3. SIGNS OF ABUSE/VICTIMIZATION

4. HEALTH EFFECTS AND IMPLICATIONS OF DOMESTIC VIOLENCE

5. HEALTH EFFECTS AND IMPLICATIONS OF SEXUAL VIOLENCE

6. IMPLICATIONS ON PREGNANCY AND PRENATAL CARE

7. HEALTH EFFECTS AND IMPLICATIONS OF CHILDREN EXPOSED TO DOMESTIC VIOLENCE

8. DOMESTIC VIOLENCE AND SEXUAL VIOLENCE IN SPECIAL POPULATIONS

9. PERPETRATORS OF DOMESTIC/SEXUAL VIOLENCE

10. ASSESSMENT AND SCREENING METHODS

11. BEST PRACTICES IN FOLLOW-UP CARE FOR VICTIMS OF VIOLENCE

12. BUILDING EFFECTIVE COMMUNITY PARTNERSHIPS AND COLLABORATIONS WITH COMMUNITY-BASED AGENCIES

13. APPROPRIATE RESPONSES AND DOCUMENTATION

14. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 2 Hour Course #94150 • The Coronavirus Disease (COVID-19) Pandemic

94150 • The Coronavirus Disease (COVID-19) Pandemic

1. BACKGROUND

2. THE 2019–2020 NOVEL CORONAVIRUS OUTBREAK: A GLOBAL THREAT

3. CLINICAL MANIFESTATIONS OF COVID-19

4. COVID-19 IN CHILDREN

5. DIAGNOSTIC TESTING FOR SARS-COV-2

6. TREATMENT OPTIONS AND VACCINE DEVELOPMENT

7. GLOBAL PUBLIC HEALTH CONCERNS AND WHO RESPONSE

8. TRANSMISSION: PUBLIC HEALTH IMPLICATIONS

9. OTHER AVAILABLE RESOURCES

Works Cited

CVD193S • Global Health Special Offer

Elizabeth T. Murane, PHN, BSN, MA

Carol Shenold, RN, ICP

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

CVD193S • Global Health Special Offer

Expiration Date: 02/28/2022

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.

91763 • Bioterrorism: An Update for Healthcare Professionals

Elizabeth T. Murane, PHN, BSN, MA

Carol Shenold, RN, ICP

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

Hospitals and clinics will have the first opportunity to recognize and initiate a response to a bioterrorism-related outbreak. Therefore, overall disaster plans must address the issue. Individual facilities should determine the extent of their bioterrorism readiness, which may range from notification of local emergency networks (i.e., calling 911) and transfer of affected patients to appropriate acute care facilities, to activation of large, comprehensive communication and management networks. This course will attempt to briefly summarize the characteristics, treatment, and prophylaxis of potential bioterror agents. The role of the medical professional will be outlined, and the appropriate "do's and don'ts" will be discussed. Reporting procedures and disaster plans will also be reviewed.

Table of Contents

91763 • Bioterrorism: An Update for Healthcare Professionals

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. UNDERSTANDING AND RESPONDING TO BIOTERRORISM

IDENTIFY

REPORT

REFER

3. BIOTERRORISM IN RECENT HISTORY

4. TYPES OF AGENTS

CATEGORY A DISEASES/AGENTS

CATEGORY B DISEASES/AGENTS

CATEGORY C DISEASES/AGENTS

DISPERSION

5. BACTERIAL AGENTS

ANTHRAX

PLAGUE

TULAREMIA

6. VIRUSES

SMALLPOX

VIRAL HEMORRHAGIC FEVERS

7. TOXINS

BOTULINUM TOXIN

RICIN

8. DETECTING AND MANAGING A BIOLOGIC ATTACK

9. APIC BIOTERRORISM READINESS PLAN

POSTEXPOSURE PROPHYLAXIS

DISASTER PLANS

PSYCHOLOGIC ASPECTS OF BIOTERRORISM

PUBLIC INFORMATION

10. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

11. RESOURCES

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

91763 • Bioterrorism: An Update for Healthcare Professionals

Education Category. Community Health

Release Date. 09/01/2020

Expiration Date. 08/31/2023

Course Overview

Hospitals and clinics will have the first opportunity to recognize and initiate a response to a bioterrorism-related outbreak. Therefore, overall disaster plans must address the issue. Individual facilities should determine the extent of their bioterrorism readiness, which may range from notification of local emergency networks (i.e., calling 911) and transfer of affected patients to appropriate acute care facilities, to activation of large, comprehensive communication and management networks. This course will attempt to briefly summarize the characteristics, treatment, and prophylaxis of potential bioterror agents. The role of the medical professional will be outlined, and the appropriate "do's and don'ts" will be discussed. Reporting procedures and disaster plans will also be reviewed.

Audience

This course is designed for all hospital and clinic staff, physicians, nurses, behavioral health professionals, and entire medical teams, all of whom are expected to respond in the case of a bioterrorist event.

Course Objective

The purpose of this course is to address the various components of a bioterrorism attack and the appropriate responses required of clinical care providers, public health professionals, and healthcare facilities.

Learning Objectives

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

1. Discuss the role of the medical professional in the event of a bioterrorism attack.

2. Reflect on the history of bioterrorism.

3. Identify the CDC categories of possible bioterror agents and diseases.

4. Explain the types of dispersion.

5. Compare available bacterial agents, their diagnosis, and treatment procedures, and how they could be used during a bioterrorist attack.

6. Analyze viral agents with the potential for bioterrorist use, including smallpox and viral hemorrhagic fevers.

7. Evaluate biologic toxins and how they might be used in biowarfare.

8. Apply a disaster plan for acts of terrorism that involve biologic weapons, including considerations for non-English-proficient populations.

Faculty

Elizabeth T. Murane, PHN, BSN, MA, received her Bachelor’s degree in nursing from the Frances Payne Bolton School of Nursing, Case Western Reserve University in Cleveland, Ohio and a Master of Arts in Nursing Education from Teachers College, Columbia University, New York, New York.

Her nursing experience includes hospital nursing on pediatric, medical, and surgical units. She lived for 15 years in a village in Eastern Papua New Guinea providing medical and linguistic/literacy services for the villagers. She was a public health nurse for a year with the Brooklyn, New York Health Department and 20 years with the Shasta County Public Health Department in Redding, California. As a public health nursing director, she developed response plans for environmental and health issue disasters for both Shasta County and adjacent Tehama County Public Health Departments.

Carol Shenold, RN, ICP, graduated from St. Paul’s Nursing School, Dallas, Texas, achieving her diploma in nursing. Over the past thirty years she has worked in hospital nursing in various states in the areas of obstetrics, orthopedics, intensive care, surgery and general medicine.
Mrs. Shenold served as the Continuum of Care Manager for Vencor Oklahoma City, coordinating quality review, utilization review, Case Management, Infection Control, and Quality Management. During that time, the hospital achieved Accreditation with Commendation with the Joint Commission, with a score of 100.
Mrs. Shenold was previously the Infection Control Nurse for Deaconess Hospital, a 300-bed acute care facility in Oklahoma City. She is an active member of the Association for Professionals in Infection Control and Epidemiology (APIC). She worked for the Oklahoma Foundation for Medical Quality for six years.

Faculty Disclosure

Contributing faculty, Elizabeth T. Murane, PHN, BSN, MA, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Contributing faculty, Carol Shenold, RN, ICP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

John V. Jurica, MD, MPH

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

Alice Yick Flanagan, PhD, MSW

James Trent, PhD

Randall L. Allen, PharmD

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

The United States government expects healthcare professionals to be on the front line of defense and treatment in the event of a bioterrorism attack in our country. This includes most medical personnel, but especially physicians, nurses, physician assistants, mental health professionals, and dentists. Increasing awareness and knowledge of possible bioterrorism agents and attacks will increase healthcare professionals' ability to respond properly.

Hospitals and clinics will have the first opportunity to recognize and initiate a response to a bioterrorism-related outbreak. Therefore, overall disaster plans must address the issue. Individual facilities should determine the extent of their bioterrorism readiness, which may range from notification of local emergency networks (i.e., calling 911) and transfer of affected patients to appropriate acute care facilities, to activation of large, comprehensive communication and management networks [1].

This course will attempt to briefly summarize the characteristics, treatment, and prophylaxis of potential bioterror agents. The role of the medical professional will be outlined, and the appropriate "do's and don'ts" will be discussed. Reporting procedures and disaster plans will also be reviewed.

2. UNDERSTANDING AND RESPONDING TO BIOTERRORISM

There are many definitions of bioterrorism. Most are similar to the definition provided by the Centers for Disease Control and Prevention (CDC): "The intentional release of viruses, bacteria, or other germs that can sicken or kill people, livestock, or crops" [2].

What is the role of the practicing medical professional in the event of a bioterrorism attack and what is the expected response? This may be broken down into three simple steps: Identify, Report, and Refer [3].

IDENTIFY

- Be aware of the signs and symptoms of a bioterror agent

- Know the appropriate tests to request

- Have an awareness of possible differential diagnoses

REPORT

- Be able to contact the appropriate agencies

- Initiate the preprogrammed response by public and government agencies

REFER

- Be able to refer victims of possible bioterror to bioterrorism experts or specialists

- Refer any media requests to these individuals as well

The CDC and other public health agencies recommend being extra vigilant with patients, sharing information with them, allaying their fears, and helping them to understand the limits of the bioterror agents. Conversely, these organizations strongly advise against:

- Prescribing antibiotics inappropriately

- Stockpiling antibiotics

- Recommending gas masks

- Unnecessarily alarming patients or peers

It is important to remember that no single antibiotic will protect against all potential bacterial agents. The duration of protection from antibiotics is short. Indiscriminate use will waste supplies, induce drug resistance, and may lead to adverse effects. In addition, the organism used in an attack may have been engineered to be resistant to the commonly prescribed antibiotics [3].

3. BIOTERRORISM IN RECENT HISTORY

Though not a new threat, the possibility of a biologic warfare attack on the United States has received markedly increased attention as a result of several world events, including the September 11, 2001, terrorist attacks by al-Qaeda and the 2001 anthrax letter attacks (presumably by an American bioweapons researcher). In decades past, medical defense against biologic warfare was an area of study for military healthcare providers and did not readily apply to the day-to-day scope of caring for patients in peacetime. However, because the threat of biologic attacks against both soldiers and civilians enjoys a substantive existence today, education regarding prevention and treatment of biologic warfare casualties is indispensable.

The most successful bioterrorist attack in the United States before 2001 occurred in Oregon in 1984, when members of the Rajneesh commune attempted to influence the outcome of an election by infecting the salad bars of 10 restaurants with Salmonella spp. bacteria. They believed that if the local citizens were inflicted with diarrhea, they would not be able to vote. More than 750 people were sickened by the attack, but if this had been done with volatized anthrax spores, there could have been hundreds of fatalities [4,5]. The lead medical investigator admitted that public health officials were unprepared to deal with an attack of greater magnitude.

General antiterrorism training efforts intensified following the New York City World Trade Center bombing in 1993. The Tokyo subway sarin nerve agent release and Oklahoma City federal building bombing, both occurring in 1995, stimulated an additional increase in awareness of bioterrorism. In November 1997, Secretary of Defense William Cohen announced that all U.S. military troops would be immunized against anthrax as a precaution [6]. Additionally, the disclosure that a sophisticated offensive biologic warfare program existed in the former Soviet Union along with information obtained after the 2001 attacks on New York and Washington, D.C., reinforced the need for increased training and education.

The need for education on the subject of bioterrorism is evident. Preparation for such an event must include knowledge of the potential biologic agents with emphasis on their diagnosis, treatment, and management.

4. TYPES OF AGENTS

The CDC has defined three categories of possible bioterror agents and diseases. Agents are categorized according to their priority as risks to national security [7].

CATEGORY A DISEASES/AGENTS

These are high-priority agents, including organisms that pose a risk to national security because they:

- Can be easily disseminated or transmitted from person to person

- Result in high mortality rates and have the potential for major public health impact

- Might cause public panic and social disruption

- Require special action for public health preparedness

Representative Category A Agents

- Anthrax (Bacillus anthracis)

- Botulism (Clostridium botulinum toxin)

- Plague (Yersinia pestis)

- Smallpox (variola major)

- Tularemia (Francisella tularensis)

- Viral hemorrhagic fevers (e.g., Ebola)

CATEGORY B DISEASES/AGENTS

The second highest priority agents include those that:

- Are moderately easy to disseminate

- Result in moderate morbidity rates and low mortality rates

- Require specific enhancements of CDC's diagnostic capacity and enhanced disease surveillance

Representative Category B Agents

- Brucellosis (Brucella species)

- Epsilon toxin of Clostridium perfringens

- Food safety threats (e.g., Salmonella species, Escherichia coli O157:H7, Shigella)

- Glanders (Burkholderia mallei)

- Melioidosis (Burkholderia pseudomallei)

- Psittacosis (Chlamydia psittaci)

- Q fever (Coxiella burnetii)

- Ricin toxin from Ricinus communis (castor beans)

- Staphylococcal enterotoxin B

- Typhus fever (Rickettsia prowazekii)

- Viral encephalitis

- Alphaviruses

- Water safety threats (e.g., Vibrio cholerae, Cryptosporidium parvum)

CATEGORY C DISEASES/AGENTS

The third highest priority agents include emerging pathogens that could be engineered for mass dissemination in the future because of:

- Availability

- Ease of production and dissemination

- Potential for high morbidity and mortality rates and major health impact

Category C agents are generally emerging infectious diseases, such as hantaviruses or Nipah virus.

Any disease that is contagious would be worrisome in our highly mobile society because people travel every day to many regions of the country and the world. If infected in an attack, a victim might fly from city to city or country to country before he/she becomes symptomatic, spreading the infecting agent at an alarming rate. However, this course will focus primarily on those agents deemed highest priority (Category A) by the CDC. Information pertaining to chemical agents will also be provided.

While the wild forms of the various bioterrorism pathogens are frightening and available, the threat of genetically engineered infectious agents is also a consideration. For example, it is known that researchers in Moscow created a recombinant strain of anthrax, raising the possibility that the current vaccine would be ineffective. With the constant advances in bioengineering, it is inevitable that biologic weapons will be created that are resistant to current postexposure treatments and vaccines [8].

DISPERSION

Despite the very different properties of bacteria, viruses, and toxins, most biologic and chemical agents that can be used as weapons share some common characteristics. The most important characteristic is the ability of the agent to be dispersed in aerosols, with a particle size of 1–5 microns. These particles can remain suspended (in certain weather conditions) for hours and, if inhaled, will penetrate the distal bronchioles and terminal alveoli of victims. Particles larger than 5 microns would tend to be filtered out in the upper airway [9]. An indoor or domed stadium is a high-risk potential target for aerosolized biologic or chemical weapon attack.

Many of these agents may also be dispersed by contamination of foodstuffs, as was the case with the 1984 Rajneesh Salmonella attacks, although the effect is localized. It is estimated that less than 1 gram of botulinum toxin could poison 100,000 individuals if added to the commercial milk supply; nearly 600,000 could be poisoned with 10 grams [10]. Parasites (e.g., tapeworm eggs) could presumably be placed into a salad bar, salsa bar, or drinking water dispensers, and symptoms would not be seen until weeks or years after becoming infected [11]. This type of bioterrorist attack could be carried out for many months without being detected. Even after presentation of symptoms, diagnosis may not be rapid because many healthcare professionals are unfamiliar with tapeworm infections [11].

Waterborne dispersion is also a concern; however, the threat of harming large numbers of people by dispersing biologic or chemical agents into reservoirs is often mitigated by water treatment. Nonetheless, there have been successful bioterrorist attacks on drinking water supplies. One such incident occurred in Edinburgh, Scotland, in 1990, when nine individuals in the same apartment complex were infected with Giardia[11]. The apartment complex had an unsecured water supply, which was purposefully contaminated with feces. A bioterrorist might tap into and contaminate a large building's water supply, which is unlikely to undergo additional purification.

Naturally occurring outbreaks, such as the 1999 New York County Fair E. coli and Campylobacter well-water outbreak (900 sickened and 2 dead) and the 1993 Milwaukee Cryptosporidium parvum outbreak (403,000 affected), further exemplify the susceptibility of drinking water to contamination and bioterrorism [11]. Some agents, such as anthrax, are resistant to routine water treatment processes, and the Milwaukee outbreak occurred despite filtration and chlorination [12]. Public pools, recreational water parks, and interactive fountains have been the source of several outbreaks of naturally occurring infections, sickening almost half of attendees in some cases [11]. These systems are particularly vulnerable to bioterrorist attack.

5. BACTERIAL AGENTS

Bacterial agents are among the most probable sources of bioterror and include anthrax, brucellosis, plague, tularemia, and Q fever. They are generally easily accessible and fairly simple to spread. Bacteria can cause diseases in humans and animals by two possible means: by invasion of tissues or by production of toxins that cause a pathologic response. In many cases, pathogenic bacteria possess both properties. Fortunately, this group of agents often responds to specific therapy with antibiotics. The following sections will examine the more common bacterial agents in detail.

ANTHRAX

Background

Anthrax is a zoonotic disease (an animal disease transmitted to humans) that is transmissible to humans through handling or consumption of contaminated animal products. The CDC considers Bacillus anthracis, the bacteria that causes anthrax, to be one of the biological agents most likely to be used in the event of a bioterrorist attack [108]. There are several reasons for this. The anthrax spores are easily found in nature, can be produced in the laboratory, and are stable for long periods of time. B. anthracis is easy to cultivate, and spore production is readily induced. The spores are highly resistant to sunlight, heat, and disinfectants. Anthrax spores can be released quietly and in many forms (e.g., powders, sprays, food, water) without being seen, smelled, or tasted. These are very desirable properties when choosing a bacterial weapon.

Anthrax has been used as a weapon before. Anthrax spores were actively experimented with as possible weapons by the United States in the 1950s and 1960s, before the military program was terminated. At least 17 nations are believed to have had offensive biologic weapons programs, but it is unclear how many were working with anthrax. In August 1991, Iraq admitted to a United Nations inspection team that it had performed research on the offensive use of B. anthracis prior to the Persian Gulf War of 1991 and, in 1995, also admitted to actively producing and testing anthrax as a bioweapon [9,13]. In 2001, powered anthrax spores were deliberately put into letters that were then mailed through the United States postal system. Twenty-two persons, including 12 mail handlers, got anthrax and 5 died [108].

Anthrax can be produced in either a wet or dried form and stabilized for use as a weapon. It can be delivered as an aerosol cloud either from a line source, such as an aircraft, or as a point source from a spray device. If used as a weapon, an anthrax aerosol would be odorless and invisible following release and would have the potential to travel many kilometers before dissipating. Evidence suggests that following an outdoor aerosol release, persons indoors could be at as high a risk for exposure as those who are outdoors [14].

Four forms of anthrax occur in humans, with manifestations depending on how the organism is contacted. The diseases are distinct; however, infection with one form presents a risk for contracting the others.

Cutaneous Anthrax

Cutaneous anthrax is the most common naturally occurring form, with an estimated 2,000 human cases reported annually worldwide; however, it is extremely rare in the United States (0 to 2 cases per year) [15,16]. The disease typically follows exposure to anthrax-infected animals. 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 (GI) Anthrax

Gastrointestinal (GI) anthrax is not commonly seen; however, outbreaks have occurred in Africa and Asia [16]. GI anthrax follows the ingestion of insufficiently cooked contaminated meat or tainted liquids. Officials believe it is unlikely that gastrointestinal anthrax would be used as a bioterror agent because a very high infective dose is required [11].

Inhalation Anthrax

Inhalation anthrax is the most deadly form of the disease, but it occurs less frequently as a naturally occurring disease than the cutaneous or GI 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. As noted, it has been weaponized by several countries because it is easy to cultivate, the spores are resistant to heat and disinfection, and it can be produced in massive amounts relatively inexpensively. Prior to the cases in 2001, inhalation anthrax had not been reported in the United States since 1976 [14,16]. This makes even a single case a cause for alarm today.

Injection Anthrax

Injection anthrax was recently identified in heroin-injecting drug users in northern Europe, but to date, no cases have been reported in the United States. The symptoms of injection anthrax are similar to those of the cutaneous form, but there may also be infection deep beneath the skin or in the muscle where the drug was injected. Injection anthrax spreads through the body quickly and is more difficult to recognize and treat than cutaneous or inhalation forms. Cases of injection anthrax typically develop within one to four days of exposure and more than 25% of individuals with confirmed cases die [15,17].

Diagnosis

The first evidence of a clandestine release of anthrax as a biologic weapon would most likely be the sudden appearance of a large number of patients in a localized area, with the acute onset of a flu-like illness. A case fatality rate of 80% or more, with nearly half of all deaths occurring within 24 to 48 hours, is highly likely to be anthrax or pneumonic plague [14,16]. (Following the small-scale 2001 anthrax attacks, the case fatality rate was 45% [16].)

The initial symptoms are often followed by a short period of improvement [14]. Following this, 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. In later stages, mortality approaches 90% despite aggressive treatment [14]. Physical findings can be nonspecific. The chest x-ray is usually disease-specific, revealing a widened mediastinum with pleural effusions, typically without infiltrates [2]. Thoracic trauma can have similar signs, but often with infiltrates [18]. A hemorrhagic mediastinitis often develops.

Subclinical or clinical meningitis should also be suspected in victims of all types of anthrax [19]. Meningeal involvement has been documented in 77% of nonhuman primate models, and hemorrhagic leptomeningitis and meningoencephalitis have been reported in roughly half of human inhalation anthrax cases, including the 2001 letter attacks [5,19].

The 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 [2,14]. Pronounced edema is often associated with the lesions because of the release of an edema-producing toxin by B. anthracis. The lymph nodes in the area may become involved and enlarged. The incubation period in humans is usually one to seven days but could be prolonged to almost two weeks [2,14]. 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 vesicle 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 cutaneous form of anthrax progresses to systemic disease in 10% to 20% of the cases, with a fatality rate of up to 20% if untreated [2,14]. Laboratory tests of blood products are usually normal if the disease is not disseminated. The systemic symptoms of cutaneous anthrax infection include fever, headache, regional lymph node involvement, and myalgia [2].

Laboratory Analysis

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, and specimens (e.g., blood, skin lesion exudates, pleural fluid) should be collected before starting antimicrobial therapy [20]. On gram stain, the organism can be recognized as a large, rod-shaped, gram-positive, spore-forming bacillus. More positive identification requires lysis by gamma phage and direct fluorescent antibody (DFA) analysis or most positively by immunohistochemical staining. There is an enzyme-linked immunosorbent assay (ELISA) test available but generally only at reference laboratories [21]. A negative culture does not rule out cutaneous anthrax, especially if obtained after antibiotics are started.

Treatment

In 2014, the CDC published updated guidelines for the prevention, diagnosis, and treatment of anthrax [23]. These guidelines addressed best practices for management of patients with naturally occurring or bioterrorism-related anthrax in conventional medical settings. However, an aerosolized release of B. anthracis spores over densely populated areas could become a mass-casualty incident that overwhelms conventional resources. In order to prepare for this possibility, the government has stockpiled equipment and therapeutics (medical countermeasures) for anthrax prevention and treatment. In 2015, the CDC published an additional set of guidelines for intravenous antimicrobial and antitoxin use, diagnosis of anthrax meningitis, and management of complications in the setting of a mass-casualty incident [109].

Most B. anthracis strains are sensitive to a broad range of antibiotics. Penicillin, ciprofloxacin, or doxycycline is usually recommended for the treatment of anthrax, although penicillin alone is not used [22]. To be effective, treatment should be initiated early; if left untreated, the disease is highly fatal. Anthrax treatment regimens were updated in the years following the 2001 letter attacks, due to the high mortality rate (45%) despite aggressive treatment [19].

Immediate postexposure prophylaxis with ciprofloxacin 500 mg or doxycycline 100 mg orally, twice daily, is commonly recommended. Treatment should continue for 60 days. If individuals are unvaccinated, a three-dose series of anthrax vaccine adsorbed (AVA) should also be administered [23]. Levofloxacin is approved by the U.S. Food and Drug Administration (FDA) for postexposure prophylaxis in patients 18 years of age and older, but it is recommended as a second-line agent only, with use dictated by other medical issues [19,23]. Though off label, moxifloxacin and clindamycin are recommended alternatives [23].

In 2013, a new antibiotic derived from a marine actinomycete, anthracimycin, was discovered [24]. Although it is not yet FDA-approved, the agent shows significant activity against B. anthracis, and it may have a place in the treatment of anthrax in the future.

For treatment of systemic forms of anthrax infection in adults (e.g., inhalation anthrax, GI anthrax, meningitis and bacteremia), an intravenous (IV) combination antimicrobial regimen is recommended for two to three weeks, followed by single-drug oral therapy for an additional six weeks to reduce the risk of clinical relapse [23,25]. Initial empiric treatment for anthrax when meningitis is suspected or cannot be ruled out should include three antimicrobial agents with activity against B. anthracis, including one or more drugs with bactericidal activity and one protein synthesis inhibitor to reduce exotoxin production. All should have good central nervous system (CNS) penetration. Based on efficacy studies, antimicrobial activity, and achievable CNS levels, the usual preferred regimen consists of a quinolone (ciprofloxacin) plus a carbapenem (meropenem) for bactericidal effect, combined with linezolid and administered for two to three weeks or until the patient is stable [23]. In cases in which linezolid is contraindicated or unavailable, clindamycin is an acceptable alternative.

If meningitis is ruled out, the initial IV regimen for systemic anthrax may be reduced to a single bactericidal agent (e.g., ciprofloxacin or levofloxacin) combined with a protein synthesis inhibitor (either linezolid or clindamycin). If the infecting strain is susceptible to penicillin, then penicillin G is considered equivalent to quinolone options for primary bactericidal therapy [23].

After combination parenteral therapy has been completed and the patient is clinically stable, treatment can be transitioned to single-drug oral therapy to complete a total 60-day course of treatment [23]. This prolonged maintenance phase of therapy is intended to treat surviving spores of B. anthracis in patients who may have sustained an inhalational exposure. Antimicrobial selection is the same as for postexposure prophylaxis— ciprofloxacin, 500 mg every 12 hours, or doxycycline, 100 mg every 12 hours.

Treatment for special groups, such as children and pregnant women, must be considered carefully. Fluoroquinolones are not generally recommended because of possible side effects involving the skeletal system. Balancing risks against the concerns regarding engineered antibiotic-resistant anthrax strains, the Working Group on Civilian Biodefense (Working Group) and the CDC recommend that ciprofloxacin be used in pregnant women and in children for first-line therapy and postexposure prophylaxis [14,22]. Doxycycline should not be started in pregnant women unless the patient is in the third trimester, but it may be administered to children [19]. Amoxicillin may be used in pediatric treatment if the anthrax strain is susceptible to penicillin. The recommended pediatric dose is amoxicillin 45 mg/kg/day in three divided doses given at exact eight-hour intervals [26]. Elderly patients should be assessed for potential drug interactions and comorbidities, and treatment should be adjusted accordingly [19]. In general, the cephalosporins are not useful in treating anthrax because the anthrax organism produces an enzyme that neutralizes them.

Supportive therapy for shock, fluid volume deficit, and airway management may also be needed. Early and aggressive pleural fluid drainage is recommended for all hospitalized inhalation anthrax patients [19]. Drainage protocols similar to those for empyema or complicated pneumonia should be followed and should significantly reduce mortality [19].

Treatment of cutaneous anthrax requires treatment with oral ciprofloxacin or doxycycline for 7 to 10 days, or IV ciprofloxacin or doxycycline for severe, naturally acquired cases [19]. Other fluoroquinolones or penicillin can be substituted as oral regimens for uncomplicated cutaneous anthrax if well monitored. Treatment for bioterrorism-related cutaneous anthrax cases requires a 60-day course of postexposure prophylaxis with the recommended antibiotics due to the possibility of aerosol exposure [19]. Cutaneous anthrax cases with lesions of the head or neck, extensive edema, or systemic involvement should also be treated using the recommended 60-day multidrug approach, as discussed for the treatment of severe disease.

Human-derived anthrax immune globulin (AIG) was used to successfully treat a naturally occurring inhalation anthrax case in Pennsylvania in 2006 [19]. In 2015, the FDA approved AIG for the treatment of inhalation anthrax [27]. 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.

Vaccine

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. AVA is the only licensed human anthrax vaccine in the United States [16,28]. The approved pre-exposure prophylaxis schedule consists of five 0.5-mL injections administered intramuscularly (IM) in the deltoid region, at 0 and 4 weeks and 6, 12, and 18 months [16]. Individuals with contraindications to IM injections may receive the vaccine subcutaneously. (Routine subcutaneous pre-exposure vaccination with AVA is no longer recommended due to high incidence of adverse effects, approximately 6% for local inflammation and 2% to 3% for systemic symptoms.) The vaccine is approved only for healthy, nonpregnant adults, but may be considered during pregnancy when the benefits outweigh the risks [16,19]. As noted, a 60-day course of antibiotics is recommended for everyone potentially exposed to B. anthracis spores. Anthrax vaccine is also recommended for post-exposure prophylaxis in order to extend the duration of protection for a longer period of time.

AVA supplies may be insufficient to immunize an entire population potentially exposed following a wide-area aerosol attack, as in a major city. To address this possibility, the CDC has published guidelines for a risk-based approach to handling prioritization of AVA following an intentional release of B. anthracis spores [110]. The risk for inhalation anthrax following exposure to B. anthracis spores is best estimated by the degree of exposure, not by health status or age. In the aftermath of an aerosol attack, respiratory or inhalational exposure to B. anthracis spores may be immediate (primary aerosol) or delayed (secondary aerosols). Primary aerosols are particles dispersed into the air following the initial release, while secondary aerosols arise from later environmental disturbance and re-suspension of settled particles. The degree of exposure (hence the risk of inhalation anthrax) may be less from secondary than primary aerosols because re-aerosolization produces larger-diameter particles and lower airborne concentrations. The CDC recommendations specify that the degree of exposure to B. anthracis spores should determine prioritization of AVA vaccine usage. Highest priority should be given to any individual who was potentially exposed to primary aerosolization and therefore is at highest risk for inhalational anthrax. Secondary priority should be given to those with greatest risk from re-aerosolization (i.e., in the days and weeks after an event). Exposure risks for children and adults are judged to be indistinguishable based on present knowledge. The CDC guidance includes detailed vaccine priority risk tiers based on primary exposure, risk to responders and essential workers, occupational risk groups, and progressive distance from the central affected area [110].

The approved postexposure vaccination schedule consists of three injections of 0.5 mL of the vaccine administered subcutaneously [16]. After the first injection, the follow-up doses are given two and four weeks later. Despite the associated adverse reactions, subcutaneous AVA vaccination results in rapid anti-PA antibody production at much higher levels than the IM route [16].

Infection Control

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 [9]. 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 aerosol at the time of the attack.

Standard disinfectants used for hospital infection control are effective in cleaning surfaces contaminated with infected bodily fluids. In the setting of an announced alleged anthrax release, any person coming in direct physical contact with a substance thought to be anthrax should perform thorough washing with soap and water [14].

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 [14].

PLAGUE

Background

Plague is a word that brings visions of death and destruction. Indeed, the disease caused by the gram-negative bacillus Yersinia pestis has been responsible for millions of deaths throughout history. Of the three main types of plague, bubonic, septicemic, and pneumonic, the most likely source of bioterror would be pneumonic plague [29,30]. Two other less common forms of the disease, plague meningitis and plague pharyngitis, also occur [30]. Y. pestis occurs in nature and could be isolated and cultivated in a laboratory. An aerosol attack could cause multiple cases of the pneumonic form of plague followed by secondary spread to others via exhaled droplet nuclei, resulting in rapid propagation of disease.

Historically, plague represented disaster for Africa, Asia, and Europe [29,31]. At times, there were not enough people left alive after an outbreak to bury the dead. The cause of plague was unknown, and the outbreaks caused massive panic. It was believed by many that the disease was a form of punishment. Innocent people blamed for spreading plague found themselves persecuted by panicked masses. Even now, a suspected plague outbreak can incite mass panic [18,31].

Some speculate that the 14th century plague pandemic (the "Black Death") moved west out of Asia along with the advance of the Mongol Tartar army, which was recurrently affected by plague outbreaks [32]. In fact, during the 1346 Siege of Caffa, the Tartar invaders hurled plague-infected cadavers over the city walls using catapults. At the time, it was thought that the stench of the rotting bodies was enough to kill, but in actuality the bodies may have carried infected fleas that spread the disease [11]. Those who managed to escape Caffa fled to other Italian towns, where the plague flourished. Other scholars speculate that infected fleas were brought to Caffa along the Silk Road among trade goods (e.g., furs) or foodstuffs (e.g., rice) [11].

There is evidence that Japan investigated the use of Y. pestis as a biologic weapon during World War II [11]. They reportedly worked on a plan for attacking enemy troops with the organism by releasing plague-infected fleas [9]. In 1941, a Japanese plane was observed dropping grain and wadded cotton and paper over the business center in Changteh, China [11]. Roughly one week later many people began dying of plague. A similar incident occurred in 1940 in another Chinese city, where 99 individuals died of plague. Both towns were in nonendemic regions.

The United States worked with Y. pestis as a potential biowarfare agent in the 1950s and 1960s, before the biowarfare program was terminated [29]. American forces were accused of dropping insects on North Korea during the Korean War to cause a variety of infectious diseases; however, these claims have never been substantiated [11].

Humans may acquire plague from the bite of infected fleas, contact with or ingestion of contaminated tissue, inhalation of bacteria-laden droplets from humans or animals (particularly cats) infected with plague pneumonia, or from artificially generated aerosols [11]. Bubonic plague is the most common form of infection, resulting from the bacteria being taken up by the host macrophages in the lymph nodes [29]. The "bubo" is an inflamed, enlarged, and painful lymph node. From the infected lymph node, bacteria may multiply and become bloodborne, occasionally lodging in the lungs. Patients may progress from bubonic or septicemic plague to pneumonic plague if untreated [33].

When plague becomes pneumonic, direct person-to-person transmission via bacterial aerosolization becomes a real threat [33]. Progression of pneumonic plague is rapid and, if untreated, may lead to death in a few days [29]. Pneumonic plague is rare and requires close contact for transmission to occur, except in the case of weaponization. Prompt antibiotic treatment following early diagnosis is effective against all forms of plague infection [33]. If plague is suspected, local and state health departments should be notified immediately. If pneumonic signs are present, the patient should be isolated and placed on droplet precautions.

Few physicians in the United States have ever seen a case of pneumonic plague, although Y. pestis is distributed worldwide. Techniques for mass production and aerosolization are readily available. The fatality rate of primary pneumonic plague is high, with potential for secondary spread [29]. A biologic attack with plague is considered a serious threat. With sporadic cases likely to be missed or not attributed to a deliberate act, any suspected case of plague should be reported immediately by telephone to the local health department. A sudden appearance of many patients presenting with fever, cough, a fulminant course, and high fatality rate should raise suspicion for anthrax or plague. The tentative diagnosis of pneumonic plague is favored if the cough is accompanied by hemoptysis [34].

As noted, less common manifestations of plague include plague meningitis and plague pharyngitis [29]. Plague meningitis, resulting from spread of the bacilli into the meninges, is characterized by fever, nuchal rigidity, photophobia, and headache. Plague that primarily affects the pharynx is caused by inhalation or ingestion of Y. pestis and is generally recognized by the associated cervical lymphadenopathy [29].

Diagnosis

The clinical presentation of bubonic plague is differentiated from other syndromes consisting of fever, malaise, headache, and chills by the presence of extremely painful lymph nodes [35]. The nodes involved may be axillary, inguinal, or cervical, with inguinal involvement being the most common. The nodes become fluctuant and tender and may necrose and drain. The bubo is often a discolored, necrotic mass [31]. Advanced cases of the disease may progress to secondary pneumonic or septicemic plague. The typical incubation period for bubonic plague is two to six days [29]. A history of camping in an endemic area or of contact with infected animals (usually rodents) is a clue to the diagnosis [35].

Primary septicemic plague presents in the same general manner as other gram-negative bacterial septicemias. Like bubonic plague, there is usually a high fever, chills, headache, and malaise. Gastrointestinal disturbance may be present as well. In addition, there may be progression to septic shock with meningitis, coma, and coagulopathy. Secondary pneumonic plague may also develop. Laboratory tests may be required to differentiate it from other causes of gram-negative sepsis. A clue to the diagnosis of septicemic plague is the development of thrombosis in the acral vessels, resulting in gangrene of the fingers and toes [29]. Y. pestis is likely the only gram-negative bacterium that can cause extensive, fulminant pneumonia with bloody sputum [11].

Primary pneumonic plague has an incubation period of two to four days [36]. Patients present with a very high fever of acute onset, chest pain, myalgia, a cough that may be purulent or bloody, malaise, headache, and increased respiratory and heart rates. The pneumonia may progress rapidly to multiple organ failure and death [29]. Other clinical manifestations may include coagulopathy with acral cyanosis, petechiae, dyspnea, stridor, and, finally, respiratory failure. A chest x-ray after two to three days of incubation will reveal a patchy or consolidated bronchopneumonia. Unless appropriate antibiotics are administered within 24 hours of the onset of symptoms, the death rate approaches 100% [9].

Laboratory Analysis

The initial screening for plague is by microscopic analysis of stained samples from appropriate fluids, such as lymph node aspirate, blood, sputum, and/or cerebrospinal fluid. Specimens should be taken prior to initiation of antibiotic therapy [35]. Gram stain can show a characteristic gram-negative rod with a bipolar ("safety pin") appearance that is very suggestive of Y. pestis[29]. When Wayson staining is used, the organism shows up as a light blue bacillus with dark blue polar bodies in a pink background. The nonspecific finding of increased leukocytes with a left shift is usually present.

Isolation on culture media, biochemical testing, and phage lysis (for confirmation) may be performed [11]. Culture is slow and may appear negative at 24 hours. Reference laboratories may perform polymerase chain reaction (PCR)-based assays and direct fluorescent antibody tests to detect the plague-specific Fraction 1 (F1) capsular antigen. A rapid diagnostic dipstick test, utilizing monoclonal antibodies to the F1 antigen, can provide results in as little as 15 minutes [11]. This test has proven useful in field trials in Madagascar, and two commercially available dipsticks demonstrated "diagnostic potential" in a 2011 study [37]. However, some virulent strains of Y. pestis, either natural or engineered, lack F1 protein capsules and would be undetected by these tests [38].

Treatment

The Working Group on Civilian Biodefense has developed recommendations for healthcare providers to follow in the event plague is used as a biologic weapon [29]. Rapid administration of antibiotics plus supportive care is imperative.

Clinical suspicion of plague should prompt immediate intravenous antibiotic treatment. Gentamicin and fluoroquinolones are typically first line therapy in the United States [29,39]. Aminoglycosides (streptomycin, gentamycin) and fluoroquinolones (ciprofloxacin, levofloxacin) are bactericidal against the plague bacillus. Doxycycline and chloramphenicol are bacteriostatic but effective. Historically, streptomycin was the treatment of choice for plague, but the advent of equally effective and less toxic aminoglycosides has meant that streptomycin is no longer widely available in the United States. In a retrospective analysis of 50 patients reported between 1985 and 1999, gentamicin alone or in combination with doxycycline was as effective as streptomycin for treatment of human plague [111]. The Working Group suggests adding chloramphenicol (25 mg/kg IV, four times daily) for patients with plague meningitis. Supportive therapy includes maintaining fluid levels with IV fluids and monitoring of the patient's hemodynamic status [29]. The duration of antibiotic treatment is 10 to 14 days, or until 2 days after fever subsides. Oral therapy may be substituted when the patient has improved. If fever recurs after a favorable initial therapeutic response, the patient may have secondary infection, drug fever, or a suppurative bubo that requires incision and drainage [34]. The CDC provides guidance regarding the specific antibiotic regimens for adults and children, including postexposure prophylaxis and links to additional information on antimicrobial therapy of plague [39].

In a mass casualty setting, doxycycline (100 mg orally, twice daily) or ciprofloxacin (500 mg orally, twice daily) are recommended and should be continued for 10 days [29,39]. Tetracyclines and chloramphenicol are alternative choices. The Working Group also suggests that persons with close contact to a plague patient be given antibiotics prophylactically for seven days following the last known exposure [29]. For prophylaxis, streptomycin is the drug of choice, but gentamicin can be used when streptomycin is not readily available. For prophylaxis in a mass casualty setting, doxycycline (and tetracycline), ciprofloxacin, and chloramphenicol are recommended.

Infection Control

For bubonic plague, general care includes hospitalization and use of drainage and secretion precautions for 48 hours after the start of effective therapy. With pneumonic plague, strict droplet and standard precautions against airborne spread are required until 48 hours of appropriate antibiotic therapy have been completed with favorable clinical response [29]. Anyone who was in the household or had face-to-face contact with pneumonic plague-infected patients should be provided chemoprophylaxis [34].

Private rooms are recommended when possible. If not available, patients with similar symptoms and the same presumptive diagnosis (i.e., pneumonic plague) should be in the same room. Maintain spatial separation of at least 3 feet between infected patients and others whenever possible. Avoid placement of patients with droplet precautions in the same room with immunocompromised patients. Special air handling is not necessary, and doors may remain open. Limit movement and transport of patients on droplet precautions to essential medical purposes only. Minimize dispersal of droplets by placing a surgical-type mask on the patient when transport is necessary [9,29].

Vectors and reservoirs (i.e., fleas and rodents, respectively) of disease should be eliminated to prevent a disease cycle in the local area [9]. Flea barriers should be considered for use in patient care areas.

Vaccine

Prior to 1999, a licensed, killed, whole-cell vaccine was available in the United States for use in those considered to be at risk of exposure to plague [9]. The vaccines that have been used have not been effective against pneumonic plague [29,40]. At this time, there is no vaccine available, although research is taking place to develop one that is suitable. Much of this research is occurring outside the United States; however, vaccines have been developed and tested by the U.S. Army Medical Research Institute of Infectious Diseases [9]. A fusion protein vaccine has been found to protect mice for up to one year.

TULAREMIA

Background

Tularemia is primarily a zoonotic 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 [41]. Humans can become infected by ingestion of or contact with contaminated water, food, or soil. Transmission can also occur through inhalation of aerosols, handling of infected animal tissues or fluids, and the bites of infective arthropods (usually ticks). Person-to-person transmission has never been reported [41,42].

Tularemia is one of the most infectious diseases known; as few as 10 F. tularensis bacteria can cause disease in humans [41,42]. Consequently, it has been widely exploited as a weapon of bioterror. The Japanese studied it for use between 1932 and 1945, the Soviet Union may have used it on the Eastern Front in World War II, and the United States possessed a 450 kg weaponized dry-form stockpile until the use of biologic arsenals was eliminated [41,43]. The most probable dissemination of F. tularensis as a weapon would be as an aerosol [42]. In fact, epidemics have occurred after harvests in Northern Europe, where the organism became aerosolized and infected hundreds of people. The organism is quite hardy and can survive for prolonged periods of time in water, mud, and animal carcasses. Even frozen, F. tularensis is highly infectious, and laboratory workers have become infected while inspecting incubation plates [41]. It is estimated that a 50 kg aerosolized release over a 5 million inhabitant metropolitan area could infect 250,000 people and kill nearly 20,000 [43].

Diagnosis

There are several classification systems for clinical tularemia. One such system categorizes tularemia as either ulceroglandular (occurring in the majority of patients) or typhoidal [44,45]. Ulceroglandular disease is characterized by lesions on the skin or mucous membranes (including conjunctiva), lymph nodes larger than 1 cm, or both. Typhoidal tularemia describes systemic manifestation of the disease without skin or mucous membrane lesions [41,45]. In addition to these two types, pneumonic tularemia, caused by inhalation and primarily manifesting as pleuropneumonic disease, also occurs [41,45]. 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 [41]. This type of tularemia is caused by inhalation or ingestion of bacilli and may involve significant gastrointestinal symptoms. It is believed that typhoidal tularemia would be most prevalent during an act of bioterrorism [44].

The incubation period is usually 3 to 6 days (range: 1 to 21 days), although aerosol exposures have been shown to result in incapacitation in the first day [41,44]. Symptoms may include fever with chills, headache, myalgia, sore throat, anorexia, nausea, vomiting, diarrhea, abdominal pain, and cough [44]. Patients may develop tularemia sepsis, which can be fatal. This syndrome manifests with hypotension, respiratory distress syndrome, renal failure, disseminated intravascular coagulation, and shock [44].

Pneumonic Tularemia

Pneumonic tularemia results from inhalation of infected aerosols or spread of existing untreated disease. Hemorrhagic inflammation of the airways is an early sign [41]. Radiologic studies show pleuritis with adhesions and effusions and peribronchial infiltrates; hilar lymphadenopathy is also common [41,44]. These signs, however, are not always present. Patients may develop acute respiratory distress syndrome and require mechanical ventilation [44].

Ulceroglandular Tularemia

Ulceroglandular tularemia is generally caused by an arthropod bite or handling a contaminated animal carcass [41,45]. 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 [41,45]. Lymphadenopathy develops in 85% of patients [44]. The nodes are usually tender and 0.5–10 cm in diameter [44,45]. Affected nodes may become fluctuant, rupture, or persist for months to years [44]. In most cases, there is a single ulcer, 0.4–3.0 cm in diameter, with raised borders. Other symptoms include fever, chills, headache, and cough [44].

Ulceroglandular tularemia can also be complicated by oculoglandular disease or oral/pharyngeal involvement. Oropharyngeal tularemia is caused by ingestion of contaminated food, water, or droplets and results in severe throat pain, exudative pharyngitis, stomatitis, or tonsillitis [44,46]. Oculoglandular tularemia, caused by direct contamination of the eye, is characterized by purulent conjunctivitis and pre-auricular adenopathy on the involved side of the face [41,45].

Laboratory Analysis

There are several biologic variants or subspecies of F. tularensis. Type A is considered to be more virulent, while the European variant, F. tularensis biovar palaearctica, typically causes a more mild form of the disease [41]. Both types can be identified with 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, making it difficult to identify [47]. Due to the strong possibility of laboratory workers becoming infected, routine analysis should take place in biosafety level-2 (BSL-2) facilities and handling of identified cultures should be in a BSL-3 lab [41,45]. F. tularensis can be grown in appropriate cultures but may not be identifiable until after 48 hours. Antibody or other serologic tests and/or cultures are necessary for confirmation of the diagnosis. Antibody detection assays include ELISA, tube agglutination, and microagglutination, but significant antibodies may not appear until 10 to 14 days after the onset of the illness [44,45]. A positive DFA test on a culture can confirm the diagnosis.

Treatment

All forms of tularemia may be treated with streptomycin or, alternatively, gentamicin for 10 to 14 days [9,41,48]. Gentamicin may be more readily available and easier to administer. Also, because streptomycin has been associated with ototoxicity in fetuses, gentamicin is the drug of choice for pregnant women [41,44]. In a mass casualty situation, doxycycline or ciprofloxacin are preferred [41]. Doxycycline should be continued for 14 to 21 days, due to risk of relapse [9]. The use of chloramphenicol is generally discouraged due to the associated serious side effects; however, the Working Group states that it is an alternative, although not FDA approved [41]. Ciprofloxacin is suggested by the Working Group for mass casualty and confined cases, although it also is not FDA approved [41]. Dosages are similar to those for plague, except chloramphenicol, the dose for which is 15 mg/kg IV, four times daily [29,41].

Cases of tularemia meningitis require special treatment, as the penetration of streptomycin or gentamicin into cerebrospinal fluid is suboptimal. Chloramphenicol 25 mg/kg IV, four times daily, plus an aminoglycoside (particularly streptomycin) is the recommended treatment for meningeal infections [44,49]. Doxycycline has also been used to treat tularemia meningitis [49].

Infection Control

Because tularemia is not believed to be transmissible from person to person, respiratory isolation rooms are not required [44]. In general, standard precautions are sufficient [41]. Ulcers, when present, should be covered and contact isolation maintained, as F. tularensis remains present in such lesions for more than a month [44]. All postmortem procedures likely to cause aerosols should be performed using respiratory precautions or avoided altogether [18,41,44]. It must be reinforced that significant personal safety precautions be taken when handling tissues or other samples possibly containing F. tularensis because it is the second most common cause of laboratory-associated infections in the United States [47,50].

Vaccine

A live, attenuated tularemia vaccine was available as an investigational new drug (IND), but it was not approved by the FDA [41]. An attenuated vaccine has been used in the former Soviet Union to immunize tens of millions of people [51]. The live vaccine strain has proven effective in preventing laboratory-acquired tularemia, although its effectiveness in preventing pneumonic tularemia is limited. The degree of protection depends upon the magnitude of the challenge dose [9,41]. Research is being conducted to find a suitable vaccine that can be used widely in the United States [52]. Currently, there is no effective vaccine available [9].

6. VIRUSES

SMALLPOX

Background

It is estimated that smallpox killed 500 million people worldwide in the 20th century, but a successful ring vaccination campaign ended outbreaks by 1980. [11]. The variola virus (the smallpox causative organism) is quite stable in the environment and is highly infectious when spread by the respiratory route. It is also spread easily through direct contact. The likelihood of contracting smallpox approaches 90% for susceptible persons exposed to someone with active infection. The case fatality rate is approximately 30% among those who have not been vaccinated [112].

Variola can be used as a biologic weapon in aerosol form or deposited onto surfaces. Because smallpox vaccination of the general population in the United States was discontinued in the 1980s, the use of the smallpox virus as a weapon constitutes a large threat, especially because certain countries may be harboring stockpiles of the agent.

The use of smallpox as a biologic weapon has a long history. In 1520, the Aztecs captured one of Cortés' men who was infected with smallpox. The resulting epidemic aided the Spaniards in defeating the Aztecs.

It is commonly believed that contaminated blankets were given to American natives by the U.S. Army to assist in their conquest during the French and Indian War [53,54]. Although it is clear that this approach was discussed among military officers, it is unclear whether intentional infection through the use of "smallpox blankets" was ever carried out. Some scholars propose other routes of transmission leading to smallpox outbreaks among indigenous Americans, such as raids on infected European settlements by natives, non-military European contact, grave robbing, and contact with Mexican traders [54].

Diagnosis

Variola virus belongs to the family Poxviridae, subfamily Chordopoxvirinae, and genus Orthopoxvirus. It is a single, linear, double-stranded DNA molecule of 140–375 kb pairs. It replicates in cell cytoplasm. Electron micrographs show that variola viruses are shaped like bricks. This brick shape distinguishes variola from varicella zoster, the virus that causes chickenpox and shingles [55].

Smallpox is transmitted from one person to another by droplets. Droplets containing the variola virus can be transmitted through face-to-face contact while talking, singing, coughing, or sneezing. It is also transmitted by saliva through sharing food or drink and kissing on the mouth. These activities contribute to a more vulnerable population than in the days before eradication.

The virus is not shed during the incubation period, which can be from 7 to 17 days but most commonly is 10 to 14 days (Figure 1). During the incubation period, the virus enters the respiratory tract, seeds the mucous membranes, passes quickly to the lymph nodes, and multiplies in the reticuloendothelial system [55]. It is believed that only a few virions (virus particles) are sufficient to cause infection [56].

Figure 1: COURSE OF SMALLPOX (VARIOLA)

Source: [55]

The prodromal phase, which follows the incubation period, lasts from one to four days, begins abruptly, and is characterized by a fever of at least 38.5–40.5 degrees C (101–105 degrees F) and at least one of the following [57,58,59]:

- Prostration

- Severe (splitting) headache (90%)

- Backache (90%)

- Chills (60%)

- Vomiting (50%)

- Delirium (15%)

- Abdominal colic (13%)

- Diarrhea (10%)

- Convulsions (7%)

At the end of the prodromal phase (about 24 hours before the skin rash erupts), minute red spots (the enanthem) appear on the tongue and soft palate. The patient may complain of a sore throat, as lesions may also be present lower in the respiratory tract. When the lesions in the mouth and pharynx open and release the virus, the patient is contagious. Patients are most contagious for the first week but can still transmit the disease until all the epidermal scabs from the skin lesions have fallen off, usually in approximately 21 to 28 days.

The smallpox rash erupts at the end of the prodrome. A few lesions usually appear first on the face, especially on the forehead. These are called the "herald spots." Occasionally, the rash is first seen on the forearms. Lesions tend to appear on the proximal portions of the extremities and the trunk, and then on the distal portions of the extremities. However, the rash usually progresses so quickly that it is apparent on all parts of the body within 24 hours and the patient does not notice how the rash progressed. Normally, more lesions appear over the next one or two days, possibly followed by a few fresh lesions later. Generally, the rash is distributed in a "centrifugal" pattern. The rash is most dense on the face and denser on the extremities than on the trunk. It is more prominent distally than proximally and on the extensor rather than on the flexor surfaces. There may also be lesions on the palms and soles [57,59].

The rash of smallpox passes through stages of macules, papules, and vesicles. Mature smallpox lesions are round, well-circumscribed vesicles that are deep-seated and firm. As they continue to develop, the lesions become umbilicated, having a central "naval-like" depression. The more confluent the lesions, the poorer the prognosis [59]. Another distinguishing feature of the smallpox rash is that the lesions on any specific area of the body are all in the same state of development, meaning that they are all simultaneously vesicles, pustules, or umbilicated lesions [59]. In contrast, the rash of chickenpox starts as a vesicle on top of erythema. Chickenpox lesions arrive in "crops," so in any one area of the body there will be a variety of vesicles, pustules, and crusts (scabs). The palms and soles are rarely involved, and patients are rarely toxic or moribund [58].

There are many possible secondary complications in smallpox. Most are due to viral activity in an unusual site or secondary bacterial infections. Smallpox can affect several systems. The skin lesions can become infected with bacteria, but the broad-spectrum antibiotics available today and good hygiene will prevent many of these secondary infections. Mild conjunctivitis at the time of the skin eruptions is part of the disease; however, corneal ulceration and keratitis may occur, causing blindness. Mostly, corneal lesions occur in patients with confluent or semiconfluent rashes. The joints may be involved, causing arthritis in approximately 1.7% of survivors [60]. The elbow is the most commonly affected joint. Respiratory complications may develop around day 8, and pulmonary edema is fairly common in hemorrhagic and flat-type smallpox [60]. However, cough is a rare symptom in smallpox. Encephalitis occurs in 1 in 500 cases, usually appearing between day 6 and 10 [60]. If the patient recovers, the recovery is slow but usually complete. The sequelae in persons who recover from smallpox, in order of frequency, are facial pockmarks, blindness (due to corneal scarring), and limb deformities (due to osteomyelitis and arthritis) [57].

Laboratory Analysis

Laboratory analysis for the distinct diagnosis of smallpox is not always easy because the pox viruses can only be rapidly distinguished from one another by PCR assay or electron microscopy (EM) [61]. For EM, skin samples (e.g., scrapings from papules, vesicular fluid, pus, or scabs) may be collected. This can provide rapid identification of the pox viruses, including smallpox, cowpox, and monkeypox. Skin samples may also be used for agar gel immunoprecipitation, immunofluorescence, or PCR assay. In the event of known exposures, early postexposure (0 to 24 hours) nasal swabs and induced respiratory secretions may be collected for viral culture, fluorescent antibody assay, and PCR assay. After two days, blood may be collected for viral culture. Serologic tests may be useful for confirmation or early presumptive diagnosis [61]. The CDC has outlined the type of specimen to be collected according to the stage of the disease [62].

Treatment

The treatments for smallpox are limited [63,64,65]. Therefore, the development of smallpox vaccine has been a significant medical achievement. The severity of disease can be greatly lessened or prevented by administration of vaccine up to four days postexposure [63]. There is some evidence that vaccination four to seven days postexposure can prevent or somewhat lessen the severity of the disease [64].

Because there have been no natural cases of smallpox since 1977, the antivirals currently available have never officially been tested on human smallpox infections. In 2018, the FDA approved the first medication for the treatment of smallpox—tecovirimat [106]. The efficacy of oral tecovirimat was established in two placebo-controlled, nonhuman primate models (monkeypox and rabbitpox) in which treatment was associated with greater than 90% survival [113]. The same investigators included a randomized placebo-controlled safety trial in human adult volunteers, showing that tecovirimat was well-tolerated and that most reported adverse events were mild. The antiviral agent cidofovir (used to treat cytomegalovirus retinitis in immunocompromised patients) has also been used to effectively reduce morbidity and mortality of human smallpox in animal models and has been used to treat severe adverse reactions to the smallpox vaccine [65,66]. Cidofovir may only be used under IND protocol for the treatment of either vaccination reaction or smallpox infection. Kidney failure has occurred in some patients with only one or two doses of cidofovir [67].

Vaccinia immune globulin (VIG) has been used in the past to treat smallpox and was administered when vaccinating patients at high risk for an adverse reaction (e.g., those with inflammatory skin conditions); a new purified IV form (VIG-IV) is available from the CDC [66]. Indications for use include postvaccination moderate-to-severe generalized vaccinia, progressive vaccinia, eczema vaccinatum, and certain accidental implantations; VIG-IV is the recommended first-line treatment for these conditions [66]. Concomitant use of VIG-IV is not recommended when vaccinating susceptible individuals because efficacy has not been studied in clinical trials and stores of the antibody are low [66]. For active infections, VIG-IV may shorten the duration of the disease [68].

Management of active infections relies heavily on supportive care. This consists of [60]:

- Skin care

- Monitoring for and treatment of complications

- Monitoring and maintaining fluid and electrolyte balance

- Isolation of the patient to prevent transmission of variola virus to nonimmune persons

Infection Control

Smallpox patients should be considered infectious until scabs separate, usually about three weeks from the time of infection. Patients should be handled using standard precautions, and isolation with droplet and airborne precautions should be exercised for infected individuals and all contacts for a minimum of 16 to 17 days following exposure. In cases of mass casualties, isolation in the home or other non-hospital facilities should be considered where possible, as the risk for transmission is high and few hospitals will have enough negative pressure rooms for proper isolation. Immediate vaccination, if available, should be given to all medical personnel. Outside of the hospital setting, patients and household contacts should wear an N95 mask. Caregivers should wear disposable gowns and gloves as well. Bed linens, clothing, and other exposed articles must be sterilized or incinerated [61].

Vaccine

As of 2020, there are two licensed smallpox vaccines [69]. Until 2007, the only available vaccine was Dryvax (approved by the FDA in the early 1930s), which was manufactured from a sample of the New York City Board of Health strain of vaccinia grown on calf skin and freeze dried for storage and use. However, Dryvax is no longer manufactured [69]. In 2007, a second-generation smallpox vaccine, ACAM2000, was approved by the FDA [69,70]. This vaccine is derived from a clone of Dryvax, purified and produced using cell culture technology rather than by using live animal models [69,71]. The biologic profile is similar to Dryvax, and the vaccine has equivalent efficacy and tolerability. A third-generation smallpox vaccine, IMVAMUNE, was approved for manufacture by the FDA in 2010, and as of 2014, at least 20 million doses had been delivered to the CDC Strategic National Stockpile (SNS) [72]. The IMVAMUNE vaccine is generated from a highly attenuated, replication-deficient vaccinia strain (modified vaccinia Ankara [MVA] strain) [70]. Aventis Pasteur Smallpox Vaccine is an investigational vaccine stored in the SNS. It has an efficacy and safety profile anticipated to be similar to ACAM2000. It would be made available under an IND in case of a smallpox emergency in circumstances where ACAM2000 is depleted, not readily available, or contraindicated [73]. A second MVA-based vaccine against smallpox and monkeypox was approved in 2019 and is included in the SNS [107].

It should be noted that although these vaccinations are called "smallpox vaccinations," they do not contain any smallpox virus and cannot transmit the disease. However, the vaccines can transmit vaccinia and can produce life-threatening adverse events in some cases [64]. The FDA has required "black box" warnings to be included with the smallpox vaccines due to the possibility of encephalitis, myopericarditis, ocular complications, and skin and systemic infections (i.e., progressive vaccinia, generalized vaccinia, severe vaccinial skin infections, and erythema multiforme major) [74]. The goal of the third-generation vaccine is to provide complete protection from the disease (i.e., equal to that of ACAM2000) while increasing the safety profile. It is estimated that in a widespread vaccination scenario, approximately 25% of the population would be at risk for developing complications of ACAM2000 [70,72]. In a safety study of an earlier version of MVA conducted in Germany, 120,000 people were given the vaccine with few observed complications. The efficacy of IMVAMUNE in humans is thought to be equivalent to that of ACAM2000 based on animal testing using the FDA "animal rule," which states that animal studies to verify efficacy are valid when it is impractical or unethical to use human test subjects [70]. Clinical trials to assess the safety of IMVAMUNE are ongoing.

The "ring vaccination" strategy will be the first-line strategy in a smallpox emergency. It vaccinates the contacts of patients with confirmed smallpox and also those who are in close contact with those contacts. This may include [75,76]:

- Face-to-face close contacts (≤6.5 feet or 2 meters) or household contacts (without contraindications to vaccination) to smallpox patients after the onset of the smallpox patient's fever, and nonhousehold members with three or more hours of contact with a case with rash

- Persons exposed to the initial release of the virus (if the release was discovered during the first generation of cases and vaccination may still provide benefit)

- Persons involved in the direct medical care, public health evaluation, or transportation of confirmed or suspected smallpox patients

- Laboratory personnel involved in the collection and/or processing of clinical specimens from suspected or confirmed smallpox patients

- Other persons who have a high likelihood of exposure to infectious materials (e.g., personnel responsible for hospital laundry, waste disposal, and disinfection)

- Personnel involved in contact tracing and vaccination; quarantine/isolation or enforcement; or law-enforcement interviews of suspected smallpox patients

VIRAL HEMORRHAGIC FEVERS

Background

The viral hemorrhagic fevers (VHFs) are a group of diseases that can be transmitted to humans from animal reservoirs or arthropod vectors. There are four families of RNA viruses that are known to cause the infections: Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae [77]. The diseases produced by these organisms vary according to the type, but in general, they present as very contagious hemorrhagic fevers with almost no known cure. Person-to-person transmission has been well documented for almost all of the VHFs, with the exception of the flaviviruses and Rift Valley fever [77].

The associated reservoirs and vectors are known for all of the virus types except the filoviruses (Table 1). In addition to natural disease potential, many of the VHF agents are potential biologic warfare threats. These viruses are highly infectious by aerosol, and they are associated with high morbidity and, in some cases, high mortality. They have been shown to replicate sufficiently well in cell culture to permit use as a weapon [77]. Some of these agents are known to have been weaponized by Russia and the United States. The filovirus types, which include Ebola and Marburg viruses, as well as some of the arenavirus types, specifically Machupo and Junin, were stockpiled by the former Soviet Union and Russia until 1992 [77]. Yellow fever (a flavivirus), Rift Valley fever (a bunyavirus), and Argentine hemorrhagic fever (an arenavirus) were developed as weapons by the United States prior to the program termination in 1969. More recently, the Japanese cult group, Aum Shinrikyo, attempted to obtain Ebola, a filovirus, for use as a bioweapon [77]. Hantavirus and dengue fever are sometimes included in this group, but they are more common as naturally occurring diseases in the United States and are not considered major bioterror threats. VHFs are frightening to the public and frustrating to the medical profession. Steps to ensure containment are needed when studying these viruses, and therefore progress in understanding them has been slow. The ease of contagion, lack of curative drugs, and vague initial presentation warrant their inclusion in this discussion.

Table 1: VIRAL HEMORRHAGIC FEVERS (VHFs) OF BIOWARFARE INTEREST

Virus Type

Name and Species

Region

Vector

Incubation Period (Days)

Treatment

Arenaviridae

Argentine HF (Junin)

South America

Rodent

7 to 14

Ribavirina and supportive

Bolivian HF (Machupo)

South America

Rodent

9 to 15

Ribavirina and supportive

Brazilian HF (Sabia)

South America

Rodent

7 to 14

Ribavirina and supportive

Venezuelan HF (Guanarito)

South America

Rodent

7 to 14

Ribavirina and supportive

Lassa Fever (Lassa)

West Africa

Rodent

5 to 16

Ribavirina and supportive

Unnamed HF (Whitewater Arroyo)

North America

Rodent

Unknown

Ribavirina and supportive

Bunyaviridae

Crimean-Congo HF

Africa, Asia, Middle East, Eastern Europe

Tick

3 to 12

Ribavirina and supportive

Rift Valley HF

Africa, Middle East

Mosquito

2 to 6

Ribavirina and supportive

Filoviridae

Ebola HF

Africa

Unknown

2 to 21

Supportive

Marburg HF

Africa

Unknown

2 to 14

Supportive

Flaviviridae

Dengue HF

Africa, Asia, Pacific, Americas

Mosquito

Unknown

Supportive

Kyanasur Forest Disease

India

Tick

2 to 9

Supportive

Omsk HF

Central Asia

Tick

2 to 9

Supportive

Yellow Fever

Africa, Americas

Mosquito

3 to 6

Supportive

aIntravenous ribavirin is available as an investigational new drug (IND) in the United States.

Source: [11,74,77,78,79]

Diagnosis

There is a variety of clinical presentations of VHFs, and not all patients show the classic signs and symptoms of the diseases. However, common initial clinical manifestations include fever, hypotension, bradycardia, tachypnea, conjunctivitis, and pharyngitis [77]. The overall incubation period can range from 2 to 21 days, which is followed by pronounced headache, high fever, nausea, abdominal pain, and diarrhea [77]. Hepatic involvement is common, but clinical jaundice is usually only seen in Rift Valley fever and yellow fever. The filovirus, flavivirus, and bunyavirus diseases usually have an abrupt onset, while the arenavirus diseases demonstrate a more gradual and insidious pattern of signs and symptoms [77].

The diseases progress to advanced stages, in which hemorrhagic diathesis is evident and includes petechiae, mucous membrane and conjunctival hemorrhage, hematuria, hematemesis, and bloody diarrhea [77]. Central nervous system dysfunction may occur, with convulsions, delirium, and coma. Eventually, there may be evidence of intravascular coagulation and circulatory collapse, followed by death [77].

A high index of suspicion is required because of the similarity of the initial presentation to so many other diseases, especially if the usual risk factors are not evident (as would be the case in a biologic warfare attack).

Laboratory Analysis

Only the most secure laboratories are able to process any tissues, blood, or secreta that may be obtained for clinical analysis [77]. Of course, any suspected cases must be immediately reported to the appropriate public health and other government agencies [80].

The methods of detection include antigen-capture ELISA, PCR, and viral isolation. The most useful methods are reverse transcriptase PCR analysis and antibody detection [77]. The ELISA test usually does not become positive until late in the disease. Convalescent serum showing a four-fold rise in immunoglobulin G (IgG) titer or the presence of IgM can help make a presumptive diagnosis.

Treatment

General principles of supportive care apply to the hemodynamic, hematologic, pulmonary, and neurologic manifestations of VHF regardless of the specific etiologic agent. Patients are either moribund or recovering by the second week of illness, but only intensive care will save the most severely ill. Fluid resuscitation and invasive hemodynamic monitoring should be used, but extra precautions should be taken with needles due to the risk for nosocomial transmission of viral agents. Due to the bleeding associated with VHFs, IM injections, aspirin, and anticoagulants should be avoided [9].

There is no available cure for the VHFs. In fact, there are no medications FDA-approved for the treatment of these diseases [77,79]. Ribavirin (not commercially available), a nucleoside analog, has shown some benefit for the management of arenavirus and bunyavirus infections; however, it requires an emergency IND (EIND) application for compassionate use and availability is limited [77]. It has not been an effective agent, in vivo or in vitro, against the filoviruses or flaviviruses. Convalescent plasma (also only available as an EIND) may be effective in the treatment of Argentine or Bolivian VHFs [9]. The Working Group has additional recommendations available in the event of a contained or mass casualty situation [77].

In an emergency outside regular business hours, IV ribavirin can be obtained through the FDA by telephone without an EIND application (through the FDA Emergency Coordinator at 1-866-300-4374) [81]. The FDA Division of Anti-Viral Products Emergency Coordinator should be contacted to approve its shipment and use, and the manufacturer of IV ribavirin (Valeant Pharmaceuticals, 1-866-246-8245) should be contacted to request the drug.

Infection Control

The Working Group has made some very stringent recommendations about personal safety for those who must come in contact with victims of VHFs. They stress that these diseases can be very easily transmitted and suggest the following protective measures to ensure that absolutely no skin is exposed [77,82,83]:

- Strict adherence to hand hygiene

- Double gloves

- Impermeable gowns

- N95 masks or air purifying respirators

- Surgical hood completely covering the neck and hair and worn over the N95 mask

- Negative isolation rooms with 6 to 12 air changes per hour

- Leg and shoe coverings

- Outer midcalf apron in cases of vomiting/diarrhea

- Face shields

- Goggles

- Restricted access for all except necessary personnel

- All VHF patients housed together

- Dedicated medical equipment that stays with the patient

- Environmental disinfection with appropriate materials

In addition, all personal protective equipment must not allow penetration of fluids. The CDC recommends that patients who have died as a result of a VHF should be handled as little as possible [80]. Remains should not be embalmed, and cremation or burial (in a sealed casket) should take place as soon as possible.

Vaccine

In the United States, there are no licensed vaccines for any of the VHFs, with the exception of yellow fever; some additional VHF vaccines are available in other countries (e.g., Candid #1, an Argentine hemorrhagic fever vaccine available in Argentina). The yellow fever vaccine, 17D, was developed when outbreaks caused widespread disease among workers and military forces in endemic areas [9]. The vaccine is a live attenuated preparation that is very effective when administered to travelers and those in endemic areas [77]. It is not available in large amounts and would not be useful in preventing disease in multiple areas or in large populations. It would also not be useful in a postexposure scenario because yellow fever has an incubation period significantly shorter than the time it takes for the inoculated person to develop the neutralizing antibodies [77].

7. TOXINS

BOTULINUM TOXIN

Background

Botulinum toxins gained widespread recognition as a result of the introduction of botulinum Type A (Botox) into the field of cosmetology. The toxins have been medically significant for many years due to the serious and often fatal consequences of ingesting improperly canned or bottled foods. 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 serotype A having an estimated toxic dose of 0.001 mcg/kg of body weight oral or injected and 0.07 mcg/kg of body weight inhaled [84]. These neurotoxins act by binding at the presynaptic nerve terminals and at the cholinergic autonomic sites. They also block acetylcholine transmission, causing skeletal muscle weakness and paralysis as well as bulbar palsies [85,86]. If effectively dispersed in aerosol form, 1 gram of botulinum toxin has the potential to kill more than 1 million people [87].

Human disease is caused by strains A, B, E, and rarely F and G [84]. The type A strain is the most virulent and is the type most commonly found in the United States, primarily in the eastern part of the country [86]. The disease can also be caused by wounds infected with C. botulinum, 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 transmission of botulism from person to person. The airborne transmission of botulism does not occur naturally, but if produced as a weapon or by accident in a laboratory, its effects would be catastrophic. From a study of three human cases of accidental inhalation botulism, it is postulated that inhaled C. botulinum will cause a similar symptom complex as the foodborne disease [88].

Diagnosis

The typical incubation period for foodborne botulism is 12 to 72 hours but may range from 2 hours to 8 days, depending on the dose and strain [11,84]. Serotype E infection symptoms typically have a more narrow median range (within 24 hours) than that of serotypes B (0 to 5 days) and A (0 to 7 days). The early symptoms of the disease are nausea, vomiting, abdominal cramps, and diarrhea; other symptoms include sore throat, dry mouth, dizziness, fatigue, and constipation [11]. Initial neurologic symptoms include diplopia, blurred vision, ptosis, and photophobia [86]. 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, which, combined with associated mechanical ventilation secondary infection, is the typical cause of death [11,87]. Interestingly, the patient usually remains alert and afebrile, although there may be bulbar palsies such as dysarthria, dysphagia, diplopia, 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 have been evident in most patients within 24 hours of the ingestion of the tainted item [84,86]. In the few documented cases of inhalation botulism, patients displayed dysphagia, dizziness, unsteady gait, and ocular paralysis [87]. The reported case fatality rate for botulism is about 5% [89]. Early deaths result from respiratory failure that supervenes before the diagnosis; late deaths are usually related to complications of prolonged paralysis.

Clinical Tests and Laboratory Analysis

Some cases of botulism might be confused with disorders such as Guillain-Barré syndrome, myasthenia gravis (MG), Lambert-Eaton syndrome, or tick paralysis [84]. It has been suggested that the edrophonium (Tensilon) test may be used to differentiate botulism from MG, but because it may be transiently positive in botulism, its actual usefulness is in doubt [89]. The Tensilon test requires that the patient have a sign, such as ptosis, which can be reversed with an intravenous injection of a cholinesterase agent like edrophonium. A thorough physical examination can rule out tick paralysis. The absence of carcinomas may rule out Lambert-Eaton [11]. Electromyography (e.g., repetitive nerve stimulation showing facilitation, usually occurring only at 50 Hz) may be used to distinguish botulism from MG or Guillain-Barré but not Lambert-Eaton [11]. In many cases, the distinctive paralysis associated with botulism is the defining characteristic [87].

Laboratory confirmation of botulism requires the demonstration of botulinum toxin in samples of serum, stool, or suspect food source [89]. Positive stool or wound culture for C. botulinum or other subtypes provides strong supportive evidence. The preferred test for botulinum toxin in clinical specimens is the mouse neutralization bioassay [84,86]. This assay can detect as little as 0.03 ng of botulinum toxin within one to four days of exposure.

Survivors usually do not develop an antibody response to the toxin due to the subimmunogenic amount of material required to produce major symptoms. In addition, cultures are not helpful in cases of inhalation botulism. As opposed to ingested botulinum toxin, inhaled toxin may not be identified in serum or stool. However, an ELISA test might possibly detect the toxin on nasal mucous membranes within 24 hours after inhalation [86].

Treatment

Because the initial diagnosis of botulism is based on clinical symptoms, the CDC stresses that treatment should not be delayed pending laboratory confirmation [89]. 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 two to eight weeks (or longer) and feeding by enteral tube or parenteral nutrition [84,86,87].

In 2013, the FDA approved the heptavalent botulinum antitoxin (HBAT), which is now available from the CDC and is the only botulinum antitoxin available in the United States for noninfant cases and for cases of infant botulism caused by nerve toxins other than types A and B [87,90,91]. However, as with previous antitoxins, it only halts the progression of future symptoms and does not reverse the existing clinical presentation. HBAT, which is effective against all seven known serotypes, superseded the licensed bivalent preparation for types A and B and the investigational type E antitoxin [90]. Botulism cases should be immediately reported to the state health department, which will contact the CDC to arrange antitoxin delivery. Additional consultation is available from the CDC botulism duty officer (1-770-488-7100). Botulism immune globulin for infants (BabyBIG) is still available through the California Infant Botulism Treatment and Prevention Program for the treatment of infant botulism types A and B [90].

HBAT is of equine origin, which means that skin testing must be performed to help prevent serum sickness or anaphylaxis in susceptible individuals [86]. Treatment does not need to be modified for special groups. In cases of exposure to large amounts of the toxin, patients' serum should be retested after antitoxin administration to ensure adequate treatment [87].

It should also be noted that antitoxin would need to be administered prior to the development of significant symptoms (up to 48 hours postexposure) in the general public to be effective in the event of an aerosolized botulinum biowarfare attack [11]. HBAT is not considered effective after the onset of respiratory failure and may not be effective in cases when patients present with respiratory distress. One review found that even with antitoxin therapy in foodborne cases, shortness of breath at presentation was associated with a mortality rate of 94% [92].

Infection Control

Botulism poisoning is not an infection. It is not transmitted from person to person, and only standard precautions are required to control its spread [89]. As botulism poisoning is not transmittable, patients do not need to be isolated. A 10% bleach solution is approved by the Occupational Safety and Health Administration (OSHA) for decontamination purposes to kill the botulinum spores [86].

RICIN

Background

In 2003, ricin was discovered at a postal facility in South Carolina, and in 2004, letters containing the toxin were sent to two members of the U.S. Senate [93,94]. In 2008, ricin that was subsequently linked to a possible bioterrorism plot was found in a hotel room in Nevada [95]. In April 2013, three letters (intended for the President, a U.S. Senator, and a Mississippi judge) were confirmed positive for ricin by the FBI. Nearly 20 incidents involving ricin have occurred in the United States since 1980. This potent agent is considered a low-level risk for use in biowarfare; however, it is obvious that it can and has been used as a weapon of terror. Some reports have indicated that quantities of ricin were found in the caves evacuated by al-Qaeda militants in Afghanistan [94].

Ricin is a protein toxin extracted from the bean of the castor plant, Ricinus communis, either by direct isolation of the toxin or as a byproduct of the production of castor oil from the castor bean [8]. The mechanism of action is an inhibition of protein synthesis, specifically RNA ribosomal damage that leads to cell necrosis [8].

For use as a biologic weapon, ricin can be made into an aerosol for widespread airborne dissemination (though the particle size must be less than 5 microns to be effective) [96]. In addition, it can also be used in powder or liquid form to contaminate water or food, or it can be injected or penetrated through the skin to induce a parenteral exposure [8,47]. These exposures are far less lethal than inhalation.

Ricin is on the CDC's B list of agents as a potential bioterrorism weapon [97]. Although it is relatively easy to make in small quantities, the toxin is considered a moderate threat because it is generally unsuitable for producing mass casualties.

Diagnosis

The gastrointestinal signs and symptoms of oral ricin poisoning include abdominal pain, vomiting, gastrointestinal hemorrhage with bloody diarrhea, fluid and electrolyte depletion, hypotension, tachycardia, and eventually hepatic, splenic, pancreatic, and renal necrosis [47]. The incubation period depends on the amount ingested and is usually four to six hours, although some cases have been seen with symptoms beginning within 15 minutes [8]. As noted, the initial dose can be as low as 1 mg, but this is not commonly seen. Death can occur in three to five days from organ failure and hypovolemic shock [47]. However, the death rate for ricin (or at least castor bean) ingestion is less than 2% and depends greatly on the dose [11].

The signs and symptoms of aerosol exposure to ricin include rapid onset of chest pain, fever, dyspnea, and weakness [47]. A cough is usually present, along with conjunctival irritation, optic nerve damage, diaphoresis, arthralgias, and the signs and symptoms seen with oral ingestion of ricin. Pulmonary edema, acute respiratory distress syndrome, and death can occur if the dose inhaled was sufficient to produce these major problems [47].

Parenteral exposure would not be expected as a means of bioterror attack. The presentation would be similar to sepsis, with fever, headache, dizziness, nausea, anorexia, hypotension, and abdominal pain [8]. There may also be tissue necrosis at the injection site [8].

The laboratory diagnosis includes analysis of nasal or throat swabs for toxin within 24 hours of exposure or toxin assay for antibody response in a serum sample obtained within one to two days after exposure. IgM and IgG increases six days after exposure [47].

Management

There is no specific treatment or antidote for ricin poisoning [47]. Supportive treatment, including pulmonary care and fluid replacement, is required. A single dose of charcoal may be considered for patients who are not vomiting, although the efficacy is unknown [8]. Patients who have been exposed to aerosolized ricin may require oxygen, bronchodilators, endotracheal intubation, and supplemental positive end-expiratory pressure [8]. Some patients may require long-term hemodialysis or, in severe cases, renal transplant [98]. Close scrutiny of all affected patients must be continued for several days [47].

Vaccine

In 2004, the FDA approved the University of Texas Southwestern Medical Center to begin safety trials in humans of an experimental ricin vaccine. The vaccine, RiVax, is a genetically engineered protein that has been found safe and capable of eliciting ricin-neutralizing antibodies in first-phase human trials [98]. In January 2011, the FDA granted orphan drug status to RiVax. A nasal formulation of RiVax is also in development. In addition, scientists at the U.S. Army Medical Research Institute have created a vaccine, RTA 1-33/44-198 (now known as RTEc), that has shown promise in animal studies [98,99]. A 2013 study found that RiVax and RTEc were similarly effective in eliciting an immune response [100]. In 2016, Soligenix, Inc., received funding from the National Institute of Allergy and Infectious Diseases to advance development of a heat-stable ricin vaccine [101]. Clinical trials are ongoing, but as of 2017, no ricin vaccine is available.

Infection Control

There is no person-to-person transmission of ricin, and secondary transmission of aerosols from victims of ricin poisoning is not documented [47,102]. If ricin is released as an aerosol, careful decontamination will be necessary to prevent re-aerosolization. Ricin-infected patients' clothing and personal effects should be removed and disposed of according to safety regulations. Whenever possible, this should take place prior to arrival at a healthcare facility [98]. Exposed skin can be decontaminated with soap and water and a 0.1% sodium hypochlorite solution, which inactivates the ricin toxin [47]. Eyes may be irrigated with a saline solution.

8. DETECTING AND MANAGING A BIOLOGIC ATTACK

A thorough epidemiologic investigation of a disease outbreak, whether natural or artificial, will assist healthcare professionals in identifying the pathogen and instituting appropriate medical interventions. The CDC realized this as early as 1951, when the Epidemic Intelligence Service was created to train epidemiologists in case a biologic warfare attack took place against the United States during the Cold War [85]. Documenting who is affected, possible routes of exposure, signs and symptoms of disease, and the rapid identification of the causative agents will greatly increase the ability to plan an appropriate medical and public health response. Good epidemiologic information will also allow the appropriate follow-up of those potentially exposed, as well as help determine public information guidelines and responses to the media [85].

The general steps for epidemiologic assessment of any disease can be applied to a biologic warfare or terrorist attack. First, public health authorities and healthcare personnel should formulate a case definition to determine the number of actual cases (verify the epidemic) and, from that, the approximate attack rate. The potential exists for hysteria to be confused with actual disease; therefore, objective criteria should be used to document the number of people affected. Once a case definition has been determined, description of the epidemic can be completed with respect to the timing, place, and characteristics of those who are ill. The investigation must be done expeditiously, but even rudimentary information can be of assistance in determining the source and potential consequences of an outbreak [85].

The disease pattern that develops is an important factor in differentiating between a natural epidemic and a terrorist or warfare attack. In most naturally occurring epidemics, there is a gradual rise in disease incidence as individuals are progressively exposed to an increasing number of patients, vectors, or fomites that spread the pathogen. In contrast, those exposed to a single, large-scale biologic warfare attack would all come in contact with the agent at approximately the same time. Even taking into account varying incubation periods based on exposure dose and physiologic differences, a compressed epidemic curve, with a peak in a matter of days or even hours, would occur [85].

Other possible clues to a biologic warfare or terrorist attack include [1,85]:

- High disease rates among exposed individuals

- A naturally vector-borne disease occurring in an area that lacks the appropriate vectors for normal transmission

- More than one epidemic occurring at the same time

- Suspicious activity or discovery of a potential delivery system, such as a spray device

- Higher morbidity and mortality than normally expected for a disease

- A rapidly increasing disease incidence (hours or days) in a normally healthy population

- An epidemic curve rising and falling in a short period of time

- Unusual increase in people with fever or respiratory symptoms seeking treatment

- An endemic disease emerging quickly at an unusual time or geographic location

- Lower attack rates among people who had been indoors compared to those outdoors

- Clusters of patients arriving from a single locale

- Large numbers of rapidly fatal cases

- Any patient presenting with an uncommon disease, such as pneumonic anthrax, tularemia, or plague

Due to the rapid progression to illness and potential for dissemination of the agents, diagnostic laboratory confirmation may take too long. A response may be based on the recognition of high-risk syndromes that should alert healthcare practitioners to the possibility of a bioterrorism-related outbreak [85]. If an attack with biologic agents is suspected, the proper local authorities, whether military or civilian, should be notified immediately. State emergency response authorities should contact the CDC Emergency Preparedness and Response Branch at 1-770-488-7100 [103]. All others who suspect an emergency should call 911.

9. APIC BIOTERRORISM READINESS PLAN

The Association for Professionals in Infection Control and Epidemiology (APIC) has prepared a review of some of the factors involved in managing a bioterror attack. A brief summary of their suggestions follows.

POSTEXPOSURE PROPHYLAXIS

Up-to-date prophylaxis recommendations should be obtained in consultation with local and state health departments and the CDC. Facilities should ensure that policies are in place to identify and manage healthcare workers exposed to infectious patients [1].

More specific recommendations, a reference list, a directory of FBI field offices, and a directory of State and Territorial Public Health Directors are included in the APIC Bioterrorism Readiness Plan, which can be found on the APIC website (https://apic.org) [104].

DISASTER PLANS

Every medical facility should have a plan in place to delineate how to deliver care in the event of a large-scale bioterrorist event. This disaster plan should be created with input from the infection control committee, administration, emergency department, laboratory directors, and nursing directors [1]. Processes for triage, safe housing, and care for potentially large numbers of affected individuals should be included in the bioterrorism plan. The needs of the facility will vary based on the size of the regional population served. Triage and management planning for large-scale events may include the following [1]:

- Establishing communication networks and lines of authority required to coordinate on-site care

- Planning for cancellation of nonemergency services and procedures

- Identifying sources able to supply vaccines, immune globulin, antibiotics, and antitoxins

- Planning for efficient evaluation and discharge of patients

- Developing discharge instructions for noninfectious patients

- Identifying sources for additional medical equipment and supplies

- Planning for the allocation or re-allocation of scarce equipment

- Determining the ability to handle a sudden increase in the number of cadavers on site

PSYCHOLOGIC ASPECTS OF BIOTERRORISM

Evidence Based Practice Recommendation

According to the American Academy of Child and Adolescent Psychiatry, clinicians should use the principles of psychological first aid as the primary intervention to address the psychologic aspects of a bioterrorism event.

https://www.jaacap.org/article/S0890-8567(13)00550-9/pdf

Last Accessed: August 21, 2020

Level of Evidence: Expert Opinion/Consensus Statement

Fear and panic can be expected from patients and healthcare providers following a bioterrorism-related event. Public mental health crises may be an issue. Horror, anger, unrealistic concerns about infection, and fear of contagion will have to be handled. Collaboration with emergency response agencies will be essential as will be working relationships with mental health support personnel [1].

Clearly explaining risks, offering careful, rapid medical evaluation, and avoiding unnecessary isolation for quarantine can minimize panic. Anxiety can be treated with reassurance or anxiolytics. Providing bioterrorism readiness education and inviting active, voluntary involvement in the planning process and in drills may alleviate staff fears [1].

PUBLIC INFORMATION

In the event of bioterrorism, clear, consistent information should be provided in briefs to patients, visitors, and the general public. Visitors may be strictly limited, and the reasoning behind this should be explained. Facilities should plan in advance the methods of communication to inform the public. Failure to provide a public forum for information exchange has the danger of increasing anxiety, misunderstanding, and fear [1].

10. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

Obtaining a detailed patient history is a vital aspect of diagnosing many bioterrorism-related conditions, particularly those that are rare or that display similar signs and symptoms to other conditions. Furthermore, communication with patients regarding diagnostic procedures and treatment regimens 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 [105].

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. RESOURCES

Association for Professionals in Infection Control and Epidemiology

https://apic.org

Centers for Disease Control and Prevention Emergency Preparedness and Response Branch

https://emergency.cdc.gov

U.S. Department of Homeland Security

https://www.dhs.gov

U.S. Federal Emergency Management Agency (FEMA)

https://www.fema.gov

1-800-621-3362

U.S. Food and Drug Administration Division of Antiviral Products

301-796-1500

U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID)

https://www.usamriid.army.mil

U.S. Public Health Service Commissioned Corps

https://www.usphs.gov

American Dental Association

https://success.ada.org/en/practice-management/bioterrorism

American Red Cross

https://www.redcross.org

1-800-733-2767

Salvation Army

https://www.salvationarmyusa.org

12. CONCLUSION

Weapons of bioterror have been used since ancient times. As scientific knowledge has progressed, so has the sophistication of weaponry utilizing biologic agents. As discussed, bacterial, viral, fungal, chemical, nuclear, and other biologically harmful materials have been devised for use as weapons of terror. They can be delivered by many means to both combatants and innocent civilians. Bombs, aerosols, and direct application of toxic materials are only some of the methods that have been used to cause injury. The ease with which these many harmful agents can be obtained, produced, and delivered is alarming. Conversely, the knowledge that they have been used so rarely in our history could be evidence that our fear of these weapons may actually be greater than the reality of their danger.

Fortunately, there has also been a considerable amount of research into the ways in which these weapons can be neutralized. In addition, antidotes, vaccines, and other means have been discovered to help protect the public or treat those who become victims of an attack. All medical personnel must be prepared with the knowledge and ability to perform their role as front-line respondents in the event that biologic weapons are used.

Works Cited

1. English JF, Cundiff MY, Malone JD, et al. Bioterrorism Readiness Plan: A Template for Healthcare Facilities. Washington, DC: Association for Professionals in Infection Control and Epidemiology; 1999.

2. Centers for Disease Control and Prevention. Travelers' Health: Anthrax. Available at https://wwwnc.cdc.gov/travel/yellowbook/2020/travel-related-infectious-diseases/anthrax. Last accessed August 18, 2020.

3. Placer County Health and Human Services and Placer/Nevada County Medical Society. Zebra Primer on Bioterrorism. Auburn, CA: Placer County Health and Human Services; 2001.

4. Crutcher M. Response to biological terrorism. Paper presented at: Epidemiologists and Professionals in Infection Control (EPIC) Meeting; May 2000, Oklahoma City, OK.

5. Federal Bureau of Investigation. Amerithrax or Anthrax Investigation. Available at https://archives.fbi.gov/archives/about-us/history/famous-cases/anthrax-amerithrax. Last accessed August 18, 2020.

6. Office of the Secretary of Defense. Proliferation: Threat and Response Briefing. Available at https://fas.org/irp/threat/prolif97/t11251997_t1125ptr.html. Last accessed August 18, 2020.

7. San Francisco Department of Public Health. Recognizing Bioterrorism. Available at https://www.sfcdcp.org/health-alerts-emergencies/recognize-an-illness-associated-with-bioterrorism. Last accessed August 18, 2020.

8. Audi J, Belson M, Patel M, Schier J, Osterloh J. Ricin poisoning: a comprehensive review. JAMA. 2005;294(18):2342-2351.

9. Dembek ZF, Alves DA, Cieslak TJ, et al. (eds). USAMRIID's Medical Management of Biological Casualties Handbook. 7th ed. Fort Detrick, MD: U.S. Army Medical Research; 2011.

10. Wein LM, Liu Y. Analyzing a bioterror attack on the food supply: the case of botulinum toxin in milk. Proc Natl Acad Sci USA. 2005;102(28):9984-9989.

11. Dembek ZF. Medical Aspects of Biological Warfare. Washington, DC: TMM Publications; 2007.

12. Weber DJ, Sickbert-Bennett E, Gergen MF, Rutala WA. Efficacy of selected hand hygiene agents used to remove Bacillus atrophaeus (a surrogate of Bacillus anthracis) from contaminated hands. JAMA. 2003;289(10):1274-1277.

13. Katzman K. Iraq: Weapons Programs, U.N. Requirements, and U.S. Policy. Available at https://digital.library.unt.edu/ark:/67531/metacrs4231/m1/1/high_res_d/IB92117_2003Mar26.pdf. Last accessed August 18, 2020.

14. Inglesby TV, O'Toole T, Henderson DA, et al.; Working Group on Civilian Biodefense. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002;287(17):2236-2252.

15. Centers for Disease Control and Prevention. Anthrax: Basic Information. Available at https://www.cdc.gov/anthrax/basics/index.html. Last accessed August 14, 2020.

16. Wright JG, Quinn CP, Shadomy S, Messonnier N; Centers for Disease Control and Prevention. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR. 2010;59(RR6):1-30.

17. Centers for Disease Control and Prevention. Yellow Book: Chapter 3: Infectious Diseases Related to Travel. Available at https://wwwnc.cdc.gov/travel/yellowbook/2020/table-of-contents. Last accessed August 18, 2020.

18. Johnson S. Response to bioterrorism: the role of laboratories. Paper presented at: Epidemiologists and Professionals in Infection Control (EPIC) Meeting; August 17, 2000; Oklahoma City, OK.

19. Stern EJ, Uhde KB, Shadomy SV, Messonnier N. Conference report on public health and clinical guidelines for anthrax. Emerg Infect Dis. 2008;14(4).

20. Centers for Disease Control and Prevention. Anthrax: Recommended Specimens for Microbiology and Pathology for Diagnosis of Anthrax. Available at https://www.cdc.gov/anthrax/specificgroups/lab-professionals/recommended-specimen.html. Last accessed August 18, 2020.

21. Centers for Disease Control and Prevention. Recommended Specimens for Microbiology and Pathology for Diagnosis of Anthrax. Available at https://wwwn.cdc.gov/nndss/conditions/anthrax/case-definition/2010. Last accessed August 14, 2020.

22. Centers for Disease Control and Prevention. Update: investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR. 2001;50(42):909-919.

23. 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).

24. 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.

25. Barclay L. Anthrax Guidelines Address Nonpregnant, Pregnant Adults. Available at https://www.medscape.com/viewarticle/819274. Last accessed August 18, 2020.

26. Alexander JJ, Colangelo PM, Cooper CK, Roberts R, Rodriguez WJ, Murphy MD. Amoxicillin for postexposure inhalational anthrax in pediatrics: rationale for dosing recommendations. Pediatr Infect Dis J. 2008;27(11):955-957.

27. 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 August 18, 2020.

28. Advisory Committee on Immunization Practices. Notice to readers: use of anthrax vaccine in the response to terrorism: supplemental recommendations of the Advisory Committee on Immunization Practices. MMWR. 2002;51(45):1024-1026.

29. Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a biological weapon: medical and public health management. JAMA. 2000;283(17):2281-2290.

30. Centers for Disease Control and Prevention. Plague Training Module. Available at https://emergency.cdc.gov/agent/plague/publications-training.asp. Last accessed August 18, 2020.

31. Centers for Disease Control and Prevention. Plague. Available at https://www.cdc.gov/plague. Last accessed August 18, 2020.

32. Wheelis M. Biological warfare at the 1346 siege of Caffa. Emerg Infect Dis. 2002;8(9):971-975.

33. Centers for Disease Control and Prevention. Frequently Asked Questions about Plague. Available at https://emergency.cdc.gov/agent/plague/faq.asp. Last accessed August 18, 2020.

34. Heymann DL (ed). Control of Communicable Disease Manual. 20th ed. Washington, DC: American Public Health Association; 2014.

35. Centers for Disease Control and Prevention. Plague: Diagnosis and Evaluation. Available at https://emergency.cdc.gov/agent/plague/diagnosis.asp. Last accessed August 14, 2020.

36. Kool JL. Risk of person-to-person transmission of pneumonic plague. Clin Infect Dis. 2005;40(8):1166-1172.

37. Sha J, Endsley JJ, Kirtley ML, et al. Characterization of an F1 deletion mutant of Yersinia pestis CO92, pathogenic role of F1 antigen in bubonic and pneumonic plague, and evaluation of sensitivity and specificity of F1 antigen capture-based dipsticks.J Clin Microbiol. 2011;49(5):1708-1715.

38. Friedlander AM, Welkos SL, Worsham PL, et al. Relationship between virulence and immunity as revealed in recent studies of the F1 capsule of Yersinia pestis. Clin Infect Dis. 1995;21(Suppl 2):S178-S181.

39. Centers for Disease Control and Prevention. Plague: Resources for Clinicians. Available at https://www.cdc.gov/plague/healthcare/clinicians.html. Last accessed August 14, 2020.

40. Jefferson T, Demicheli V, Pratt M. Vaccines for preventing plague. Cochrane Database Syst Rev. 2000(2):CD000976.

41. Dennis DT, Inglesby TV, Henderson DA, et al. Tularemia as a biological weapon: medical and public health management. JAMA. 2001;285(21):2763-2773.

42. Centers for Disease Control and Prevention. Francisella tularensis (Tularemia). Available at https://emergency.cdc.gov/agent/tularemia/facts.asp. Last accessed August 14, 2020.

43. World Health Organization. Health Aspects of Chemical and Biological Weapons: Report of a WHO Group of Consultants. Geneva: World Health Organization; 1970.

44. Sacramento County Public Health Division. Medical Treatment and Response to Suspected Tularemia: Information for Health Care Providers During Biologic Emergencies. Available at https://dhs.saccounty.net/PUB/Documents/PUB_ZTularemia.pdf. Last accessed August 18, 2020.

45. Cleveland KO. Tularemia. Available at https://emedicine.medscape.com/article/230923-overview. Last accessed August 18, 2020.

46. Penn RL. Francisella tularensis (tularemia). In: Bennet JE, Dolin R, Blaser MJ (eds). Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 8th ed. New York, NY: Saunders; 2014: 2060-2068.

47. County of Los Angeles Department of Public Health and the Emergency Medical Services Agency of the Los Angeles County Department of Health Services. Terrorism Agent Information and Treatment Guidelines for Clinicians and Hospitals. Los Angeles, CA: County of Los Angeles Public Health; 2012.

48. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Cin Infect Dis. 2014;59(2):e10-e52.

49. Hofinger DM, Cardona L, Mertz GJ, Davis LE. Tularemic meningitis in the United States. Arch Neurol. 2009;66(4):523-527.

50. Lamps LW, Havens JM, Sjostedt A, Page DL, Scott MA. Histologic and molecular diagnosis of tularemia: a potential bioterrorism agent endemic to North America. Mod Pathol. 2004;17(5):489-495.

51. French GR, Plotkin SA. Miscellaneous limited-use vaccines. In: Plotkin S, Orenstein W, Offit PA (eds). Vaccines. 6th ed. Philadelphia, PA: Saunders; 2012: 728-733.

52. Oyston PCF, Quarry JE. Tularemia vaccine: past, present, and future. Antoine van Leeuwenhoek. 2005;87(4):277-281.

53. Barquet N, Domingo P. Smallpox: the triumph over the most terrible of the ministers of death. Ann Intern Med. 1997;127(8): 635-642.

54. Dowd GE. War Under Heaven: Pontiac, the Indian Nations, & the British Empire. Baltimore, MD: Johns Hopkins University Press; 2004.

55. Brennan JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med. 2002;346(17):1300-1308.

56. Alibek K, Handelman S. Biohazard: The Chilling True Story of the Largest Covert Biological Weapons Program in the World. New York, NY: Random House; 1999.

57. Fenner F, Henderson DA, Arita A, Jezek Z, Ladnyl ID. Smallpox and its Eradication. Geneva: World Health Organization; 1988.

58. Centers for Disease Control and Prevention. Acute, Generalized Vesicular or Pustular Rash Illness Protocol in the United States. Available at https://www.cdc.gov/smallpox/pdfs/rash-illness-protocol.pdf. Last accessed August 18, 2020.

59. Centers for Disease Control and Prevention. Smallpox: Diagnosis and Evaluation. Available at https://www.cdc.gov/smallpox/clinicians/diagnosis-evaluation.html. Last accessed August 14, 2020.

60. Centers for Disease Control and Prevention. Smallpox: Detection and Response. Available at https://www.cdc.gov/smallpox/bioterrorism/public/detection-response.html. Last accessed August 14, 2020.

61. Texas Department of Health. Emergency Preparedness and Response. Available at https://www.texascountyhealth.org/Emergency%20Preparedness.aspx. Last accessed August 18, 2020.

62. Centers for Disease Control and Prevention. Specimen Collection and Transport Guidelines for Suspect Smallpox Cases. Available at https://www.cdc.gov/smallpox/lab-personnel/specimen-collection/specimen-collection-transport.html. Last accessed August 18, 2020.

63. World Health Organization. Smallpox. Available at https://www.who.int/csr/disease/smallpox/en. Last accessed August 18, 2020.

64. Centers for Disease Control and Prevention. Smallpox: Vaccine Basics. Available at https://www.cdc.gov/smallpox/vaccine-basics/index.html. Last accessed August 14, 2020.

65. Lanier R, Trost L, Tippin T, et al. Development of CMX001 for the treatment of poxvirus infections. Viruses. 2010;2(12):2740-2762.

66. Centers for Disease Control and Prevention. Smallpox. Medical Management of Adverse Reactions. Available at https://www.cdc.gov/smallpox/clinicians/vaccine-medical-management6.html. Last accessed August 18, 2020.

67. MedlinePlus. Cidofovir Injection. Available at https://medlineplus.gov/druginfo/meds/a696037.html. Last accessed August 18, 2020.

68. University of Maryland Medical Center. Smallpox. Available at https://health.umd.edu/sites/default/files/inline-files/Important%20Information%20About%20Vaccinia%20%28Smallpox%29%20Vaccine.pdf. Last accessed August 18, 2020.

69. U.S. Food and Drug Administration. Questions About Vaccines: Smallpox. Available at https://www.fda.gov/vaccines-blood-biologics/vaccines/smallpox. Last accessed August 18, 2020.

70. Hatch GJ, Graham VA, Bewley KR, et al. Assessment of the protective effect of Imvamune and Acam2000 vaccines against aerosolized monkeypox virus in cynomolgus macaques. J Virol. 2013;87(14):7805-7815.

71. U.S. Food and Drug Administration. ACAM2000 (Smallpox Vaccine) Questions and Answers. Available at https://www.fda.gov/vaccines-blood-biologics/vaccines/acam2000-smallpox-vaccine-questions-and-answers. Last accessed August 18, 2020.

72. Bavarian Nordic. Bavarian Nordic Completes Delivery of 20 Million Doses of IMVAMUNE Smallpox Vaccine to the U.S. Strategic National Stockpile. Available at https://www.bavarian-nordic.com/investor/news/news.aspx?news=3051. Last accessed August 18, 2020.

73. Centers for Disease Control and Prevention. Smallpox. Vaccination. Available at https://www.cdc.gov/smallpox/clinicians/vaccination.html. Last accessed August14, 2020.

74. LexiComp Online. Available at https://online.lexi.com. Last accessed August 18, 2020.

75. Petersen BW, Damon IK, Pertowski CA, et al. Clinical guidance for smallpox vaccine use in a postevent vaccination program. MMWR. 2015;64(RR02):1-26.

76. Centers for Disease Control and Prevention. Smallpox: Ring Vaccination. Available at https://www.cdc.gov/smallpox/bioterrorism-response-planning/public-health/ring-vaccination.html. Last accessed August 14, 2020.

77. Borio L, Inglesby TV, Peters CJ, et al. Hemorrhagic fever viruses as biological weapons: medical and public health management. JAMA. 2002;287(18):2391-2405.

78. U.S. Army Medical Research and Materiel Command. Treatment of Viral Hemorrhagic Fevers With Intravenous Ribavirin in Military Treatment Facilities. Available at https://clinicaltrials.gov/ct2/show/NCT00992693. Last accessed August 18, 2020.

79. World Health Organization. Application for Inclusion of Ribavirin in the WHO Model List of Essential Medicines. Available at http://archives.who.int/eml/expcom/expcom15/applications/newmed/ribaravin/ribavirin.pdf. Last accessed August 18, 2020.

80. Centers for Disease Control and Prevention. Interim Guidance for Managing Patients with Suspected Viral Hemorrhagic Fever in U.S. Hospitals. Available at https://www.cdc.gov/hai/pdfs/bbp/vhfinterimguidance05_19_05.pdf. Last accessed August 18, 2020.

81. U.S. Food and Drug Administration. Emergency Investigational New Drug (EIND) Applications for Antiviral Products. Available at https://www.fda.gov/drugs/investigational-new-drug-ind-application/emergency-investigational-new-drug-eind-applications-antiviral-products. Last accessed August 18, 2020.

82. California Department of Industrial Relations, Division of Occupational Safety and Health. Interim Guidance on Ebola Virus in Inpatient Hospital Settings. Available at https://www.dir.ca.gov/dosh/documents/Cal-OSHA-Guidance-on-Ebola-Virus.pdf. Last accessed August 18, 2020.

83. Centers for Disease Control and Prevention. Guidance on Personal Protective Equipment (PPE) To Be Used By Healthcare Workers during Management of Patients with Confirmed Ebola or Persons under Investigation (PUIs) for Ebola who are Clinically Unstable or Have Bleeding, Vomiting, or Diarrhea in U.S. Hospitals, Including Procedures for Donning and Doffing PPE. Available at https://www.cdc.gov/vhf/ebola/healthcare-us/ppe/guidance.html. Last accessed August 18, 2020.

84. Public Health Agency of Canada. Clostridium botulinum. Available at https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/clostridium-botulinum.html. Last accessed August 18, 2020.

85. Frantz DR, Jahrling PB, Friedlander AM, et al. Clinical recognition and management of patients exposed to biological warfare agents. JAMA. 1997;278(5):399-411.

86. 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.

87. Alguire P (ed). ACP bioterrorism resource guide. ACP Observer. 2004;5.

88. Villar RG, Elliott SP, Davenport KM. Botulism: the many faces of botulinum toxin and its potential for bioterrorism. Infect Dis Clin North Am. 2006;20(2):313-327.

89. Centers for Disease Control and Prevention. Botulism: Information for Health Professionals. Available at https://www.cdc.gov/botulism/health-professional.html. Last accessed August 14, 2020.

90. 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.

91. U.S. Food and Drug Administration. FDA Approves First Botulinum Antitoxin for Use in Neutralizing All Seven Known Botulinum Nerve Toxin Serotypes. Available at https://wayback.archive-it.org/7993/20161022134538/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345128.htm. Last accessed August 18, 2020.

92. Varma JK, Katsitadze G, Moiscrafishvili M, et al. Signs and symptoms predictive of death in patients with foodborne botulism—Republic of Georgia, 1980–2002. Clin Infect Dis. 2004;39(3):357-362.

93. Centers for Disease Control and Prevention. Investigation of a ricin-containing envelope at a postal facility—South Carolina, 2003. MMWR. 2003;52(46):1129-1131.

94. Shea D, Gottron F. CRS Report for Congress. Ricin: Technical Background and Possible Role in Terrorism. Washington, DC: Library of Congress; 2004.

95. Centers for Disease Control and Prevention. Health Advisory: CDC Alert on Ricin. Available at https://emergency.cdc.gov/agent/ricin/han_022008.asp. Last accessed August14,2020.

96. Centers for Disease Control and Prevention. Ricin: Epidemiological Overview for Clinicians. Available at https://emergency.cdc.gov/agent/ricin/clinicians/epidemiology.asp. Last accessed August 14, 2020.

97. Centers for Disease Control and Prevention. Bioterrorism Agents/Diseases. Available at https://emergency.cdc.gov/agent/agentlist.asp. Last accessed August 14, 2020.

98. U.S. Department of Health and Human Services Office of Public Health Emergency Preparedness. Response to a Ricin Incident: Guidelines for Federal, State, and Local Public Health and Medical Officials. Washington, DC: Department of Health and Human Services; 2006.

99. U.S. Army Medical Research and Material Command. USAMRIID Begins Clinical Trial of New Vaccine to Protect Against Ricin Toxin. Available at https://www.usamriid.army.mil/press_releases/Ricin%20News%20Release%2013%20Apr%202011.pdf. Last accessed August 18, 2020.

100. O'Hara JM, Brey RN 3rd, Mantis NJ. Comparative efficacy of two leading candidate ricin toxin a subunit vaccines in mice.Clin Vaccine Immunol. 2013;20(6):789-794.

101. Soligenix. Soligenix Receives Additional NIAID Funding to Advance Development of Heat Stable Ricin Vaccine. Available at https://www.prnewswire.com/news-releases/soligenix-receives-additional-niaid-funding-to-advance-development-of-heat-stable-ricin-vaccine-300476933.html. Last accessed August 18, 2020.

102. Brey RN III, Mantis NJ, Pincus SH, Vitetta ES, Smith LA, Roy CJ. Recent advances in the development of vaccines against. Ricin. Hum Vaccin Immunother. 2016;12(5):1196-1201.

103. Centers for Disease Control and Prevention. Emergency Preparedness and Response. Available at https://emergency.cdc.gov. Last accessed August 14,2020.

104. Association for Professionals in Infection Control and Epidemiology. Available at https://apic.org. Last accessed August 18, 2020.

105. Hwa-Froelich DA, Westby CE. Considerations when working with interpreters. Commun Disord Q. 2003;4(2):78-85.

106. U.S. Food and Drug Administration. FDA Approves the First Drug with an Indication for Treatment of Smallpox. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-indication-treatment-smallpox. Last accessed August 18, 2020.

107. U.S. Food and Drug Administration. FDA Approves First Live, Non-Replicating Vaccine to Prevent Smallpox and Monkeypox. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-live-non-replicating-vaccine-prevent-smallpox-and-monkeypox. Last accessed August 18, 2020.

108. Centers for Disease Control and Prevention. Anthrax: Bioterrorism: The Threat. Available at https://www.cdc.gov/anthrax/bioterrorism/threat.html. Last accessed August 14, 2020.

109. Centers for Disease Control and Prevention. Clinical framework and medical countermeasure use during an anthrax mass-casualty incident: recommendations and reports. MMWR. 2015;64(RR4):1-28.

110. Centers for Disease Control and Prevention. Considerations for Anthrax Vaccine Adsorbed (AVA) Post-Exposure Prioritization Final. Available at https://www.cdc.gov/anthrax/pdf/ava-post-event-prioritization-guidance.pdf. Last accessed August 18, 2020.

111. Boulanger LL, Ettestad P, Fogarty JD, et al. Gentamicin and tetracyclines for the treatment of human plague: review of 75 cases in New Mexico, 1985–1999. Clin Infect Dis. 2004;38:663-669.

112. Meyer H, Ehmann R, Smith GL. Smallpox in the post-eradication era. Viruses. 2020;12:138.

113. Grosenbach DW, Honeychurch K, Rose E, et al. Oral tecovirimat for the treatment of smallpox. N Engl J Med. 2018;379:44-53.

Evidence-Based Practice Recommendations Citations

1. Pfefferbaum B, Shaw JA, American Academy of Child and Adolescent Psychiatry Committee on Quality Issues. Practice parameter on disaster preparedness. J Am Acad Child Adolesc Psychiatry. 2013;52(11):1224-1238. Available at https://www.jaacap.org/article/S0890-8567(13)00550-9/pdf. Last accessed August 21, 2020.

97790 • Domestic and Sexual Violence

Alice Yick Flanagan, PhD, MSW

John M. Leonard, MD

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Victims of domestic and sexual 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 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.

Table of Contents

97790 • Domestic and Sexual Violence

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. AN OVERVIEW OF THE ISSUE

DEFINING DOMESTIC VIOLENCE

DEFINING SEXUAL VIOLENCE

CONTRACEPTIVE COERCION

3. SIGNS OF ABUSE/VICTIMIZATION

DOMESTIC VIOLENCE

SEXUAL VIOLENCE

4. HEALTH EFFECTS AND IMPLICATIONS OF DOMESTIC VIOLENCE

5. HEALTH EFFECTS AND IMPLICATIONS OF SEXUAL VIOLENCE

NON-GENITAL BODILY INJURY

GENITAL INJURY

LONG-TERM PSYCHOSOCIAL IMPACT

SEXUALLY TRANSMITTED INFECTION

6. IMPLICATIONS ON PREGNANCY AND PRENATAL CARE

7. HEALTH EFFECTS AND IMPLICATIONS OF CHILDREN EXPOSED TO DOMESTIC VIOLENCE

8. DOMESTIC VIOLENCE AND SEXUAL VIOLENCE IN SPECIAL POPULATIONS

ELDERLY

LESBIAN, GAY, BISEXUAL, AND TRANSGENDER VICTIMS

HOMELESS INDIVIDUALS

PEOPLE WITH PHYSICAL AND/OR COGNITIVE DISABILITIES

PEOPLE WITH BEHAVIORAL HEALTH PROBLEMS

CHILDREN AND ADOLESCENTS

LOW-INCOME POPULATIONS

PEOPLE LIVING IN RURAL COMMUNITIES

IMMIGRANTS AND REFUGEES

PEOPLE OF COLOR

9. PERPETRATORS OF DOMESTIC/SEXUAL VIOLENCE

10. ASSESSMENT AND SCREENING METHODS

SCREENING

ASSESSMENT

11. BEST PRACTICES IN FOLLOW-UP CARE FOR VICTIMS OF VIOLENCE

12. BUILDING EFFECTIVE COMMUNITY PARTNERSHIPS AND COLLABORATIONS WITH COMMUNITY-BASED AGENCIES

13. APPROPRIATE RESPONSES AND DOCUMENTATION

LEGAL INTERVENTIONS

CASE MANAGEMENT

SHELTERS

14. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

97790 • Domestic and Sexual Violence

Education Category. Ethics - Human Rights

Release Date. 06/01/2019

Expiration Date. 05/31/2022

Course Overview

Victims of domestic and sexual 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 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.

Audience

This course is designed for a wide range of healthcare and mental health professionals, including physicians, physician assistants, nurses, social workers, mental health/rehabilitation counselors, and marriage and family therapists.

Course Objective

The purpose of this course is to provide healthcare professionals with the skills and confidence necessary to identify victims of sexual or domestic violence and to intervene appropriately and effectively.

Learning Objectives

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

1. Identify common types of domestic and sexual violence.

2. Outline signs of abuse or victimization.

3. Describe the health effects and implications of domestic violence and/or sexual assault, including effects on pregnancy, developing fetuses, and child witnesses.

4. Evaluate the unique risk factors for and consequences of domestic and sexual violence in special populations.

5. Discuss traits of perpetrators of domestic and/or sexual violence.

6. Analyze screening and assessment methods to identify victims of abuse.

7. Describe appropriate responses to domestic and sexual violence, including best practices for follow-up care.

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.

John M. Leonard, MD, Professor of Medicine Emeritus, Vanderbilt University School of Medicine, completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers before joining the Vanderbilt faculty in 1974. He is a clinician-educator and for many years served as director of residency training and student educational programs for the Vanderbilt University Department of Medicine. Over a career span of 40 years, Dr. Leonard conducted an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.

Faculty Disclosure

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

Contributing faculty, John M. Leonard, MD, 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

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

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. AN OVERVIEW OF THE ISSUE

DEFINING DOMESTIC VIOLENCE

Domestic violence, termed 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. The Centers for Disease Control and Prevention (CDC) defines IPV as, "physical violence, sexual violence, stalking, and psychologic aggression (including coercive tactics) by a current or former intimate partner (i.e., spouse, boyfriend/girlfriend, dating partner, or ongoing sexual partner)" [1].

Domestic violence can consist of any of many behaviors or combination of behaviors, falling under physical, psychologic, verbal, sexual, and financial/economic abuse (Table 1).

Table 1: DOMESTIC VIOLENCE BEHAVIORS

Physical Abuse

Psychologic/Verbal Abuse

Sexual Abuse

Financial/Economic Abuse

Kicking, punching, biting, slapping, strangling, choking, abandoning in unsafe places, burning with cigarettes, throwing acid, throwing objects, refusing to help when sick, stabbing, shooting

Intimidation, humiliation, put-downs, ridiculing, control of victim's movement, stalking, threats, threatening to hurt victim's family and children, social isolation, ignoring needs or complaints

Rape, forms of sexual assault (such as forced masturbation, fellatio, or oral coitus), sexual humiliation, perpetrator refuses to use contraceptives, coerced abortion

Withholding of money, refuse to allow victim to open bank account, all property is in the perpetrator's name, victim is not allowed to work

Source: Compiled by Author

It is important for healthcare professionals to understand that domestic violence, in the form of emotional and psychologic abuse and physical violence, is prevalent in society. Unfortunately, domestic violence and abuse has become a fact of life for many Americans. This course will use the terms "domestic violence" and "IPV" interchangeably.

DEFINING SEXUAL VIOLENCE

According to the Massachusetts Coalition Against Sexual Assault and Domestic Violence, sexual violence is defined as "a multi-layered oppression that occurs at the societal and individual level and is connected to and influenced by other forms of oppression, in particular, sexism, racism, and heterosexism…On an individual level, sexual violence is a wide range of sexual acts and behaviors that are unwanted, coerced, committed without consent, or forced either by physical means or through threats" [2].

Whether out of impulse, compulsion, anger, or the assertion of power, sexual assault is a criminal act of violence imposed on the vulnerable and the innocent, causing immediate physical and emotional suffering and often having long-lasting adverse psychologic effects. Rape is the legal term for a sexual assault during which there is penetration of a body orifice (vagina, anus, or mouth) involving force, the threat of force, or incapacity and nonconsent of the victim.

It is important to consider that there is a wide range of sexual violence that can manifest in many different ways. For example, reproductive coercion (e.g., forced abortion, forced pregnancy) is considered a form of sexual violence [2].

CONTRACEPTIVE COERCION

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), preventing or forcing abortion, or stopping a partner from using birth control [3]. Research indicates that this form of violence is relatively common. A study of young women (16 to 29 years of age) presenting to family planning clinics in California found that 53% of respondents reported physical or sexual partner violence, 19% reported experiencing pregnancy coercion, and 15% reported birth control sabotage [4]. Of those who reported being victims of partner violence, 35% reported reproductive control. Studies suggest that reproductive control and unintended pregnancy may disproportionately affect women of color [5].

According to the American College of Obstetricians and Gynecologists (ACOG), interventions that focused on awareness of reproductive and sexual coercion and provided harm-reduction strategies reduced pregnancy coercion by 71% among women who experienced IPV [6]. The ACOG recommends the following screening questions:

- Has your partner ever forced you to do something sexually that you did not want to do or refused your request to use condoms?

- Has your partner ever tried to get you pregnant when you did not want to be pregnant?

- Are you worried your partner will hurt you if you do not do what he wants with the pregnancy?

- Does your partner support your decision about when or if you want to become pregnant?

Interventions targeted to protect victims of contraceptive coercion include helping conceal contraceptives, placement of an intrauterine device or other implanted birth control, and appropriate referrals [6].

3. SIGNS OF ABUSE/VICTIMIZATION

DOMESTIC VIOLENCE

It is imperative that healthcare professionals work together to establish specific guidelines that will facilitate identification of batterers and their victims. In a 2016 study of 288 healthcare facilities in Florida, 78% understood the importance of IPV screening and had some type of IPV screening policy institute in their setting [7]. However, many of the respondents did not know which screening tool was used or the types of screening questions asked. These guidelines should review appropriate interview techniques and should also include the utilization of screening tools, such as intake questionnaires. The following is a review of certain signs and symptoms that may indicate the presence of abuse. Although victims of domestic violence do not display typical signs and symptoms when they present to healthcare providers, there are certain cues that may be attributable to abuse. The obvious cues are the physical ones. 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. In addition to physical signs and symptoms, domestic violence victims also exhibit psychologic cues that resemble an agitated depression.

Unfortunately, healthcare professionals may respond to these women by diagnosing the patient to be neurotic or irrational [8]. Healthcare professionals should cast aside these misperceptions of abused victims and work within their respective practice settings to develop screening mechanisms to detect women who exhibit these symptoms. In addition, it is important to recognize that vulnerable populations, including lesbian, gay, bisexual, transgender, and other gender/sexual minority (LGBT+) individuals, those with HIV, individuals with disabilities, and veterans are also at risk and should be screened for IPV [9].

SEXUAL VIOLENCE

Although most cases of sexual violence are accompanied by physical force and/or active resistance, visible injuries are rare. Possible signs of sexual violence victimization include [10]:

- Unwanted touching

- Rape (i.e., actual or attempted unwanted vaginal, oral, or anal penetration by an object or body part)

- Being forced or manipulated into doing unwanted, painful, or degrading acts during intercourse

- Being taken advantage of while one is drunk or otherwise not likely to give consent

- Being denied contraception or protection against sexually transmitted infections

- Taking any kind of sexual pictures or film without consent

- Being forced to perform sexual acts on film or in person for money

- Threatening break up when sex is refused

4. HEALTH EFFECTS AND IMPLICATIONS OF DOMESTIC VIOLENCE

As is clear, victims of domestic violence experience a wide range of physical and psychologic injuries. Typical injury patterns include contusions or minor lacerations to the head, face, neck, breast, or abdomen. These are often distinguishable from accidental injuries, which are more likely to involve the periphery of the body. In one hospital-based study, domestic violence victims were 13 times more likely to sustain injury to breast, chest, or abdomen than accident victims. Abuse victims are also more likely to have multiple injuries than accident victims. When this pattern of injuries is seen in a patient, particularly in combination with evidence of old injury, physical abuse should be suspected [11].

As a result of prolonged stress, victims often manifest various psychosomatic symptoms that generally lack an organic basis. For example, they may complain of backaches, headaches/migraines, and gastrointestinal problems. Often, they will complain of chronic pain, fatigue, restlessness, insomnia, or loss of appetite. Great amounts of anxiety, guilt, and depression or dysphoria are also typical [11,12]. In many women, this constellation of symptoms has been labeled "battered women's syndrome."

The long-term health implications should also be considered. In a study conducted by MORE magazine and the Verizon Foundation, 88% of women who have experienced sexual abuse and 81% of women who have experienced any form of domestic violence report having chronic health conditions (compared with 62% among women who experienced no domestic violence) [13]. In this study, the most common chronic health conditions among victims were low back pain (35%), headaches (32%), difficulty sleeping (30%), and depression/anxiety (30%). Victims of violence were also found to have increased incidences of diabetes, cervical pain, gastroesophageal reflux disease, irritable bowel syndrome, and post-traumatic stress disorder.

5. HEALTH EFFECTS AND IMPLICATIONS OF SEXUAL VIOLENCE

Research indicates that victims of sexual violence experience a range of acute and long-term physical and psychologic injuries as a result of the violence [14].

NON-GENITAL BODILY INJURY

Non-genital bodily injury is seen in more than half of all rape victims presenting to emergency departments [15,16]. In one study of 162 women examined between 2002 and 2006, signs of bodily injury were found in 61% of patients, with genital injury present in 39% [17]. Most common were bruises (56%) and abrasions (41%), followed by lacerations, penetrating injury, and bites. Evidence of injury was higher in the 137 cases examined within 72 hours of assault (66% vs. 33%) and in cases in which the assaults occurred outdoors (79% vs. 52%).

On examination, one should inspect carefully for evidence of blunt traumatic injury to the head, neck, arms, legs, and torso, looking for signs of penetrating injury, lacerations, and bite marks. Bruising may be evident on the neck (attempted strangulation), hands, arms, breasts, or thighs. Signs of bodily injury are more prevalent in women younger than 30 years of age. Other factors showing a strong positive association with bodily injury include alcohol consumption, history of prior assault, and assault by strangers [15].

GENITAL INJURY

Signs of genital traumatic injury are not always found after sexual assault, and in such cases should not be taken as evidence that sexual assault did not occur [17]. When routine inspection is combined with additional examination techniques, such as colposcopy and toluidine blue staining, the rate for identifying genital injury approaches 70% [18]. Observed rates of genital injury are highest in women examined within 72 hours (40% vs. 7%), in those of virginal state (60% vs. 33%), and in cases involving assault by strangers or multiple assailants [19].

The common types and location of genital injuries, and thus the areas to be examined most closely, are:

- Bruises and abrasions to the labia, fossa navicularis, or perianal area

- Ecchymoses, tears, or lacerations of the hymen

- Abrasions and/or tears of the posterior fourchette

- Tears/lacerations in the perianal area

LONG-TERM PSYCHOSOCIAL IMPACT

The impact of sexual assault leads to immediate and long-term physical and mental health consequences. In addition to the potential risk for acquiring a sexually transmitted disease (STD), approximately 1% to 5% of rape victims become pregnant [20]. The National Violence Against Women Survey (NVAWS) found that 33% of women and 24% of men received counseling from a mental health professional as a direct result of their last assault; 28% and 10%, respectively, lost time from work [21]. Survivors of sexual assault are also at increased risk for re-victimization and experience higher rates of depression, post-traumatic stress disorder, substance abuse, and suicide.

In the aftermath of sexual assault, a variety of chronic somatic, cognitive, and emotional sequelae have been observed in sexual assault victims (Table 2). The individual's response and subsequent ability to cope with the trauma of the assault are influenced by a number of related factors. These include the nature and severity of the assault itself, age of the victim, relationship between the victim and assailant, prior history of abuse, and the person's own ambient life stress and coping mechanisms. For some, the impact of a sexual assault experience is severe and long-lasting, often resulting in difficulty with interpersonal relationships and tasks of daily living, sexual dysfunction, loss of work-time, and increased utilization of healthcare resources [22,23,24].

Table 2: LONG-TERM PHYSICAL AND EMOTIONAL IMPACT OF SEXUAL ASSAULT

Chronic Somatic Disorders

Psychosocial Disorders

Pelvic pain, dyspareunia

Functional gastrointestinal disorder

Fibromyalgia

Multisystem physical complaints

Headaches

Abdominal pains

Anxiety, depression, phobias

Post-traumatic stress disorder

Sexual dysfunction

Sleep disturbance

Anorexia

Work absenteeism

Source: [22,23,24,25,26,27]

A meta-analysis of clinical studies published between 1980 and 2002 revealed a significant association between prior sexual assault and the lifetime diagnosis of fibromyalgia, chronic pelvic pain, and functional gastrointestinal disorders [25]. In a cross-sectional, randomly selected study of 219 women followed in a Veterans Administration (VA) primary care clinic, a history of prior sexual assault was found to be associated with a significant increase in somatization scores, multisystem physical complaints, anxiety, work absenteeism, and health care utilization [26]. Among another cohort of women receiving VA medical and mental health care, the prevalence of post-traumatic stress disorder was found to be seven to nine times higher in women who had experienced a prior sexual assault, compared with those having no assault history [27].

To summarize, the priorities of acute care counseling are to provide emotional support, assure a plan for patient safety, and assess coping skills and strength of support system post-discharge. When possible, arrangements should be made for ongoing counseling through sexual assault crisis programs. In anticipation of the long-term adverse effects of sexual assault, arrangements should be made for primary care follow-up and patients and families should be offered information and access to mental health services.

SEXUALLY TRANSMITTED INFECTION

The infections commonly reported in women after sexual assault are Chlamydia, gonorrhea, trichomoniasis, bacterial vaginitis, and pelvic inflammatory disease (PID) [28]. The possible exposure to hepatitis B virus and human immunodeficiency virus (HIV) is also an important consideration. In general, the risk of infection is relatively low; published estimates are 3% to 16% for chlamydia, 7% for trichomoniasis, and 11% for PID [29]. The risk, however, does vary directly with the degree of genital trauma, associated bleeding (sustained by the victim or assailant), and the number of assailants. The CDC has published guidelines for the assessment, counseling, and preventive treatment of infection following sexual assault, including common pelvic infections, hepatitis B, human papillomavirus (HPV), and HIV [28].

Follow-up within one to two weeks after the initial evaluation provides the opportunity to review previous test results, complete an assessment for STDs, and ensure safety and adherence to prescribed medication. CDC guidelines advise that a follow-up examination at one to two months should be considered to re-evaluate for development of anogenital warts, especially in patients who received a diagnosis of other STDs following the assault. If initial tests were negative and infection in the assailant could not be ruled out, serologic tests for syphilis can be repeated at four to six weeks and three months. To exclude acquisition of HIV, tests for acute infection should be repeated at six weeks, three months, and six months after the assault [28].

6. IMPLICATIONS ON PREGNANCY AND PRENATAL CARE

Because a gynecologist or obstetrician is frequently a woman's primary care physician, these healthcare providers should be particularly sensitive to domestic violence issues [30]. According to the CDC, IPV affects as many as 324,000 pregnant women each year [31]. This represents approximately 8% of all pregnant women in the United States. As with all domestic violence statistics, this number is 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 [31]. Because 96% of pregnant women receive prenatal care, this is an optimal time to screen for domestic violence and develop trusting relationships with the women. Possible factors that may predispose pregnant women to IPV include young maternal age, unintended pregnancy, delayed prenatal care, lack of social support, and use of tobacco, alcohol, or illegal drugs [31,32].

The overarching problem of violence against women cannot be ignored, especially as both mother and unborn child are at risk. One study found that pregnant women who had been treated at a hospital after a violent incident had an eight-fold increased risk of fetal death [33]. 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 [11,34]. 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, and victims are less likely to obtain prenatal care and to develop postpartum depression [33,35,36].

Low birth weight can result from either preterm birth or growth restriction in utero, both of which can be directly linked to stress. Living in an abusive and dangerous environment marked by chronic stress can therefore be an important risk factor for maternal health, as well as affecting birth weight [37].

The risk of becoming pregnant after vaginal rape is estimated to be 5% [16]. It is generally recommended that rape victims of childbearing age have a baseline urine or serum pregnancy test performed, in anticipation of offering prophylaxis against pregnancy if the result is negative.

Postexposure emergency contraceptive treatment options are available for preventing pregnancy after unwanted intercourse [38]. The simplest and best-studied product is levonorgestrel (Plan B), an oral progestin-only medication developed for this purpose. The dosage regimen is 1.5 mg (two 0.75-mg tablets) administered as a single oral dose. It is considered to be most effective when administered within 12 hours of the assault. In one carefully conducted study, the success rate (prevention of pregnancy) exceeded 95% when administered up to 120 hours after unprotected intercourse [39]. This medication is safe and well tolerated, even if given to someone who is pregnant. Systemic side effects, such as headache, nausea, fatigue, and gastrointestinal/abdominal complaints, occur in less than 10% of patients. Transient vaginal bleeding in the days following treatment is more common (25% to 30%).

7. HEALTH EFFECTS AND IMPLICATIONS OF CHILDREN EXPOSED TO DOMESTIC VIOLENCE

Children may be victims of domestic violence either directly (if victims of the perpetrator) or indirectly (if witnessing the violence or suffering the fallout). However, there is evidence that child abuse and intimate partner violence often occur within the same household and that exposure to violence in childhood may increase the risk of experiencing or perpetrating different forms of violence later in life [40].

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 [12]. 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 [41]. 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 [41].

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 [43,44,45]. 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 [46,47].

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 [48]. Research indicates that between 30% and 60% of husbands who batter their wives also batter their children [49]. Moreover, victims of abuse will often turn on their children; statistics demonstrate that 85% of domestic violence victims abuse or neglect their children. 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 [8]. 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 [50]. 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.

8. DOMESTIC VIOLENCE AND SEXUAL VIOLENCE IN SPECIAL POPULATIONS

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 [51]. 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 [52].

The prevalence rate of elder abuse in institutional settings is not clear. However, in one nonprobability study, 36% of nursing and aide staff disclosed to having witnessed at least one incident of physical abuse by other staff members in the preceding year. When asked whether they themselves perpetrated physical abuse against an elderly resident, 10% admitted they had [53]. 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 [54].

It is important to understand that the needs of older patients 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 [55].

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 for abuse and neglect in all older or vulnerable adults.

https://jamanetwork.com/journals/jama/fullarticle/2708121

Last Accessed: May 7, 2019

Level of Evidence: 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 [55]. 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.

LESBIAN, GAY, BISEXUAL, AND TRANSGENDER VICTIMS

Domestic violence exists in LGBT+ communities, and the rates are thought to mirror those of heterosexual women—approximately 25% [56]. However, women living with female intimate partners experience less IPV than women living with men. Conversely, men living with male intimate partners experience more IPV than do men who live with female intimate partners. In addition, 77% of IPV homicide victims reported in 2015 were transgender women or cisgender men [57]. 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 [56].

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 [57].

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 [58]. 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.

Twenty-six percent of transgender and gender non-conforming individuals have been physically assaulted and 10% have been sexually assaulted [59]. In a study of transgender women, 78.1% experienced gender-related psychologic abuse and 50% experienced gender-related physical abuse [60]. The Transgender Day of Remembrance is held in November of each year to memorialize those who were killed due to anti-transgender hatred or prejudice. In total, 717 murders have been documented between 1970 and 2012 [61]. The National Center for Transgender Equality recommends that ending violence against transgender people should be a public health priority, because of the direct and indirect negative effect violence has on both victims and on the healthcare system that treats them.

HOMELESS INDIVIDUALS

The intersection of homelessness and domestic and/or sexual violence is bidirectional and complex. Studies indicate up to 92% of homeless women have experienced severe physical or sexual abuse at some point in their lives, and as many as 57% of all homeless women report domestic violence as the immediate cause of their homelessness [62,63,64]. Homeless domestic violence victims face unique barriers to accessing help, including affordable housing, as a result of actions of their perpetrator. They may face housing discrimination, lack stable employment histories, and have poor credit as a result of their abuse histories [62]. In addition, a study published by the National Online Resource Center on Violence Against Women found that homeless women are "particularly vulnerable to multiple forms of interpersonal victimization, including sexual and physical assault at the hands of strangers, acquaintances, pimps, sex traffickers, and intimate partners on the street, in shelters, or in precarious housing situations" [63]. The sexual assault experiences of homeless women are more likely to be violent and include multiple sexual acts than women with housing [65].

Because homeless victims of violence face specific barriers to seeking and receiving services, interventions and assistance should be targeted to their specific needs. It is also important to remember that additional marginalizing factors (e.g., gender/sexual minority status, geographic isolation) compound the problems experienced by survivors.

PEOPLE WITH PHYSICAL AND/OR COGNITIVE DISABILITIES

Research indicates that disability predicts recent intimate partner violence victimization in both men and women [66]. National data indicate that women with a disability are significantly more likely to report experiencing every form of intimate partner violence, including rape, other sexual violence, physical violence, stalking, psychologic aggression, and control of reproductive or sexual health [66]. Stalking and psychologic aggression by an intimate partner are more likely in men with disabilities. Most perpetrators are acquaintances of the victim [67].

The type of disability may also be an indicator or risk. In a national sample of victims of sexual assault who were disabled, the majority (60.5%) had a psychiatric disability and 25% had an intellectual/developmental disability; the smallest percentage (15.6%) had physical/sensory disabilities [67]. People with intellectual disabilities are sexually assaulted at a rate seven times higher than those without disabilities [68].

Although persons with disabilities are more likely to be victimized, it can be difficult for them to seek and obtain help. Legal action was taken in only 13.6% of cases [67]. Differently able individuals may be less likely to be believed when they report abuse or may be unable to effectively communicate their experiences [69]. Police and prosecutors are often reluctant to take these cases because they are difficult to win in court [68]. In addition, there is a lack of coordinated community services and supports for disabled survivors of sexual assault [67].

PEOPLE WITH BEHAVIORAL HEALTH PROBLEMS

Behavioral health problems, including substance use disorders, eating disorders, and compulsive behaviors, commonly co-occur with intimate partner violence and sexual violence. According to the American Society of Addiction Medicine, substance abuse co-occurs in 40% to 60% of IPV incidents, with several lines of evidence suggesting that substance use/abuse plays a facilitative role in IPV by precipitating or exacerbating violence [70]. Both victims and abusers are 11 times more likely to be involved in domestic violence incidents on days of heavy substance use [71].

It is unclear if substance abuse precedes the violence, or vice versa. However, victimization is considered a positive risk factor for substance use disorders, and women in abusive relationships have often reported being coerced into using alcohol and/or drugs by their partners [70].

Women with a history of eating disorders are also at increased risk for intimate partner violence [72]. In a study of undergraduate women, recent (i.e., last three months) sexual assault was associated with more severe eating disorder symptoms [73,74].

CHILDREN AND ADOLESCENTS

Dating Violence

Perpetrators of dating violence among young adults include witnessing interparental violence, experiencing child abuse, alcohol abuse, adherence to traditional gender roles, and relationship power dynamic issues [75]. Female perpetrators are more likely than men to display internalizing symptoms (e.g., depression), trait anger and hostility, and to be victims of past dating violence; young male perpetrators are more likely than women to report lower socioeconomic status and educational attainment, antisocial personality characteristics, and increased relationship length [75]. Sexting has also been identified as a unique risk factor for dating violence in young adulthood [76].

Young women are more likely than men to experience dating violence, as is the case among most subgroups. However, nonsexual violence in dating relationships is more likely to involve the reciprocal use of violence by both partners (mutual aggression) than adult abusive relationships [77].

Sexual Assault

In contrast to sexual victimization of adolescents and adults, who usually present in the aftermath of an assault, pre-pubertal victimization of children tends to be "discovered" when the child is found to have signs of physical or sexual abuse (e.g. genital injury or scarring) or when a sexually transmissible infectious agent is identified. Gonorrhea, syphilis, and HIV (not linked to prior blood transfusion or maternofetal transmission) acquired during the postnatal period of childhood are indicative of sexual abuse. Chlamydia infection might be indicative of sexual abuse in children 3 years of age of older. Sexual abuse should be suspected when genital herpes, Trichomonas vaginalis, or anogenital warts are diagnosed [28]. In cases in which any STD has been diagnosed in a child, further evaluation for other STDs and for the possibility of sexual assault/abuse should be made in consultation with a specialist.

Just as the identification of a sexually transmissible infection in a child raises suspicion for prior sexual assault/abuse, so too does known or suspected childhood sexual assault/abuse warrant an assessment for STDs. The decision to perform a diagnostic evaluation and to collect vaginal or other specimens should be made on an individual case basis. Among factors to consider in the decision to screen a child for STDs are [28,78]:

- Child has experienced penetration or has evidence of recent or healed penetrative injury.

- The perpetrator of the abuse is a stranger.

- The perpetrator is known to have an STD or is at high risk for STDs.

- Child has a relative or another person in the household with an STD.

- Child has symptoms or signs of active infection (e.g., vaginal discharge or pain, genital itching or odor, genital lesions or ulcers).

- Child or parent requests STD testing.

The physical examination and collection of vaginal specimens is often frightening or uncomfortable for a child and should be conducted by an experienced clinician. The CDC and the American Society of Pediatrics provide updated guidance for healthcare providers involved in the evaluation of childhood sexual assault/abuse.

LOW-INCOME POPULATIONS

As with most sociodemographic risk factors for domestic and sexual violence, the correlation between lower socioeconomic status and violence is potentially bidirectional. Economic abuse (considered a form of intimate partner violence) may precede more severe forms of physical and sexual violence. Women who are financially dependent on their abusers are less able to leave and more likely to return to an abusive relationship [79]. Greater economic dependence is associated with more severe abuse.

Financial instability is also a potential adverse effect of intimate partner violence. Current or past exposure to violence has been found to negatively affect ability to sustain stable employment, and women in abusive relationships frequently lose their jobs, experience high job turnover, are forced to quit, or are fired [80].

Victims of sexual violence also experience short- and long-term economic consequences, and low-income individuals are more vulnerable. Victims exceed non-victims in the average number and cost of medical care visits. Beyond medical costs, there are productivity costs and other long-term costs to victims and their families such as pain and suffering, trauma, disability, and risk of death. Sexual violence and the trauma resulting from it can have an impact on the survivor's employment in terms of time off from work, diminished performance, job loss, or being unable to work. These impacts disrupt earning power and have a long-term effect on the economic well-being of survivors [81].

PEOPLE LIVING IN RURAL COMMUNITIES

A large national study found that lifetime intimate partner violence victimization rates in rural areas (26.7% in women, 15.5% in men) are similar to the prevalence found among men and women in non-rural areas [82]. There is some evidence that intimate partner homicide rates may be higher in rural areas than in urban or suburban locales [83].

Substance use disorders and unemployment are more common among IPV perpetrators in rural areas [83]. It has been suggested that IPV in rural areas may be more chronic and severe and may result in worse psychosocial and physical health outcomes. Poverty in rural areas is also associated with an increased risk for IPV victimization and perpetration for both men and women [84]. Residents of rural areas are less likely to support government involvement in IPV prevention and intervention than urban residents [83].

Although the rates are similar, the risk factors, effects, and needs of rural victims are unique. For example, research indicates that rural women live three times further from their nearest IPV resource than urban women. In addition, domestic violence programs serving rural communities offer fewer services for a greater geographic area than urban programs [85].

It is important to assess victims' proximity to available resources and to help in times of crisis. Rural victims may benefit from improved access to services, including technology-based outreach (e.g., videoconferencing, telehealth programs) [86].

IMMIGRANTS AND REFUGEES

A variety of persons migrate to the United States, including legal immigrants granted the indefinite or time-limited right to live in the United States by immigration authorities; undocumented immigrants who have not been granted such a right; and refugees who are unable or unwilling to return to their country of origin due to fears of persecution based on their race or ethnicity, religion, nationality, political opinion, or gender identity or sexual orientation. For simplicity, all three groups are referred to as immigrants [87].

Recent immigrants are at increased risk for violence victimization. In one study of Chinese immigrants in the United States, acculturation and socioeconomic status were associated with severity, frequency, length, and type of abuse [88]. Persons who are displaced due to conflict in their home countries are also vulnerable to sexual violence. Studies indicate that approximately one in five refugees or displaced women in complex humanitarian settings have experienced sexual violence, but this is likely an underestimation [89]. Refugees may also experience torture and sexual violence prior to being displaced. Among male survivors, sexual torture is substantially under-reported, and estimates indicate that 5% to 15% of male survivors were sexually abused by threats of castration or rape, being raped or forced to perform sex in view of others, or receiving electric shock or mutilation to the genitals [90,91]. Fewer women than men are tortured in aggregate, but around 50% of female torture survivors report sexual torture, typically by rape and sometimes in front of family members [92,93,94].

Immigrants tend to underuse health services, especially undocumented immigrants, who typically lack health insurance and may avoid seeking medical attention out of fear of being deported. Immigration status and the inability to understand domestic violence within given cultural norms are major barriers to help-seeking among recent immigrants [95]. The Violence Against Women Act puts some protections in place for noncitizen women, including the ability to self-petition for citizenship (instead of requiring a citizen sponsor) and immigration relief to victims of sexual/other violence or human trafficking [96]. Access to bilingual and culturally appropriate services is also a major concern.

PEOPLE OF COLOR

In the United States, intimate partner violence disproportionately affects women of color [97]. Black and multiracial non-Hispanic women have significantly higher lifetime prevalence of rape, physical violence, or stalking by an intimate partner [98]. Black, American Indian or Alaska Native, and multiracial non-Hispanic men have a significantly higher lifetime prevalence of rape, physical violence, or stalking compared with white non-Hispanic men. These findings may be a reflection of the many stressors that racial and ethnic minority communities continue to experience. For example, a number of social determinants of mental and physical health, such as low income and limited access to education, community resources, and services, likely play important roles. These factors and medical mistrust, historical racism and trauma, perceived discrimination, and immigration status may affect help seeking and the assessment of victims [97].

When race and ethnicity are considered, it is important to remember that there is great diversity within these groups. Certain factors may be generally applicable, but there may be unique contributions by ethnic sub-group [99].

9. PERPETRATORS OF DOMESTIC/SEXUAL 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 [100]. 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 [101]. 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) [101].

In addition, abusers often suffer from low self-esteem and their sense of self and identity is directly connected to their partner [101]. 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 [102].

In some cases, a perpetrator and victim will seek help together (joint or couples counseling) to resolve issues in their relationship. Some domestic-violence focused joint counseling approaches have been described [103]. However, many organizations, including the National Domestic Violence Hotline, the Department of Justice, the American Bar Association, and Futures Without Violence, recommend against joint counseling for violent couples due to the risk of additional harm to and isolation of the victim [104,105]. A better option for abusive partners is battering intervention and prevention programs.

10. ASSESSMENT AND SCREENING METHODS

SCREENING

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 [49]. 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 [106].

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 [49]. Although awareness and assessment for IPV has increased among healthcare providers, many are still hesitant to inquire about abuse [107]. At a minimum, those exhibiting signs of domestic violence should be screened. 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 [100].

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 experience IPV are also more likely to report asthma, irritable bowel syndrome, and diabetes [3]. 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.

Trauma-informed screening is an essential part of the intake evaluation and the treatment planning process. Trauma-informed practices include [108]:

- Reflecting an understanding of trauma and its many effects on health and behavior

- Addressing both physical and psychologic safety concerns

- Using a culturally informed, strengths-based approach

- Helping to illuminate the nature and effects of abuse on victims' everyday experience

- Providing opportunities for patients to regain control over their lives

Screening processes can be developed that allow staff without advanced degrees or graduate-level training to conduct them, whereas assessments for trauma-related disorders require a mental health professional trained in assessment and evaluation processes. The most important domains to screen among individuals with trauma histories include [109]:

- Trauma-related symptoms

- Depressive or dissociative symptoms, sleep disturbances, and intrusive experiences

- Past and present mental disorders, including typically trauma-related disorders (e.g., mood disorders)

- Severity or characteristics of a specific trauma type (e.g., forms of interpersonal violence, adverse childhood events, combat experiences)

- Substance abuse

- Social support and coping styles

- Availability of resources

- Risks for self-harm, suicide, and violence

- Health screenings

In addition to broad screening tools that capture various traumatic experiences and symptoms, other screening tools, such as the Intimate Partner Violence Screening Tool, focus on acknowledging a specific type of traumatic event [109]. These tools may be used to screen and assess for the presence of adverse or traumatic life experiences. However, it is not necessary to use a formal tool to screen for trauma and exploration of trauma should be done by trained, experienced, and skilled staff. This process requires a safe, comfortable, and respectful environment and a trusting, caring relationship. As mentioned previously, it is not necessary for an individual to disclose painful experiences to be helped. By using universal precautions and treating all people as if they have been exposed to trauma and by using trauma-informed approaches, healing and recovery can be promoted [110].

Universal Trauma-Informed Education

A trauma-informed approach to screening and care of victims of violence creates a space that is supportive, safe, and conducive to healing. Universal trauma-informed education focuses less on formalized screening tools and checklists and more on creating spaces in which traumatic experiences are freely discussed. In this approach, the practitioner conveys universal information about intimate partner violence, in some cases tailored to the specific setting or patient population [111]. These settings "facilitate disclosure for victims of IPV and meet disclosure with empathy, competence, and appropriate referrals" [111]. This approach can be used in any healthcare or human services setting.

ASSESSMENT

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 [107]. 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 [49].

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 the assessment (Table 3). If the patient is in immediate danger, referral to an advocate, support system, hotline, or shelter is indicated [49].

Table 3: 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: [49]

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 [49]. These responses will help formulate an appropriate intervention.

Culturally Sensitive Assessment

Many trauma-related symptoms and disorders are culture specific, and a patient's cultural background should be considered in screening and assessment [109]. 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 [112]. Assessment tools should be culturally appropriate for the patient, whenever possible. 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 [113]. 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 [113]. 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 [113]. 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.

Sexual Assault Victims

Given the societal context of sexual assault reporting, the practitioner should accept the person's account of his or her traumatic experience without investigating the authenticity of the claims. Victims/survivors may anticipate disbelief and denial from the clinician due to past negative responses to their disclosures from friends, family, or the criminal justice system.

Practitioner gender should also be considered when working with sexual assault survivors. Avoid assuming that a female or male patient will prefer a practitioner of either the same or the opposite gender. Instead, discuss this issue with the patient and, if possible, let him or her choose the provider gender [114].

The proper clinical assessment of a person who has been sexually assaulted requires a systematic, patient, and thorough approach. It is of necessity time-consuming and should be conducted with sensitivity and respect for the patient's emotional state. Preferably, providers who have been specifically trained for this task should perform the initial clinical examination. More than 500 hospitals and other health facilities in the United States have now addressed this need by adopting the Sexual Assault Nurse Examiner (SANE) program. A SANE is a trained nurse specialist who works within an interdisciplinary team to carry out a general and forensic clinical examination of the sexual assault patient and to develop a strategy for support and after-care [115].

The evaluation and treatment of sexual assault victims should incorporate the following components [115,116]:

- General assessment and treatment of physical injuries, with special attention to the genitalia

- Forensic evaluation, where indicated and with informed consent

- Pregnancy risk assessment and prevention

- Evaluation, treatment, and prevention of STDs

- Psychologic assessment, crisis intervention, and follow-up referral for counseling

As discussed, when appropriate, a trauma-informed approach should be used for victims of sexual violence—during both physical and psychologic assessments.

Ending Assessments and Safety Planning

Evidence Based Practice Recommendation

The World Health Organization asserts that women who disclose any form of violence by an intimate partner (or other family member) or sexual assault by any perpetrator should be offered immediate support.

https://www.who.int/reproductivehealth/publications/violence/9789241548595/en

Last Accessed: May 7, 2019

Level of Evidence: Strong/Indirect Evidence

In some contexts of repeated trauma exposure, victims presenting for treatment may remain vulnerable to ongoing threat and further trauma. With victims of domestic violence and victims of sexual assault perpetrated in their current job setting or by an intimate partner, treatment may be affected by returning to unsafe environments. In the presence of ongoing risk, interventions should initially focus on ensuring safety, stabilization, and symptom management, instead of initiating the trauma-focused components of treatment. Ensure, to the extent possible, the safety, security, and survival needs of the patient by helping secure food, hydration, clothing, hygiene, and shelter. This will include promoting patient stabilization and the importance of sleep and replacing medications that are destroyed or lost. Patients also benefit from education on the process they are experiencing. Patients should be counseled regarding limiting ongoing harm by reducing the use of alcohol, tobacco, caffeine, and illicit psychoactive substances, if needed. Family, friends, and community resources should be identified. From the initial point of contact onward, it is vital to establish a working treatment alliance with the patient and maintain a supportive, non-blaming, non-judgmental stance [114,117].

It is important to note that general safety planning does not take into account the specific needs of victims who fall into vulnerable populations or affected children [118]. Because these individuals are at higher risk of marginalization and oppression, they may feel powerless to execute a safety plan. It is important for practitioners to assess each victim and his/her readiness to change, circumstances, resources, and needs in order to tailor a specific safety plan [119].

11. BEST PRACTICES IN FOLLOW-UP CARE FOR VICTIMS OF VIOLENCE

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 [49].

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 [49].

In addition to providing acute care and scheduling follow-up appointments, providers should connect victims of violence with available resources. After identifying victims and their abusers, healthcare professionals should immediately implement a plan of action that includes providing a referral to a local domestic violence shelter to assist the victim and the victim's family. 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 is generally available by individual counselors who specialize in the care of domestic/sexual violence victims. 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 victims who are unsure of their options.

12. BUILDING EFFECTIVE COMMUNITY PARTNERSHIPS AND COLLABORATIONS WITH COMMUNITY-BASED AGENCIES

Domestic and sexual violence impact many domains of a victim's life, and collaboration between health, mental health, social service, law enforcement, and community-based agencies is vital to providing the best possible care and support. Community agencies provide services such as 24-hour hotlines, shelter, support groups, counseling, and legal advocacy. These agencies and the specialized services they provide for victims of sexual and domestic violence are essential [120].

13. APPROPRIATE RESPONSES AND DOCUMENTATION

Healthcare and mental health professionals involved in the care of patients who have been victims of abuse should fully document suspected abuse, assessment results, any evidence of abuse, and interventions/safety planning in the patient's record or clinical notes. All aspects of patient assessment, documentation, safety planning, communication, intervention, and follow-up should take into account the immediate and long-term safety of the victim and any dependents [123].

All practitioners who deal with domestic and/or sexual violence should periodically review safety planning with victims. Homicide is of high risk for victims; therefore, safety planning is crucial. When advocating a safety plan, it is important to:

- Encourage the victim to be aware of weapons in the residence.

- Have victims make a plan of what to do if violence escalates and where to go if leaving is an option.

- If children are old enough, they should be instructed about the safety plan and assigned roles.

- When possible, victims should save some money in a private bank account or hide money for escape. Victims should be informed that if the abuser finds out about a separate bank account, they could be in danger.

- Encourage victims to keep a bag packed with necessities and stored in a safe place in the event leaving must be immediate.

- Advise victims to work out a code word or signal with the children so they will know when to implement an escape plan.

- Encourage victims to keep a list of important phone numbers in their packed bag. Memorizing important numbers provides more safety.

- Recommend that copies of important documents and necessary items be available.

Although safety planning may be advocated, it does not necessarily mean victims will employ safety planning guidelines.

Ideally, the victim of a sexual or physical assault should be offered a formal forensic evaluation; this requires written documentation of informed consent. Injuries should be documented in photographs, diagrams, or sketches. A growing number of hospitals now employ dedicated forensic nurses, including SANEs, as part of a multispecialty sexual assault team [115].

SANEs have completed specialized training in the medical forensic care of the patient who has experienced physical violence, abuse, or sexual assault. An important component of the care offered by the SANE is the medical forensic examination. This consists of a medical forensic history, a detailed physical and emotional assessment, written and photographic documentation of injuries, and collection and management of forensic samples. The SANE is trained to ensure that evidence is collected and documented according to established protocol and local jurisdiction procedures and that the "chain of custody" is properly maintained in the event of later legal proceedings. Evidence collection kits designed for this purpose are available commercially or, in some states, may be obtained through designated distribution centers. Medically trained rape crisis advocates typically accompany SANEs to provide support, information, and follow-up guidance to victims [123].

Often, however, these trained specialists are not the first professionals to interact with the patient. Consequently, all healthcare professionals, particularly those in an emergency care setting, should have an understanding of the principles that govern proper collection and preservation of evidence during the examination of an assault victim. At stake is the successful prosecution of the assault perpetrator, which often is compromised by insufficient or improperly collected evidence or by not following evidence through the chain of custody.

LEGAL INTERVENTIONS

Domestic violence victims can obtain protective orders through a civil proceeding [42]. Until the enactment of Pennsylvania's Protection of Abuse Act in 1976, only two states had protective order legislation [42]. Protective orders prohibit the abuser from communicating with the victim and/or other family members in a threatening manner. The order also prohibits the abuser from going to the home or place of employment of the victim or family members. Violations of protective orders can result in fines, imprisonment, or a combination of both [42].

Victims can file for a temporary or permanent protective order. A temporary protective order does not require the abuser to be present. These orders last about 30 days or until a court date is scheduled. A permanent protective order requires both the victim and abuser to be present in court. Permanent protective orders last for about 12 months [121].

Laws for dating violence are different. All 50 states and the District of Columbia have state laws related to dating violence. However, the term "dating violence" is not used. Instead, the following terms are used: "sexual assault," "domestic violence," and "stalking" [122]. Only 39 states and the District of Columbia offer the option of protective orders for dating violence victims. The National Center for Victims of Crime is a resource to obtain additional information about state laws.

For more information about legal interventions, state coalitions for domestic violence can be contacted. The American Bar Association has compiled a list of domestic violence state coalitions. Although, the American Bar Association Commission on Domestic and Sexual Violence suggests victims do Internet searches for local domestic violence resources, they caution them to use a local library or go to a friend's home where they can access a computer without the abuser being able to track Internet and email activities [123].

CASE MANAGEMENT

Because abused women often suffer physical injuries, they will likely seek care from a healthcare professional who can make referrals to counseling services. Some women seek counseling on their own. After identifying victims and their abusers, mental health professionals should immediately implement a plan of action that includes providing referrals for available community services and safe havens to assist the victim and the victim's family.

Most abused women are in ongoing danger when seeking help. If they decide to leave, the risk factors increase significantly [124]. Accordingly, if the victim consents, acute situations should be referred immediately to local law enforcement officials. Other resources include crisis hotlines and rape relief centers. After victims are in the system, counseling and follow-up is generally available through victims of crime programs. A list of approved services is provided and includes social workers, marriage and family therapists, psychologists, psychiatrists, other mental health workers, and community mental health services. The goals are to make resources accessible and safe and to enhance support for crime victims who are unsure of their options [125].

Assisting crime victims is essential. Coordinating and accessing an array of social service benefits, which include mental health counseling, healthcare, legal and advocacy services, and other public benefits, is crucial. Consequently, it is vital for professionals to establish relationships with community organizations and be acquainted with appropriate contact persons. When working with diverse cultural and ethnic groups, it is also important to develop relationships with culturally sensitive and bilingual professionals who can provide appropriate interventions.

SHELTERS

Shelters provide a haven for domestic violence victims and their children. They provide temporary emergency housing and a range of services to help victims "get back on their feet." Services vary but may include job training, support groups, skills development groups, and counseling.

To access shelter information by geographic region, there is a valuable website sponsored by the Office for Victims of Crime Resources Center. The Directory of Crime Victim Services is available at https://ovc.ncjrs.gov/findvictimservices. This is a search engine that allows resources and services to be located by state.

14. RESOURCES

MilitaryOneSource

https://www.militaryonesource.mil/leaders-service-providers/child-abuse-and-domestic-abuse

National Coalition Against Domestic Violence

https://ncadv.org

National Domestic Violence Hotline

1-800-799-7233

1-855-812-1011 (VP)

1-800-787-3224 (TTY)

https://www.thehotline.org

Rape, Abuse, and Incest National Network (RAINN)

1-800-656-4673

https://www.rainn.org

National Center for Victims of Crime

https://victimsofcrime.org

The Network/La Red

https://tnlr.org

Matahari Women Workers' Center

https://www.mataharijustice.org

Victim Rights Law Center

https://www.victimrights.org

Works Cited

1. Centers for Disease Control and Prevention. Intimate Partner Violence Surveillance: Uniform Definitions and Recommended Data Elements, Version 2.0. Available at https://www.cdc.gov/violenceprevention/pdf/intimatepartnerviolence.pdf. Last accessed May 7, 2019.

2. Jane Doe, Inc. Sexual Violence Terms and Definitions. Available at http://www.janedoe.org/learn_more/what_is_sexual_violence/sexual_violence_terms_and_definitions. Last accessed May 7, 2019.

3. Tjaden P, Thoennes N. Full Report of the Prevalence, Incidence, and Consequences of Intimate Partner Violence Against Women: Findings from the National Violence Against Women Survey. Available at https://www.ncjrs.gov/pdffiles1/nij/183781.pdf. Last accessed May 7, 2019.

4. Miller E, Decker MR, McCauley HL, et al. Pregnancy coercion, intimate partner violence, and unintended pregnancy. Contraception. 2010;81(4):316-322.

5. Holliday CN, McCauley HL, Silverman JG, et al. Racial/ethnic differences in women's experiences of reproductive coercion, intimate partner violence, and unintended pregnancy. J Womens Health (Larchmt). 2017;26(8):828-835.

6. American College of Obstetricians and Gynecologists Committee on Health Care for Underserved Women. Committee Opinion: Reproductive and Sexual Coercion. Available at https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Health-Care-for-Underserved-Women/Reproductive-and-Sexual-Coercion. Last accessed May 7, 2019.

7. Williams JR, Halstead V, Salani D, Koermer N. Intimate partner violence screening and response: policies and procedures across health care facilities. Womens Health Issues. 2016;26(4):377-383.

8. American Medical Association Council on Ethical and Judicial Affairs. Physicians and domestic violence: ethical considerations. JAMA. 1992;267:3190-3193.

9. Ghandour RM, Campbell JC, Lloyd J. Screening and counseling for intimate partner violence: a vision for the future. J Womens Health. 2015;24(1):57-61.

10. The Center for Family Justice. What is Sexual Assault? Available at https://centerforfamilyjustice.org/faq/sexual-violence. Last accessed May 7, 2019.

11. American Medical Association Council on Scientific Affairs. Violence against women: relevance for medical practitioners. JAMA. 1992;267:3184-3189.

12. Scherer DD. Tort remedies for victims of domestic abuse. S C Law Rev. 1992;43:543-579.

13. Verizon Foundation and MORE Magazine. Survey: Exploring the Relationship between Domestic Violence and Chronic Health Conditions. Available at http://www.ncdsv.org/Verizon-More_Exploring-the-Relationship-between-DV-and-Chronic-Health-Conditions-survey-summary_10-2013.pdf. Last accessed May 7, 2019.

14. Riviello R, Sullivan J, Bhatt K, et al. Persistent adverse mental and physical health outcomes are common among women after sexual assault. West J Emerg Med. 2017;18(6.1):S7.

15. Riggs N, Houry D, Long G, Markovchick V, Feldhaus, KM. Analysis of 1,076 cases of sexual assault. Ann Emerg Med. 2000;35(4):358-362.

16. Avengo A, Mills T, Mills L. Sexual assault victimization in the emergency department: analysis by demographic and event characteristics. J Emerg Med. 2009;37(3):328-334.

17. Maguire W, Goodall E, Moore T. Injury in adult female sexual assault complaints and related factors. Eur J Obstet Gynecol Reprod Biol. 2009;142:149-153.

18. Slaughter L, Brown C, Crowley S, Peck R. Patterns of genital injury in female sexual assault victims. Am J Obst Gynecol. 1997;176(3):609-616.

19. Machielse P. Forensic Emergency Nursing: Role Integration. Available at https://www.forensicnurses.org/general/custom.asp?page=249. Last accessed May 7, 2019.

20. Holmes, M. Resnick H. Kilpatrick, D, et al. Rape-related pregnancy estimates and descriptive characteristics from a national sample of women. Am J Obstet Gynecol. 1996;175(2): 320-324.

21. Tjaden P, Thoennes N. Extent, Nature, and Consequences of Rape Victimization: Findings from the National Violence Against Women Survey. Available at https://www.ncjrs.gov/pdffiles1/nij/210346.pdf. Last accessed May 7, 2019.

22. Schwartz J. Sexual violence against women: prevalence, consequences, societal factors, and prevention. Am J Prev Med. 1991;7(6):363-373.

23. Goodman LA, Koss MP, Russo NP. Violence against women: physical and mental health effects. Part 1: research findings. Applied and Prev Psychol. 1993;2(2):79-89.

24. Ahrens C, Aldana E. The ties that bind: understanding the impact of sexual assault disclosure on survivors' relationships with friends, family, and partners. J Trauma Dissociation. 2012;13(2):226-243.

25. Paras M, Murad M, Chen L, et al. Sexual abuse and lifetime diagnosis of somatic disorders: a systematic review and meta-analysis. JAMA. 2009;302(5):550-561.

26. Stein M, Lang A, Laffaye C, Satz L, Lenox R, Dresselhaus T. Relationship of sexual assault history to somatic symptoms and health anxiety in women. Gen Hosp Psychiatry. 2004;26(3):178-183.

27. Suris A, Lind L, Kushner T, Borman P, Petty F. Sexual assault in women veterans: an examination of PTSD risk, health care utilization, and cost of care. Psychosom Med. 2004;66(5):749-756.

28. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR3):1-137.

29. Glaser JB, Schachter CM, Benes S, et al. Sexually transmitted infection in postpubertal female rape victims. J Infect Dis. 1991;164(4):726-730.

30. Lutgendorf MA, Thagard A, Rockswold PD, Busch JM, Magann EF. Domestic violence screening of obstetric triage patients in a military population. J Perinatol. 2012;32(10):763-769.

31. American College of Obstetricians and Gynecologists Committee on Health Care for Underserved Women. Committee Opinion: Intimate Partner Violence. Available at https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Health-Care-for-Underserved-Women/Intimate-Partner-Violence. Last accessed May 7, 2019.

32. Chu SY, Goodwin MM, D'Angelo DV. Physical violence against U.S. women around the time of pregnancy, 2004–2007. Am J Prev Med. 2010;38(3):317-322.

33. Alhusen JL, Ray E, Sharps P, Bullock L. Intimate partner violence during pregnancy: maternal and neonatal outcomes. J Womens Health. 2015;24(1):100-106.

34. McFarlane J, Maddoux J, Cesario S, et al. Effect of abuse during pregnancy on maternal and child safety and functioning for 24 months after delivery. Obstet Gynecol. 2014;123(4):839-847.

35. Chambliss LR. Intimate partner violence and its implication for pregnancy. Clin Obstet Gynecol. 2008;51(2):385-397.

36. Flanagan JC, Gordon KC, Moore TM, Stuart GL. Ethnic women's stress, depression, and relationship adjustment profiles as they relate to intimate partner violence and mental health during pregnancy and postpartum. Psychol Violence. 2015;5(1):66-73.

37. World Health Organization. Global and Regional Estimates of Violence against Women: Prevalence and Health Effects of Intimate Partner Violence and Non-Partner Sexual Violence. Available at https://apps.who.int/iris/bitstream/handle/10665/85239/9789241564625_eng.pdf. Last accessed May 7, 2019.

38. Stewart FH, Tressell J. Prevention of pregnancy resulting from rape: a neglected preventive public health measure. Am J Prev Med. 2000;19(4):228-229.

39. Von Hertzen H, Piaggio G, Ding H. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicenter randomized trial. Lancet. 2002;360:1803-1810.

40. Guedes A, Mikton C. Examining the intersections between child maltreatment and intimate partner violence. West J Emerg Med. 2013;14(4):377-379.

41. Cooper A, Smith EL. Homicide Trends in the United States, 1980–2008. Washington, DC: Bureau of Justice Statistics; 2011. Available at https://www.bjs.gov/content/pub/pdf/htus8008.pdf. Last accessed May 7, 2019.

42. Carlson MJ, Harris SD, Holden GW. Protective orders and domestic violence: risk factors for re-abuse. J Fam Violence. 1999;14(2):205-226.

43. National Committee for the Prevention of Elder Abuse, National Adult Protective Services Association. The 2004 Survey of State Adult Protective Services: Abuse of Adults 60 Years of Age and Older. Washington, DC: The National Center on Elder Abuse; 2006.

44. Sedlak AJ. Prevention of wife abuse. In: Van Hasselt VB, Morrison RL, Bellack AS, Hersen M (eds). Handbook of Family Violence. New York, NY: Plenum Press; 1988: 319-358.

45. Fischer K, Vidmar N, Ellis R. The culture of battering and the role of mediation in domestic violence cases. SMU Law Rev. 1993;46:2117-2174.

46. Okun L. Woman Abuse: Facts Replacing Myths. Albany, NY: State University of New York Press; 1986.

47. National Center on Elder Abuse. Statistics/Data. Available at https://ncea.acl.gov/What-We-Do/Research/Statistics-and-Data.aspx. Last accessed May 7, 2019.

48. Sonkin DJ, Martin D, Walker LE. The Male Batterer: A Treatment Approach. New York, NY: Springer Publishing Company; 1985.

49. Wallace R. Identifying potential challenges to providing emergency advocacy services to male victims of intimate partner violence. Partner Abuse. 2014;5(1):58-68.

50. Catalano S, Smith E, Snyder H. Female Victims of Violence. Available at https://www.bjs.gov/content/pub/pdf/fvv.pdf. Last accessed May 7, 2019.

51. National Center for Injury Prevention and Control. NISVS 2010 Findings on Victimization by Sexual Orientation. Available at https://www.cdc.gov/violenceprevention/pdf/nisvs_sofindings.pdf. Last accessed May 7, 2019.

52. Erez E, Bach S. Immigration, domestic violence, and the military: the case of "military brides." Violence Against Women. 2003;9(9):1093-1117.

53. U.S. Government Accountability Office. Military Personnel: Sustained Leadership and Oversight Needed to Improve DOD's Prevention and Treatment of Domestic Abuse. Available at https://www.gao.gov/new.items/d10923.pdf. Last accessed May 7, 2019.

54. Krimm J, Heinzer MM. Domestic violence screening in the emergency department of an urban hospital. J Natl Med Assoc. 2002;94(6):484-491.

55. Military One Source. Preventing Abuse and Neglect. Available at https://www.militaryonesource.mil/family-relationships/family-life/preventing-abuse-neglect. Last accessed May 7, 2019.

56. McCarroll JE, Ursano RJ, Liu X, et al. Deployment and the probability of spousal aggression by U.S. Army soldiers. Mil Med. 2010;175(5):352-356.

57. American Bar Association Commission on Domestic Violence. Domestic Violence Statistics. Available at https://www.americanbar.org/groups/domestic_violence/Initiatives/resources/statistics. Last accessed May 7, 2019.

58. 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.

59. Grant JM, Mottet LA, Tanis J, Harrison J, Herman JL, Keisling M. Injustice at Every Turn: A Report of the National Transgender Discrimination Survey. Available at https://www.thetaskforce.org/injustice-every-turn-report-national-transgender-discrimination-survey. Last accessed May 7, 2019.

60. Nuttbrock L, Hwahng S, Bockting W, et al. Psychiatric impact of gender-related abuse across the life course of male-to-female transgender persons. J Sex Res. 2010;47(1):12-23.

61. International Transgender Day of Remembrance. Available at https://tdor.info. Last accessed May 7, 2019.

62. Safe Housing Partnerships. The Intersection of Domestic Violence and Homelessness. Available at https://safehousingpartnerships.org/sites/default/files/2017-05/SHP-Homelessness%20and%20DV%20Inforgraphic_1.pdf. Last accessed May 7, 2019.

63. National Online Resource Center on Violence Against Women. No Safe Place: Sexual Assault in the Lives of Homeless Women. Available at https://vawnet.org/sites/default/files/materials/files/2016-09/AR_SAHomelessness.pdf. Last accessed May 7, 2019.

64. Doorways for Women and Families. The Facts about Sexual Assault. Available at https://www.doorwaysva.org/our-work/education-advocacy/the-facts-about-sexual-assault. Last accessed May 7, 2019.

65. National Sexual Violence Resource Center. Housing, Homelessness, and Sexual Violence Statistics. Available at https://www.nsvrc.org/sites/default/files/NSAC11_Handouts/NSAC11_Handout_With_Statistics.pdf Last accessed May 7, 2019.

66. Breiding MJ, Armour BS. The association between disability and intimate partner violence in the United States. Ann Epidemiol. 2015;25(6):455-457.

67. Browne A, Agha A, Demyan A, Beatriz E. Examining Criminal Justice Responses to and Help-Seeking Patterns of Sexual Violence Survivors With Disabilities. Available at https://www.ncjrs.gov/App/AbstractDB/AbstractDBDetails.aspx?id=272356. Last accessed May 7, 2019.

68. Shapiro J. The Sexual Assault Epidemic No One Talks About. Available at https://www.npr.org/2018/01/08/570224090/the-sexual-assault-epidemic-no-one-talks-about. Last accessed May 7, 2019.

69. Rape, Abuse, and Incest National Network. Sexual Abuse of People with Disabilities. Available at https://www.rainn.org/articles/sexual-abuse-people-disabilities. Last accessed May 7, 2019.

70. Soper RG. Intimate Partner Violence and Co-Occurring Substance Abuse/Addiction. Available at https://www.asam.org/resources/publications/magazine/read/article/2014/10/06/intimate-partner-violence-and-co-occurring-substance-abuse-addiction. Last accessed May 7, 2019.

71. DrugRehab.com. Domestic Abuse and Addiction. Available at https://www.drugrehab.com/guides/domestic-abuse. Last accessed May 7, 2019.

72. Kothari R, Easter A, Lewis R, Howard LM, Micali N. Intimate partner violence among women with eating disorders during the perinatal period. Int J Eat Disord. 2015;48(6):727-735.

73. Fischer S, Stojek M, Hartzell E. Effects of multiple forms of childhood abuse and adult sexual assault on current eating disorder symptoms. Eat Behav. 2010;11(3):190-192.

74. Bonomi A, Nichols E, Kammes R, Green T. Sexual violence and intimate partner violence in college women with a mental health and/or behavior disability. J Womens Health (Larchmt). 2018;27(3):359-368.

75. Dardis CM, Dixon KJ, Edwards KM, Turchik JA. An examination of the factors related to dating violence perpetration among young men and women and associated theoretical explanations: a review of the literature. Trauma Violence Abuse. 2015;16(2):136-152.

76. Morelli M, Bianchi D, Baiocco R, Pezzuti L, Chirumbolo A. Sexting, psychological distress and dating violence among adolescents and young adults. Psicothema. 2016;28(2):137-142.

77. O'Keefe M. Teen Dating Violence: A Review of Risk Factors and Prevention Efforts. Available at https://vawnet.org/sites/default/files/materials/files/2016-09/AR_TeenDatingViolence.pdf. Last accessed May 7, 2019.

78. Jenny C, Crawford-Jakubiak JE, Committee on Child Abuse and Neglect, et al. The evaluation of children in the primary care setting when sexual abuse is suspected. Pediatrics. 2013;132:e558-e567.

79. University of Washington Extension. Financial Capability and Domestic Violence. Available at https://fyi.uwex.edu/financialseries/files/2012/02/Financial-Capability-and-Domestic-Violence.pdf. Last accessed May 7, 2019.

80. American Psychological Association. Violence and Socioeconomic Status. Available at https://www.apa.org/pi/ses/resources/publications/violence. Last accessed May 7, 2019.

81. Center for Disease Control and Prevention. STOP SV: A Technical Package to Prevent Sexual Violence. Available at https://stacks.cdc.gov/view/cdc/39126. Last accessed May 7, 2019.

82. Breiding MJ, Ziembroski JS, Black MC. Prevalence of rural intimate partner violence in 16 U.S. states, 2005. J Rural Health. 2009;25(3):240-246.

83. Edwards KM. Intimate partner violence and the rural-urban-suburban divide: myth or reality? A critical review of the literature. Trauma Violence Abuse. 2015;16(3):359-373.

84. Edwards KM, Mattingly MJ, Dixon KJ, Banyard VL. Community matters: intimate partner violence among rural young adults.Am J Community Psychol. 2014;53(1-2):198-207.

85. Peek-Asa C, Wallis A, Harland K, Beyer K, Dickey P, Saftlas A. Rural disparity in domestic violence prevalence and access to resources. J Womens Health (Larchmt). 2011;20(11):1743-1749.

86. Gray MJ, Hassija CM, Jaconis M, et al. Provision of evidence-based therapies to rural survivors of domestic violence and sexual assault via telehealth: treatment outcomes and clinical training benefits. Train Educ Prof Psychol. 2015;9(3):235-241.

87. Public Health Agency of Canada. Canadian Guidelines on Sexually Transmitted Infections. Section 6: Specific Populations: Immigrants and Refugees. Available at https://www.canada.ca/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/sexually-transmitted-infections. Last accessed May 7, 2019.

88. Kim C, Sung HE. The effects of acculturation on intimate partner violence among Chinese immigrants in New York City. J Fam Violence. 2016;31(3):325-336.

89. Vu A, Adam A, Wirtz A, et al. The prevalence of sexual violence among female refugees in complex humanitarian emergencies: a systematic review and meta-analysis. PLoS Curr. 2014;6.

90. Loncar M, Henigsberg N, Hrabac P. Mental health consequences in men exposed to sexual abuse during the war in Croatia and Bosnia. J Interpers Violence. 2010;25(2):191-203.

91. Oosterhoff P, Zwanikken P, Ketting E. Sexual torture of men in Croatia and other conflict situations: an open secret. Reprod Health Matters. 2004;12(23):68-77.

92. Miles SH, Garcia-Peltoniemi RE. Torture survivors: what to ask, how to document. J Fam Pract. 2012;61(4):E1-E6.

93. Robertson CL, Halcon L, Savik K, et al. Somali and Oromo refugee women: trauma and associated factors. J Adv Nurs. 2006;56(6):577-587.

94. Hooberman JB, Rosenfeld B, Lhewa D, Rasmussen A, Keller A. Classifying the torture experiences of refugees living in the United States. J Interpers Violence. 2007;22(1):108-123.

95. Reina AS, Lohman BJ, Maldonado MM. "He said they'd deport me:" factors influencing domestic violence help-seeking practices among Latina immigrants. J Interpers Violence. 2014;29(4):593-615.

96. Chang-Muy F, Congress EP (eds). Social Work with Immigrants and Refugees: Legal Issues, Clinical Skills, and Advocacy. 2nd ed. New York, NY: Springer; 2016.

97. Stockman JK, Hayashi H, Campbell JC. Intimate partner violence and its health impact on ethnic minority women [corrected].J Womens Health (Larchmt). 2015;24(1):62-79.

98. Centers for Disease Control and Prevention. Intimate Partner Violence in the United States—2010. Available at https://stacks.cdc.gov/view/cdc/21961. Last accessed May 7, 2019.

99. Lacey KK, West CM, Matusko N, Jackson JS. Prevalence and factors associated with severe physical intimate partner violence among U.S. black women: a comparison of African American and Caribbean blacks. Violence Against Women. 2016;22(6): 651-670.

100. Gerlock AA. Domestic violence and post-traumatic stress disorder severity for participants of a domestic violence rehabilitation program. Mil Med. 2004;169(6):470-474.

101. Catalano S. Intimate Partner Violence, 1993–2010. Available at https://www.bjs.gov/content/pub/pdf/ipv9310.pdf. Last accessed May 7, 2019.

102. Fox CL, Corr M-L, Gadd D, Butler I. Young Teenagers' Experiences of Domestic Abuse. Available at http://www.boystomenproject.com/wp-content/uploads/2013/04/Poster-Experiences-of-DA.pdf. Last accessed May 7, 2019.

103. Stith SM, McCollum EE, Rosen KH. Couples Therapy for Domestic Violence: Finding Safe Solutions. Washington, DC: American Psychological Association; 2011.

104. Centers for Domestic Peace. Dangers of Couples Counseling. Available at http://www.centerfordomesticpeace.org/sites/default/files/Dangers%20of%20Couples%20Counseling.pdf. Last accessed May 7, 2019.

105. The National Domestic Violence Hotline. Why We Don't Recommend Couples Counseling for Abusive Relationships. Available at https://www.thehotline.org/2014/08/01/why-we-dont-recommend-couples-counseling-for-abusive-relationships. Last accessed May 7, 2019.

106. 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.

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

108. Sullivan CM, Goodman LA, Virden T, Strom J, Ramirez R. Evaluation of the effects of receiving trauma-informed practices on domestic violence shelter residents. Am J Orthopsychiatry. 2018;88(5):563-570.

109. Substance Abuse and Mental Health Services Administration. Trauma-Informed Care in Behavioral Health Services. Available at https://www.integration.samhsa.gov/clinical-practice/SAMSA_TIP_Trauma.pdf. Last accessed May 7, 2019.

110. Substance Abuse and Mental Health Services Administration. Trauma. Available at https://www.integration.samhsa.gov/clinical-practice/trauma-informed. Last accessed May 7, 2019.

111. Greville L. Mental health monitor: universal trauma-informed education—addressing intimate partner violence. Social Work Today. 2016;16(1):34.

112. 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.

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

114. Phoenix Australian Centre for Posttraumatic Mental Health. Australian Guidelines for the Treatment of Adults with Acute Stress Disorder and Posttraumatic Stress Disorder. Available at https://phoenixaustralia.org/wp-content/uploads/2015/03/Phoenix-ASD-PTSD-Guidelines.pdf. Last accessed May 7, 2019.

115. U.S. Department of Justice, Office of Violence Against Women. A National Protocol for Sexual Assault Medical Forensic Evaluations Adults/Adolescents. Available at https://www.ncjrs.gov/pdffiles1/ovw/241903.pdf. Last accessed May 7, 2019.

116. Burgess A, Fawcett J. The comprehensive sexual assault assessment tool. Nurse Pract. 1996;21(4):66, 71-76, 78.

117. U.S. Department of Veterans Affairs, Department of Defense VA/DoD Clinical Practice Guideline for Management of Post-Traumatic Stress. Available at https://www.healthquality.va.gov/guidelines/MH/ptsd/cpg_PTSD-FULL-201011612.pdf. Last accessed May 7, 2019.

118. Murray CE, Horton GE, Johnson CH, et al. Domestic violence service providers' perceptions of safety planning: a focus group study. J Fam Violence. 2015;30(3):381-392.

119. Parker EM, Gielen AC. Intimate partner violence and safety strategy use: frequency of use and perceived effectiveness. Womens Health Issues. 2014;24(6):584-593.

120. Conference of Boston Teaching Hospitals. Best Practices in Healthcare and Domestic Violence: Lessons Learned in Boston. Available at http://cobth.org/PDF/DVManual/FINAL_Best%20Practices%20in%20Healthcare%20and%20Domestic%20Violence%202018%2002%2012%2018.pdf. Last accessed May 7, 2019.

121. Carlson MJ, Harris SD, Holden GW. Protective orders and domestic violence: risk factors for re-abuse. J Fam Violence. 1999;14(2): 205-226.

122. National Center for Victims of Crime. Teen Dating Violence Fact Sheet. Available at http://www.ncdsv.org/images/NCVC_TDVFactSheet_2007.pdf. Last accessed May 7, 2019.

123. American Bar Association Commission on Domestic Violence. How An Abuser Can Discover your Internet Activities. Available at http://www.ncdsv.org/images/ABA_Abuser.pdf. Last accessed May 7, 2019.

124. Campbell J, McKenna LS, Torres S, Sheridan D, Landenburger K. Nursing care of abused women. In: Campbell J, Humphreys J (eds). Nursing Care of Survivors of Family Violence. St. Louis: Mosby; 1993: 248-289.

125. Heise L, Ellsberg M, Gottemoeller M. Ending Violence Against Women. Population Reports, Series L, No. 11. Baltimore, MD: Johns Hopkins University School of Public Health; 1999.

Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Screening for intimate partner violence, elder abuse, and abuse of vulnerable adults: U.S. Preventive Services Task Force final recommendation statement. JAMA. 2018;320(16):1678-1687. Available at https://jamanetwork.com/journals/jama/fullarticle/2708121. Last accessed May 7, 2019.

2. World Health Organization. Responding to Intimate Partner Violence and Sexual Violence against Women: WHO Clinical and Policy Guidelines. Geneva: World Health Organization; 2013. Available at https://www.who.int/reproductivehealth/publications/violence/9789241548595/en. Last accessed May 7, 2019.

94150 • The Coronavirus Disease (COVID-19) Pandemic

John M. Leonard, MD

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

Widespread outbreaks of novel (new) coronavirus infection have occurred in each of the past two decades, and the current outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale. In response to a 13-fold increase in the number of reported cases within the span of two weeks and active cases in more than 100 countries, the WHO reached a decision that the COVID-19 outbreak should be characterized as a pandemic.

Table of Contents

94150 • The Coronavirus Disease (COVID-19) Pandemic

Course Overview

Attention

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. BACKGROUND

CORONAVIRUS

HUMAN CORONAVIRUS INFECTION

2. THE 2019–2020 NOVEL CORONAVIRUS OUTBREAK: A GLOBAL THREAT

3. CLINICAL MANIFESTATIONS OF COVID-19

SEVERITY AND PROGRESSION OF ILLNESS

SYSTEMIC COMPLICATIONS OF COVID-19

RECOVERY FROM COVID-19

LATE SEQUELAE OF COVID-19

4. COVID-19 IN CHILDREN

PEDIATRIC MULTISYSTEM INFLAMMATORY SYNDROME

5. DIAGNOSTIC TESTING FOR SARS-COV-2

ANTIBODY TESTING

6. TREATMENT OPTIONS AND VACCINE DEVELOPMENT

INVESTIGATIONAL THERAPEUTICS

COVID-19 VACCINES

DURATION OF IMMUNITY AND REINFECTION

7. GLOBAL PUBLIC HEALTH CONCERNS AND WHO RESPONSE

WHO DAILY SITUATION REPORT

8. TRANSMISSION: PUBLIC HEALTH IMPLICATIONS

VARIANT STRAINS OF SARS-COV-2

CDC MONITORING AND GUIDANCE FOR HEALTHCARE PROFESSIONALS

9. OTHER AVAILABLE RESOURCES

Works Cited

94150 • The Coronavirus Disease (COVID-19) Pandemic

Education Category. Infection Control / Internal Medicine

Release Date. 02/01/2020

Review Date. 01/15/2023

Expiration Date. 02/28/2023

Course Overview

Widespread outbreaks of novel (new) coronavirus infection have occurred in each of the past two decades, and the current outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale. In response to a 13-fold increase in the number of reported cases within the span of two weeks and active cases in more than 100 countries, the WHO reached a decision that the COVID-19 outbreak should be characterized as a pandemic.

Attention

This outbreak is ongoing. As the situation evolves, the course is being revised to reflect new information. The last update was done May 27, 2022.

Audience

This course is designed for physicians, nurses, and other healthcare professionals who may identify or educate patients regarding coronavirus infection.

Course Objective

The purpose of this course is to provide physicians, nurses, and other healthcare professionals an overview of the 2019–2020 global outbreak of novel human coronavirus (SARS-CoV-2) infection, including background epidemiology, clinical features, mode of transmission, epidemic potential, and the clinical and public health measures recommended to limit the spread of infection and control the outbreak.

Learning Objectives

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

1. Differentiate between the common, ubiquitous strains of human coronavirus and novel (outbreak) strains with respect to epidemiology, modes of transmission, spectrum of illness, and public health implications.

2. Characterize the clinical and public health experience gained from the two prior novel human coronavirus epidemics, SARS and MERS, and how that informs our understanding and response to the current pandemic.

3. Recognize clinical manifestations of COVID-19 and anticipate systemic complications associated with a dysregulated immune response, and discuss the dynamics of transmission and advise patients regarding prevention of infection and the role of COVID-19 vaccines, with special attention to those at risk for severe disease.

4. Implement guideline recommendations for diagnostic testing and management of patients with recent exposure to, suspected infection with, or newly diagnosed COVID-19.

Faculty

John M. Leonard, MD, Professor of Medicine Emeritus, Vanderbilt University School of Medicine, completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers before joining the Vanderbilt faculty in 1974. He is a clinician-educator and for many years served as director of residency training and student educational programs for the Vanderbilt University Department of Medicine. Over a career span of 40 years, Dr. Leonard conducted an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.

Faculty Disclosure

Contributing faculty, John M. Leonard, MD, 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

Alice Yick Flanagan, PhD, MSW

Abimbola Farinde, PharmD, 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. BACKGROUND

CORONAVIRUS

Coronaviruses (a subfamily of Coronaviridae) are enveloped, single-stranded RNA viruses that are broadly distributed among humans, other mammals, and birds. Under electron microscopy, the outer envelope of the virion shows club-like surface projections that confer a crown-like appearance to the virus, which accounts for the name given to this family of viruses. The nucleocapsid is a long, folded strand that tends to spontaneous mutations and recombination of genomic material. When virus circulation (and replication) is high, the number of random changes within the genome grows, increasing the likelihood that such changes may impact transmissibility and pathogenicity.

In addition to four specific subtypes of coronavirus commonly found in humans, other strains are specific to many different species of animals, including bats, cats, camels, and cattle. On rare occasions, an animal coronavirus is responsible for zoonotic infection in humans, meaning that a new (novel) coronavirus is transmitted from an animal host to one or more humans, producing clinical illness that may result in secondary spread among persons in close contact. The wide distribution, genetic diversity, and frequent shifts in the genome, combined with unique human-animal interface activities, are considered important factors in the periodic emergence of new coronavirus outbreaks in human populations [1,2].

HUMAN CORONAVIRUS INFECTION

Common Strains

Human coronavirus (HCoV) was first identified in 1965, isolated from a patient with what was described as the common cold [3]. Subsequently, four types of HCoV have been detected commonly in respiratory secretions of children and adults in scattered regions of the globe, labeled HCoV-229E, -NL63, -OC43, and -HKU1. These agents are a cause of common mild-to-moderate upper respiratory illness, including the common cold, bronchitis, bronchiolitis in infants and children, and asthma exacerbation. Rarely, HCoVs have been implicated in cases of lower respiratory tract infection (viral pneumonia), a complication more common to persons with underlying cardiopulmonary disease or weakened immune systems.

Novel Coronavirus Outbreaks

In addition to the seasonal infections caused by the ambient, adaptive HCoVs described, widespread outbreaks of novel coronavirus infection have occurred in each of the past two decades, and the 2019–2020 Wuhan, China, outbreak poses the third threat of a severe novel coronavirus epidemic on a global scale [1,4]. The epidemiologic feature common to these outbreaks is an initial point source cluster of zoonotic infection followed by secondary spread of the virus via human-to-human transmission. Among the factors thought to be conducive to the emergence of such outbreaks are the following: genomic recombination in an animal CoV capsid that renders the virus better adapted to human infection (and perhaps more virulent); and dietary practices and cultural determinants that bring humans into close contact with livestock or raw meat and carcasses of wild animals and birds, thereby facilitating transmission from an infected animal host to humans. After infection is established, secondary viral transmission occurs through close person-to-person contact by way of droplet nuclei propelled into the air during coughing and sneezing. The first two known novel coronavirus outbreaks, severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, are considered to be zoonotic in origin and were associated with serious, sometimes fatal illness.

Severe Acute Respiratory Syndrome (SARS-CoV)

Infection with SARS-CoV was first recognized in China in November 2002, and signs of an outbreak in Asia were evident by February 2003 [3]. Epidemiologic investigation found that early cases of SARS-CoV were zoonotic infection involving transmission from civet cats to humans. Over the next several months, SARS-CoV spread to countries in North America, South America, Europe, and other parts of Asia before the global outbreak was contained later in the same year.

SARS-CoV infection began with fever, headache, malaise, and arthralgia/myalgia followed in two to seven days by cough, shortness of breath, and signs of pneumonia [3].

According to the World Health Organization (WHO), the 2002–2003 outbreak caused 8,098 probable cases of SARS worldwide and 774 deaths. Just eight cases were identified in the United States. Since 2004, there have been no additional known cases of SARS-CoV infection reported anywhere in the world [3].

In response to the 2003 global SARS outbreak, the Centers for Disease Control and Prevention (CDC), working in concert with the WHO, developed a strategy for controlling the epidemic that included the following elements [3]:

- Activated the Emergency Operations Center to provide around-the-clock coordination and response.

- Committed more than 800 medical experts and support staff to work on the SARS response and to assist with ongoing investigations around the world.

- Provided assistance to state and local health departments in investigating possible cases of SARS in the United States.

- Conducted extensive laboratory testing of clinical specimens from patients with SARS to identify the cause of the disease.

- Initiated a system for distributing health alert notices to travelers who may have been exposed to cases of SARS.

This experience informed the rapid public health response to the 2019–2020 coronavirus outbreak in China.

Middle East Respiratory Syndrome (MERS-CoV)

MERS-CoV was first reported in Saudi Arabia in 2012, and all cases to date have been linked to countries in or near the Arabian Peninsula. Travel-associated cases of MERS-CoV infection have been reported in many countries, including two imported cases diagnosed in the United States in 2014 involving unlinked healthcare providers recently returned from Saudi Arabia. Two modes of transmission have been identified: zoonotic infection from an animal reservoir to humans (with camels acting as the intermediate host), and person-to-person transmission via close contact with an index case, as described in association with a family case cluster and a nosocomial outbreak [5,6,7].

Most persons with confirmed MERS-CoV infection have had moderately severe respiratory illness manifest by fever, cough, and shortness of breath, often complicated by pneumonia and respiratory failure. The case-fatality rate approaches 40%. Most deaths have been in patients with pre-existing chronic conditions such as diabetes, cancer, or heart, lung, or renal disease. Sporadic cases of MERS-CoV continue to appear in various parts of the Middle East [3].

2. THE 2019–2020 NOVEL CORONAVIRUS OUTBREAK: A GLOBAL THREAT

In December 2019, Chinese physicians in Hubei Province, China, began an investigation of a cluster of cases of severe viral pneumonia in area hospitals. In the weeks following, it became evident that a large outbreak of respiratory illness was rapidly emerging within Wuhan City and nearby communities, reaching the thousands by mid-January.

On January 24, Chinese scientists reported the results of viral diagnostic studies conducted on bronchoalveolar lavage specimens obtained from three Wuhan City patients hospitalized in December with severe bilateral interstitial, alveolar pneumonia [2]. The investigation identified a viral genome matched to lineage B of the genus betacoronavirus, showing more than 85% match with a SARS-like CoV genome previously described in bats. Ultrathin sections of infected human airway epithelial cells showed inclusion bodies filled with virus particles in membrane-bound vesicles in the cytoplasm. The morphology of the virion on electron microscopy is consistent with the Coronaviridae family.

This newly identified coronavirus, the etiologic agent responsible for the Wuhan outbreak, was named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease caused by the infection is referred to as COVID-19. Like SARS-CoV and MERS-CoV, SARS-CoV-2 is a betacoronavirus that likely had its origin in bats, with one or more animals serving as the intermediate host. The actual source and timing of initial human infection is unclear. According to CDC reports, virus sequences from initial imported cases in the United States were similar to the one posted by China, indicating emergence of this virus from a point-source in Wuhan, China [12].

The rapid accumulation of many new COVID-19 cases in Wuhan City during December 2019 and January/February 2020, combined with evidence of spread to nearby provinces in central China and reports of acute infection in healthcare workers, indicated that facile human-to-human transmission of SARS-CoV-2 was the key factor responsible for propagation of the outbreak. This has been proven true throughout the pandemic. During the first six months of 2020, outbreaks of COVID-19 spread to countries in every part of the world. As of May 2022, the global COVID-19 disease burden totaled 487 million confirmed cases and more than 6 million deaths, of which 80 million cases and more than 1 million deaths have been reported in the United States [132].

Despite the availability of effective COVID-19 vaccines beginning in December 2020, the scope of the pandemic remained undiminished in Europe and the United States throughout the summer and fall of 2021, primarily because of two complimentary developments: the slow rollout and limited acceptance of COVID-19 vaccines in certain regions and population groups, and the emergence of a SARS-CoV-2 variant strains that are three to four times more infectious and spread faster than the original virus strain. By July 2021, the SARS-CoV-2 Delta variant accounted for 99% of all COVID-19 cases reported in the United States; in December 2021, Delta was rapidly supplanted by the less severe but highly infectious Omicron variant [132].

A viral variant has one or more mutations within the genome that differentiate it from other strains of the virus. Closely genetically related variants derived from a common ancestor are designated a lineage. In response to concerns that emerging SARS-CoV-2 variants may have the potential to circumvent COVID-19 countermeasures, a SARS-CoV-2 Interagency Group (SIG) was established to characterize variants and monitor their impact on transmission, disease severity, risk of reinfection, and potential to evade vaccine-induced immunity [123]. The CDC’s national genomic surveillance program identifies SARS-CoV-2 variants by genetic sequencing and tracks the proportion and distribution of COVID-19 cases caused by variants. As of April 2022, the SARS-CoV-2 Omicron lineage (subvariants BA.1, BA.2, BA.3) accounts for an estimated 100% of new cases of COVID-19 in the United States [123,124].

3. CLINICAL MANIFESTATIONS OF COVID-19

The incubation period of SARS-CoV-2 infection is 5 to 7 days on average, with a range of 2 to 14 days. It is estimated that 97.5% of persons with COVID-19 who develop symptoms will do so within 11.5 days of infection [15,18]. The onset and progression of illness is variable, with most patients experiencing some combination of fever, cough, fatigue, anorexia, myalgias, and shortness of breath. Less common presenting symptoms include rhinorrhea, sudden loss of smell (anosmia) and/or taste (ageusia), and sore throat. Atypical presentations have been described whereby some patients experience diarrhea or nausea and vomiting prior to the onset of fever and respiratory symptoms and signs. As with other infections, elderly persons may present with weakness and confusion. Older adults and persons with medical comorbidities may have delayed onset of fever and respiratory symptoms [15].

In a study designed to better characterize the symptom profiles of patients with COVID-19 in the United States, especially among nonhospitalized patients, the CDC used an optional questionnaire to collect detailed information from a sample of confirmed COVID-19 cases reported from 16 participating states [60]. Among 164 symptomatic patients with onset of illness between January 14 and April 4, 2020, a total of 158 (96%) reported fever, cough, or shortness of breath. Of 57 hospitalized adult patients, 39 (68%) reported all three of these symptoms, compared with 25 (31%) of the 81 nonhospitalized adult patients. Each of the following symptoms was reported by more than half of patients: cough (84%), fever (80%), myalgia (63%), chills (63%), fatigue (62%), headache (59%), and shortness of breath (57%). Gastrointestinal symptoms were relatively common, most frequently diarrhea (38%) and least frequently vomiting (13%). Shortness of breath was more common in patients who required hospitalization (82%) than in nonhospitalized patients (38%). Anosmia and ageusia were reported by a higher percentage of nonhospitalized patients (22%) than hospitalized patients (7%) [60].

An array of cutaneous symptoms and signs has been described in patients with COVID-19. Although the exact frequency remains unknown, reports have ranged from 0.2%, early in the pandemic, to as high as 20.4% [15]. In addition to the exanthems common to many viral infections, pernio-like lesions have been described [105]. Pernio (chilblains) is a superficial inflammatory vascular response that occurs on acral skin, usually after cold exposure. In patients with COVID-19, these lesions appear as discolored edematous plaques on the toes and fingers. An international registry was organized early in the pandemic to characterize the diversity of dermatologic manifestations. In a study of 171 registry patients with confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%) [106]. Morbilliform rashes were often pruritic and involved the trunk. Pernio morphologies were often painful/burning and involved the hands/feet. Pernio-like lesions were generally observed in patients with mild disease, whereas retiform purpura was seen exclusively in critically ill patients. Cutaneous manifestations usually appeared at the onset of or after other COVID-19 symptoms. However, in 12% of cases skin lesions occurred before other COVID-19 symptoms or signs [106]. Images of cutaneous findings are available from the American Academy of Dermatology at https://www.aad.org/public/diseases/coronavirus/covid-toes.

Although most symptomatic patients with COVID-19 experience a mild-to-moderate illness with slow convalescence, there is substantial risk of progression to bilateral pneumonia complicated by respiratory failure and death. In February 2020, the overall case fatality rate for confirmed cases of COVID-19 reported from China was approximately 3%. As the pandemic has progressed, reported case fatality rates have varied considerably among countries and regions, ranging from 3% to as high as 14%. Multiple factors account for this variance, including available health resources and access to care, differences in public health mitigation strategies, lack of uniformity in the way deaths are attributed to COVID, and the extent to which testing and contact tracing identifies asymptomatic infections. Based on reported cases and attributable deaths through mid-July 2020, the COVID-19 case fatality rate during the first six months of the pandemic was 3.6% in the United States [8]. It is more useful to consider age-adjusted case fatality rates, which range from less than 1% in persons younger than 20 years of age to more than 15% for those older than 75 years of age.

SEVERITY AND PROGRESSION OF ILLNESS

The first report describing the clinical features of hospitalized patients with COVID-19-related pneumonia in Wuhan City was published online January 24, 2020 [9]. As of January 2, 41 admitted patients had been identified as having laboratory-confirmed 2019-nCoV infection; 30 (73%) were men and 27 (66%) had been exposed to the open-air Huanan Seafood Market. The median age was 49 years, and fewer than half of the patients had a history of underlying chronic disease. Common symptoms at onset of illness were fever (98%), cough (76%), and myalgia or fatigue (44%). Dyspnea developed in 22 patients (55%), with a median time from illness onset to dyspnea of eight days. Common laboratory abnormalities included leukopenia, lymphopenia, and mild hepatic enzyme elevations. All 41 patients were reported to have pneumonia, and all save one had radiographic evidence of bilateral involvement. The typical findings on chest computed tomography (CT) images of intensive care unit (ICU) patients were bilateral multilobar and segmental areas of consolidation. Acute respiratory distress syndrome developed in 12 (32%) patients, 13 (32%) were admitted to an ICU, and 6 died (15%).

A larger retrospective study examined the clinical characteristics of COVID-19 in a cohort of 1,099 hospitalized patients in China during the first two months of the outbreak [17]. The most common symptoms were fever (43.8% on admission, 88.7% during hospitalization), cough (67.8%), and fatigue (38.1%) [17]. The most common patterns on chest CT were ground-glass opacification (36.4%) and bilateral patchy shadowing (51.8%). Some degree of radiographic or CT abnormality was evident in 82% of patients with nonsevere disease and 97% of patients with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Sixty-seven patients (6.1%) were admitted or transferred to the ICU, 2.3% required mechanical ventilation, and 1.4% died [17].

In a summary of 72,314 cases reported to the Chinese Center for Disease Control and Prevention, the severity of illness ranged from mild to critical with approximately the following distribution [15,23]:

- Mild to moderate (mild symptoms up to mild pneumonia): 81%

- Severe (dyspnea, hypoxia or >50% lung involvement on imaging): 14%

- Critical (respiratory failure, shock, or multiorgan dysfunction): 5%

The majority of cases (81%) were characterized as mild, with no or mild pneumonia [23]. The overall case-fatality rate was 2.3%, with higher rates among patient subgroups. Specifically, the case-fatality rate was 49% among critical patients, and all reported deaths occurred in critical patients [23].

Risk Factors

Risk factors for severe disease include advanced age, obesity (body mass index ≥30), and comorbidities such as hypertension, diabetes, cardiovascular disease, cancer, and chronic lung disease. Among more than 70,000 cases reported in China through February 11, 2020, 87% occurred in persons 30 to 79 years of age [23]. The proportion of case fatalities among patients 70 to 79 years of age was 8%, and among those 80 years of age or older, the rate was 14.8%. Case fatality for patients with comorbidities was elevated as well, specifically for those with cardiovascular disease (10.5%), diabetes (7.3%), chronic respiratory disease (6.3%), hypertension (6%), and cancer (5.6%). Only 2% of cases were in persons younger than 20 years of age, and no deaths were reported in those younger than 10 years of age.

Atypical presentations have been described, and older adults and persons with medical comorbidities may have delayed presentation of fever and respiratory symptoms [15]. Headache, confusion, rhinorrhea, sore throat, hemoptysis, vomiting, and diarrhea have been reported but are less common (<10%). Some persons with COVID-19 have experienced gastrointestinal symptoms such as diarrhea and nausea prior to developing fever and lower respiratory tract signs and symptoms. Anosmia or ageusia preceeding the onset of respiratory symptoms has been anecdotally reported, but more information is needed to understand its role in identifying COVID-19. Several studies have documented SARS-CoV-2 infection in patients who never develop symptoms (asymptomatic) and in patients not yet symptomatic (presymptomatic) [15].

In June 2020, the CDC issued an epidemiologic report on 1,320,488 laboratory-confirmed COVID-19 cases in the United States and territories, reported to CDC between January 22 and May 30, 2020 [55]. Cumulative incidence (403.6 cases per 100,000 persons) was similar among males (401.1) and females (406.0), highest among persons 80 years of age or older (902.0), and lowest among children younger than 9 years of age (51.1). Among 599,636 cases with known information on both race and ethnicity, 36% of persons were non-Hispanic white, 33% were Hispanic, 22% were black, 4% were Asian, and 1.3% were American Indian or Alaska Native. Among 287,320 cases with sufficient data on underlying health conditions, the most frequently reported were cardiovascular disease (32%), diabetes (30%), and chronic lung disease (18%). Overall, 184,673 (14%) patients were hospitalized, 29,837 (2%) were admitted to an ICU, and 71,116 (5%) died. The hospitalized rate was six times higher among patients with a reported underlying condition (45.4%) than among those without reported underlying conditions (7.6%). The mortality rate was 12 times higher among patients with reported underlying conditions (19.5%) compared with those with none reported (1.6%). Approximately 4% of reported cases were asymptomatic. Among 373,833 cases with data on individual symptoms, 70% noted fever, cough, or shortness of breath; 36% reported muscle aches; and 34% reported headache. Overall, 31,191 (8%) persons reported loss of taste or smell [55].

During the course of the COVID-19 pandemic in the United States, obesity has emerged as an important independent risk factor for severe disease, especially among adult patients younger than 60 years of age. Multiple reports, ranging from single-center studies to analyses of records from large patient care networks, have consistently found that severe obesity (body mass index >35) is associated with higher rates of hospitalization, respiratory failure, and mortality from COVID-19 [77,78]. The risk varies directly with degree of obesity and is independent of obesity-associated comorbidities. The impact is more striking among men than women. There are multiple mechanisms by which obesity may contribute to adverse outcomes in patients with COVID-19. In addition to obstructive pulmonary physiology and sleep apnea, severe obesity is associated with immune dysfunction (depression of anti-inflammatory signaling and increased pro-inflammatory signaling), alterations in vascular endothelium, and renin-angiotensin stimulation, which together may worsen lung inflammation and alveolar damage [78].

Although the absolute risk of severe COVID-19 is low among people of child-bearing age, the risk of severe illness and complications is substantial when infection is acquired during pregnancy. Evidence for this comes from an analysis of 409,462 women (15 to 44 years of age) with symptomatic COVID-19 reported to the CDC between January 22 and October 3, 2020 [107]. Of the total, 23,434 women (5.7%) were pregnant at the time of infection. Pregnant patients were admitted to an ICU more frequently than nonpregnant patients (10.5 versus 3.9 per 1,000 cases) and were more likely to receive invasive ventilation (2.9 versus 1.1 per 1,000 cases) or extracorporeal membrane oxygenation (ECMO) (0.7 versus 0.3 per 1,000 cases). The mortality rate was 1.5 per 1,000 cases for pregnant women compared with 1.2 per 1,000 cases for nonpregnant women. Older pregnant patients (35 to 44 years of age) with symptomatic COVID-19 were nearly four times more likely to require invasive ventilation and twice as likely to die than were nonpregnant patients of the same age [107].

Following the emergence of the Delta variant and 2021 summer surge of COVID-19, the risk for unvaccinated pregnant individuals infected with SARS-CoV-2 became even more serious. A retrospective cohort study comparing COVID-19 outcomes among unvaccinated pregnant patients infected in the pre-Delta period with those infected during the Delta surge found that proportions of severe-critical illness and ICU admissions were three-fold higher among patients in the Delta cohort than those in the pre-Delta cohort [149]. The need for intubation and mechanical ventilation was also greater among those with Delta variant infection. Maternal COVID-19 from SARS-CoV-2 Delta infection also had an adverse effect on perinatal outcomes; rates of cesarean delivery, stillbirth, preterm birth, and neonatal intensive care unit admission were all higher during the period of Delta predominance [149].

SYSTEMIC COMPLICATIONS OF COVID-19

At the cellular level, infection by a virus requires some affinity of the virion for the host cell combined with a mechanism that facilitates attachment and entry into the cell. Cell entry of SARS-CoV-2 depends on binding of the viral surface spike protein to angiotensin-converting enzyme (ACE2) receptors and activation of the spike protein by host cell transmembrane protease serine 2 [30]. ACE2 is highly expressed by epithelial cells in the nasopharynx and type II alveolar cells in the lung. ACE2 is also expressed in the heart, kidney, vascular endothelium, and intestinal epithelium, which may explain, in part, the propensity for multiorgan dysfunction and vascular complications increasingly recognized in patients with severe COVID-19. In an autopsy series of 27 patients reported from Germany, SARS-CoV-2 was detected in multiple organs, including the lungs, pharynx, kidney, heart, liver, and brain [31]. In a further analysis of renal involvement, SARS-CoV-2 viral load was detected in all kidney compartments examined, with preferential targeting of glomerular cells.

Based upon recent reports from clinical centers caring for a high volume of hospitalized patients, renal and cardiac complications are relatively common in severe COVID-19. In a retrospective study from China, 251 of 333 (75%) hospitalized patients with COVID-19 pneumonia exhibited some degree of renal involvement, as evidenced by proteinuria or hematuria, and 35 (10%) met criteria for acute kidney injury [32]. In another case series of 138 hospitalized COVID-19 patients, 7% overall and 22% of those admitted to the ICU developed elevated troponin levels or electrocardiogram abnormalities indicative of myocarditis or cardiac injury some time during hospitalization [33]. Myocardial injury affects more than one-quarter of COVID-19 cases classified as critical and presents in two patterns: acute myocardial injury and dysfunction on presentation, and myocardial injury developing as illness severity intensifies [34]. While headache and confusion are seen in some patients presenting with severe COVID-19, there is no indication that SARS-CoV-2 causes primary infection of the central nervous system (e.g., encephalitis). In an autopsy series of 18 consecutive patients who died 0 to 32 days after onset of COVID-19, histopathologic examination of brain specimens did not show encephalitis or other specific brain changes referable to the virus [56].

Coagulopathy

Hospitalized patients with advanced COVID-19 may have laboratory signs of a coagulopathy and increased risk for arterial and venous thromboembolic complications [15,39,40]. The pathogenesis is unknown but likely involves some combination of systemic inflammation, endothelial dysfunction, platelet activation, immobility, and stasis of blood flow [40]. The earliest abnormalities are elevated D-dimer levels and mild thrombocytopenia; with disease progression, fibrin degradation products are elevated and prothrombin time becomes prolonged. Laboratory measure of coagulation factors in a patient hospitalized with COVID-19 provides a way to track disease severity. The presence of an elevated D-dimer on admission carries a poor prognosis and has been associated with increased risk of requiring mechanical ventilation, ICU admission, and mortality [40,41]. The most frequently reported complications of COVID-19 coagulopathy are deep venous thrombosis (DVT) and pulmonary emboli (PE). In a prospective study of 150 critically ill patients from two centers in France, 25 patients developed PE and 3 developed DVT despite prophylactic anticoagulation [42]. In a report of 184 patients with severe COVID-19 from three centers in the Netherlands, the cumulative incidence of venous thromboembolism was 27%, including PE in 80% of the cases affected [43]. Other centers have reported lower rates. Among 393 patients from New York, venous thromboembolism was diagnosed in only 13 patients (3.3%), 10 of whom were on mechanical ventilation [44]. These differences point to the need for studies that control for clinical severity, underlying comorbidities, prophylactic regimen, and COVID-19-related therapies. At present, there are limited data available to inform clinical management around prophylaxis or treatment of venous thromboembolic complications in patients with COVID-19 [15]. One source of interim guidance recommends regularly monitoring hemostatic markers—namely D-dimer, prothrombin time, and platelet count—in all patients presenting with COVID-19 and prophylactic use of low-molecular-weight heparin in all hospitalized patients, unless there are contraindications [40]. The National Institutes of Health has developed guidelines for antithrombotic therapy in patients with COVID-19, available at https://www.covid19treatmentguidelines.nih.gov/therapies/antithrombotic-therapy.

RECOVERY FROM COVID-19

Convalescence following SARS-CoV-2 infection follows a variable course, and symptomatic recovery from severe COVID-19 may take weeks to months. A report from Italy describes a cohort of 143 patients with moderate-to-severe COVID-19, 87% of whom had persistent symptoms two months or more after discharge from hospital [68]. The mean duration of hospitalization was 13.5 days; 73% had evidence of interstitial pneumonia, 15% received noninvasive respiratory support, and 5% required mechanical ventilation. Follow-up clinical assessment was conducted a mean of 60 days after onset of the first COVID-19 symptom. At evaluation, 18 (13%) were symptom free; of the remaining participants, 32% had one or two symptoms and 55% had three or more symptoms. The most common persistent symptoms were fatigue (53%), dyspnea (43%), joint pain (27%), and chest pain (22%). None had fever or signs of acute illness. Of the total, 44% reported persistence of the decline in quality of life imposed by COVID-19.

"Long COVID" is the term applied to the syndrome of persistent symptoms four weeks or later after recovery from acute COVID-19. The majority of reported cases are adults in the 35-to-69-year age group, and women are 30% more likely to get long COVID than men [133]. The range of complaints includes residual cough, fatigue, loss of smell or taste, shortness of breath, headache, and "brain fog." The prevalence of post-COVID-19 cognitive impairment and association with disease severity was investigated in 740 adult patients with no prior history of dementia. Study participants were 38 to 59 years of age, prior COVID severity ranged mild to severe, and evaluations were performed an average of 7.6 months after diagnosis. Deficits were found in processing speed (18%), executive functioning (16%), phonetic fluency (15%) and category fluency (20%), memory encoding (24%), and memory recall (23%) [134]. Executive functioning, processing speed, and memory encoding and recall impairments were predominant among hospitalized patients.

A multistate survey conducted by the CDC found that persistent symptoms three weeks after diagnosis of SARS-CoV-2 infection was common among outpatients with milder illness [69]. Of 270 respondents who were symptomatic at diagnosis, 95 (35%) had not returned to their usual state of health 14 to 21 days from the test date, including 26% of those 18 to 34 years of age and 47% of those older than 50 years of age. Among respondents reporting cough, fatigue, or shortness of breath at the time of COVID-19 diagnosis, 43%, 35%, and 29%, respectively, continued to experience these symptoms at the time of the interview [69].

A cohort study of long-term symptoms among healthcare professionals found that after mild COVID-19, 26% of participants reported at least one moderate-to-severe symptom lasting two months and 15% reported at least one moderate-to-severe symptom lasting eight months [108]. The most common symptoms were anosmia, fatigue, ageusia, and dyspnea. These studies show that low-risk adults with mild COVID-19 commonly experience a slow convalescence with diverse long-term symptoms that may disrupt work and social activity.

LATE SEQUELAE OF COVID-19

In addition to lingering functional impairments represented by long COVID syndrome, there is growing evidence that beyond acute infection, SARS-CoV-2 may have late adverse effects on critical organ function that increase the subsequent burden of cardiovascular disease and diabetes. The lung/vascular/heart involvement of acute-phase moderate-to-severe COVID-19 reflects the trophism of SARS-CoV-2 and is augmented by a dysregulated (hyperimmune) inflammatory response to infection; this can lead to multiple complications. Microvascular dysfunction and endothelial injury may precipitate thromboembolic events. Myocarditis may impair cardiac function; acute coronary syndromes from vasculitis and plaque instability may cause myocardial ischemic injury and heart failure. Parenchymal lung injury and microvascular thrombosis may lead to interstitial fibrosis and hypoxemia, adding to the cardiac workload and subsequent risk of clinical or subclinical heart failure [159].

The cardiovascular sequelae of post-acute COVID-19 were analyzed using the databases of the U.S. Department of Veterans Affairs to build a cohort of 153,769 individuals with COVID-19, as well as cohorts of contemporary and historical controls. The study was designed to estimate risks and one-year burdens of a set of prespecified incident cardiovascular outcomes. The analysis showed that beyond the first 30 days after infection, individuals with COVID-19 were at increased risk of subsequent cardiovascular diseases spanning several categories, including dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure, and thromboembolic disease [160]. The increased risk and added burden were evident among hospitalized and nonhospitalized patients. Overall, the impact increased in graded fashion according to the clinical care setting. In a separate report, using the same database and study protocol, investigators also found that the risks and 12-month burdens of incident diabetes and antihyperglycemic use were increased among people who survived COVID-19, compared to a contemporary control group who had not contracted SARS-CoV-2 [161]. The post-acute diabetes risks and disease burdens increased in graded fashion according to severity of the acute phase of COVID-19.

Chronic, persistent SARS-CoV-2 infection following COVID-19 has been reported in patients with hematologic malignancies and immunodeficiency disorders. The common features are protracted virus shedding, fluctuating symptoms, and failure of humeral immunity many months after acute infection. In addition to the burden of ongoing symptoms and added cost of care, these patients often have to endure prolonged self-isolation and inability to resume productive lives. COVID-19 vaccines may be beneficial in such cases; in a reported case study, mRNA COVID-19 vaccination elicited humoral and cellular immune responses to SARS-CoV-2, which had failed in response to ongoing infection itself, followed by viral clearance [162].

4. COVID-19 IN CHILDREN

The CDC provides information for pediatric healthcare providers and guidance for the evaluation and care of neonates at risk for COVID-19 [45]. Acute SARS-CoV-2 infection in childhood tends to be asymptomatic or relatively mild, consisting of transient fever, cough, and other signs common to an upper respiratory viral syndrome. Severe manifestations of COVID-19 have been reported in children of all ages, though the incidence is far less common than in adults and fatalities following acute childhood infection are rare. Among more than 2,000 pediatric cases in China, 4% were asymptomatic, 51% had mild symptoms, 39% were moderately ill with some evidence of pneumonia, and 5% were severely ill with dyspnea, hypoxia, and central cyanosis [45]. Only 0.6% developed respiratory failure, shock, or multi-organ dysfunction.

Children younger than 18 years of age account for 22% of the U.S. population and represent 19% of cumulative COVID-19 cases reported since the onset of the pandemic [136]. As of April 2022, more than 12.8 million children have tested positive for COVID-19, including 7.8 million child cases added since September 2021. Severe illness from SARS-CoV-2 infection is uncommon. Among states reporting, children account for 1.2% to 4.6% of COVID-19-related hospitalizations and less than 1.5% of all child COVID-19 cases result in hospitalization. The childhood COVID-19 case fatality rate is less than 0.03% [46,136]. As in adults, children with underlying medical conditions and special healthcare needs, including genetic, neurologic, and metabolic disorders or congenital heart disease are at increased risk for severe illness from COVID-19.

Coinciding with increased circulation of the highly infectious SARS-CoV-2 Omicron variant, COVID-19-associated hospitalization rates increased rapidly among children 0 to 4 years of age, a group not yet eligible for vaccination. During the period December 2021 to February 2022, weekly hospitalizations among children 0 to 4 years of age peaked at 14.5 per 100,000, a level fivefold higher than that during the previous six months (Delta predominance) [163]. During Omicron predominance, 63% of hospitalized infants and children had no underlying medical conditions. Monthly ICU admission rates were approximately 3.5 times higher during the Omicron predominance peak in January 2022 than during the Delta predominance peak in September 2021 [163].

Long COVID has also been described in children, though to a lesser degree than in adults. Adolescents and teenagers account for the majority (70%) of reported cases [133]. In a study of 151 children with documented SARS-CoV-2 infection, 8% had post-acute COVID-19 symptoms lasting three to eight weeks [135]. The most common symptoms were residual cough and/or fatigue. On follow-up survey at six months, all 151 children had fully recovered.

PEDIATRIC MULTISYSTEM INFLAMMATORY SYNDROME

Reports from the United Kingdom, Italy, and New York describe a serious inflammatory disorder in children linked to COVID-19, with many features common to Kawasaki disease and toxic shock syndrome [46,47,48]. The term applied to this condition is multisystem inflammatory syndrome in children (MIS-C). Kawasaki disease is an acute vasculitis of unknown cause that affects infants and young children, first described in Japan and thought to involve an aberrant immune response to an unidentified pathogen in persons with a genetic predisposition [47]. Children with COVID-related MIS-C present with signs of a diffuse inflammatory disorder, including persistent fever, abdominal complaints, rash, leukocytosis, elevated C-reactive protein, and evidence of single or multiple organ dysfunction [49]. Hypotension on presentation is common, and myocarditis and other cardiovascular changes (e.g., mitral regurgitation, coronary artery dilatation) may be seen. The majority of patients have tested positive for recent SARS-CoV-2 infection by molecular diagnostic and/or antibody testing. The onset of MIS-C may come days or weeks after what appears to have been an asymptomatic or mild case of COVID-19.

During a 10-day period in mid-April 2020, pediatricians at an intensive care hospital in England noted an unprecedented cluster of eight children with hyperinflammatory shock and other clinical features similar to atypical Kawasaki disease [47]. All had been previously well, and five of the children were boys. Four of the children had known family exposure to SARS-CoV-2. Clinical presentations were similar, with unrelenting fever, variable rash, conjunctivitis, peripheral edema, and warm shock refractory to volume repletion and eventually requiring vasopressors. No clinical or virologic evidence of lower respiratory involvement was observed. All patients were treated with IV immunoglobulin (IVIG); seven recovered and one died following arrhythmia, shock, and cerebral infarction. During the course of the COVID-19 epidemic in northern Italy, physicians in Bergamo observed 10 children (median age: 7.5 years) in the span of two months with a severe form of Kawasaki-like disease, a 30-fold increase in incidence when compared to the previous five years [48]. All were positive for recent SARS-CoV-2 infection. As of June 3, 2020, the New York State Department of Health was investigating 195 reported cases of MIS-C and 3 deaths in children. Of these patients, 28% are younger than 5 years of age and 69% are between 5 and 19 years of age [46]. Of the 195 cases, 93% have tested positive for COVID-19. A targeted surveillance for MIS-C in pediatric health centers across the United States identified 186 cases in 26 states during a five-week period between March and May [61]. The median age was 8.3 years, 165 (62%) were male, and 131 (70%) tested positive for SARS-CoV-2 infection by rT-PCR or serologic antibody test.

The clinical features in the MIS-C cases investigated by the New York Department of Health have been reported [62]. Of 191 patients in the study, all presented with fever and tachycardia, 80% were admitted to the ICU, and 62% required vasopressor support. Abdominal complaints and gastrointestinal symptoms were common (62%), as was rash (60%), conjunctival injection (56%), and mucosal changes (27%). Laboratory markers of inflammation included elevated levels of C-reactive protein in all patients, positive D-dimer (91%), and elevated troponin (71%). Evidence of myocarditis was present in 53% of patients. At least one echocardiogram was obtained for 93 patients (94%); 51 (52%) had some degree of ventricular dysfunction, 32 (32%) had pericardial effusion, and 9 (9%) had a documented coronary artery aneurysm. The majority of patients were treated with IVIG and/or glucocorticoids in addition to vasopressors. The median duration of hospitalization was six days. Two patients died. As in Italy, MIS-C cases in New York followed the peak of the COVID-19 epidemic in that state and nearly all patients tested seropositive for recent SARS-CoV-2 infection [62].

Early recognition of MIS-C and prompt referral to an inpatient unit of care is essential. Approximately 50% to 60% of children and adolescents with MIS-C present with signs of cardiovascular involvement leading to warm shock and a need for vasopressor support, compared with about 5% of children with Kawasaki's disease [61,62]. Cardiac abnormalities are common, including a 9% incidence of coronary artery aneurysm. Echocardiography is recommended in all patients presenting with MIS-C, and until more is known about long-term cardiac sequelae of MIS-C, providers should consider follow-up imaging at one to two weeks and four to six weeks after treatment [61]. Clinical evaluation should include inquiry as to recent COVID-19 illness or known exposure to persons with COVID-19. There are currently no published guidelines or CDC recommendations regarding treatment for MIS-C and no studies comparing efficacy of various treatment options. Based on published reports, principles of care include close observation, correction of hemodynamic instability, diagnostic evaluation to exclude serious bacterial infection (e.g., streptococcal or staphylococcal sepsis, toxic shock syndrome), and consideration of treatment with IVIG. The CDC recommends that patients younger than 21 years of age meeting MIS-C criteria be reported to local, state, and territorial health departments. The CDC case definition for MIS-C is [49]:

- An individual younger than 21 years of age presenting with fever (>38.0°C for at least 24 hours), laboratory evidence of inflammation (including, but not limited to, one or more of the following: an elevated C-reactive protein, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase, or interleukin-6, elevated neutrophils, reduced lymphocytes, and low albumin), and evidence of clinically severe illness requiring hospitalization, with multisystem (at least two) organ involvement; AND

- No alternative plausible diagnoses; AND

- Positive for current or recent SARS-CoV-2 infection or exposure to a suspected or confirmed COVID-19 case within the four weeks prior to the onset of symptoms

All individuals should be reported if they meet the case definition for MIS-C, regardless of whether they fulfill criteria for Kawasaki disease. In addition, MIS-C should be considered in any pediatric death with evidence of SARS-CoV-2 infection.

The CDC tracks case reports of MIS-C associated with COVID-19. As of March 2022, the number of patients meeting the case definition of MIS-C in the United States totaled 7,885, with 66 deaths [137]. The median age of reported cases was 9 years, and half of children with MIS-C are 5 to 13 years of age. Of the total MIS-C cases reported, 58% are Hispanic/Latino or non-Hispanic Black, 60% are male, and 98% had a positive test for recent SARS-CoV-2 infection [137].

Vaccination with mRNA vaccine is highly effective in preventing COVID-19-associated MIS-C in children 12 to 18 years of age. A case-control study across 24 pediatric hospitals in 20 states comparing 124 patients with MIS-C with 181 hospitalized controls found that the estimated effectiveness against MIS-C following two doses of Pfizer-BioNTech vaccine was 91% [164]. Ninety-five percent of patients hospitalized with MIS-C were unvaccinated, and all 38 MIS-C patients requiring life support were unvaccinated.

5. DIAGNOSTIC TESTING FOR SARS-COV-2

There are two types of diagnostic tests for determining active SARS-CoV-2 infection: molecular tests that use the real-time reverse transcription-polymerase chain reaction (RT-PCR) to detect viral RNA, and antigen tests that detect specific proteins on the surface of the virion. The most widely used and reliable of these is RT-PCR, which can be applied to mucus specimens from the upper or lower respiratory tracts and to serum samples. SARS-CoV-2 viral RNA can be detected more readily in secretions taken by swab from the nasopharynx than in samples obtained by throat swab [15]. RT-PCR testing of deep nasopharyngeal swab specimens has become the standard procedure for the laboratory diagnosis of active SARS-CoV-2 infection [79,80]. This test is highly accurate and results can be obtained within one or two days. Antigen tests for the diagnosis of active SARS-CoV-2 infection are also performed on nasal or throat swab specimens and have the advantage of providing results much faster than the RT-PCR test (often less than one hour) [80]. However, antigen tests are less sensitive than molecular tests, which detect viral nucleic acids, and the amount of antigen in a sample decreases as the duration of illness increases. Specimens collected more than seven days after onset of illness are considered more likely to be negative compared to a RT-PCR assay [80]. Thus, a positive antigen test result is highly reliable, but a negative test may need to be confirmed with RT-PCR. Updated CDC guidance for healthcare providers who order antigen tests, receive antigen test results, or perform point-of-care testing in the community is available online at https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html.

The availability of safe, reliable, and timely SARS-CoV-2 diagnostic testing is essential for effective public health measures to control the COVID-19 pandemic. The nasopharyngeal swab specimen collection method involves close interaction between healthcare workers and patients, requires personal protective equipment, and entails a measure of discomfort for the test subject—all disadvantages to community drive-through diagnostic testing and contact tracing. Self-collected saliva could prove to be a simple, less expensive alternative that alleviates the need for personal protective equipment. There is growing evidence that the molecular test detection rate in saliva specimens from symptomatic and asymptomatic SARS-CoV-2 infected individuals is comparable to deep nasopharyngeal swab specimens. Yale investigators found that among 70 inpatients with confirmed COVID-19 and 495 asymptomatic healthcare workers, the use of self-collected saliva specimens for SARS-CoV-2 molecular diagnostic testing compared favorably with nasopharyngeal swab specimens collected by personnel [81]. In another study of 354 patients presenting to a drive-through testing center with at least one symptom consistent with COVID-19, the SARS-CoV-2 positivity rate was 22.6% for nasopharyngeal swab specimens compared with 22.9% for salivary specimens [82]. Between nasopharyngeal swab specimens and salivary specimens, the positive percent agreement was 93.8% and the negative percent agreement 97.8%.

COVID-19 diagnostic testing in the United States is available at all state and local public health laboratories and at commercial laboratories authorized by the U. S. Food and Drug Administration (FDA) [16,80]. Although in some cases viral nucleic acid can be detected in nasopharyngeal specimens for weeks after infection, studies show that SARS-CoV-2 viral cultures are usually negative within 8 to 10 days after onset of infection. Shedding of live virus may persist longer in severely ill, hospitalized patients (median range of viral shedding: 12 to 20 days) [15]. Information on specimen collection, handling, and storage is available online at https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html.

ANTIBODY TESTING

SARS-CoV-2 antibody assays are useful for epidemiologic investigation of prevalence in the general population and to identify groups at risk for infection. Unlike RT-PCR and antigen detection tests that identify acute infection, antibody tests determine whether there is evidence of prior infection, even if the person being tested never developed symptoms. The FDA has not authorized the use of serology to detect active SARS-CoV-2 infection, and the CDC does not recommend antibody testing for routine diagnosis of acute infection [79]. However, antibody testing in conjunction with viral RT-PCR may be used to support clinical assessment of persons who present late in the course of COVID-19, or a patient suspected of having a post-infectious syndrome caused by recent SARS-CoV-2 infection (e.g., MIS-C).

Following SARS-CoV-2 infection, IgM and IgG antibodies appear almost simultaneously in the serum within two to three weeks after symptom onset, at which time infectiousness likely is greatly decreased and some degree of immunity from future infection has developed [83]. Thus, early IgM assay without IgG testing is of little value. The duration of detectable antibody is unknown, and the absence of detectable IgM or IgG antibodies does not necessarily rule out previous infection. Several commercially marketed serologic assays for SARS-CoV-2 have emergency use authorization (EUA) by the FDA, which has independently reviewed their performance. A list of all tests authorized for emergency use under EUA is maintained on the FDA website [84]. All currently authorized tests are qualitative (providing a result that is positive, negative, or indeterminate) rather than quantitative (providing a quantitative assessment of antibody levels). It is important to minimize false-positive test results by choosing an assay with high specificity and by testing individuals with an elevated likelihood of previous exposure to SARS-CoV-2 [83].

6. TREATMENT OPTIONS AND VACCINE DEVELOPMENT

There is no simple, safe, and highly effective antiviral therapy for the routine treatment of COVID-19. Care is supportive and should be provided in a controlled environment under Isolation Precautions. Effective vaccines for prevention of SARS-CoV-2 began distribution at the end of 2020.

After China published the viral genome on a public database in mid-January 2020, the National Institutes of Health immediately began research efforts to improve diagnostics, identify effective treatments, and develop vaccines against SARS-CoV-2 [10]. As noted, the CDC and commercial laboratories developed a reliable diagnostic test based on genetic sequencing of the virus. Two antiviral agents—remdesivir, a drug tried unsuccessfully in the Ebola outbreak, and lopinavir/ritonavir (Kaletra), a combination antiviral used for treatment of human immunodeficiency virus (HIV)—were provided on a compassionate use basis in China. However, one study of hospitalized patients with COVID-19 in China found no difference in time to clinical improvement or outcome with lopinavir/ritonavir treatment [20].

Following successful development and clinical trials of vaccines against SARS-CoV-2 in the summer and fall of 2020, an accelerated effort was launched in the United States and other countries to implement an immunization strategy against COVID-19.

INVESTIGATIONAL THERAPEUTICS

Antiviral Therapy

Remdesivir is the only drug approved by the FDA for the treatment of COVID-19. Ritonavir-boosted nirmatrelvir (Paxlovid), molnupiravir, and certain SARS-CoV-2 monoclonal antibodies have received EUA from the FDA for treatment of COVID-19. The NIH Treatment Guidelines Panel provides updated information on these and other drugs of interest for the management of COVID-19, including recommendations for patient selection and use of specific anti-viral regimens [57].

Remdesivir

Remdesivir, an investigational antiviral drug that inhibits viral RNA polymerases, has been shown to have in-vitro activity against SARS-CoV-2 [15]. An early report described the clinical outcomes for a cohort of patients with COVID-19 who were treated with a 10-day course of intravenous remdesivir as part of a compassionate use program [26]. The study enrolled patients from the United States, Canada, Europe, and Japan who were hospitalized with confirmed SARS-CoV-2 infection and signs of lower respiratory tract disease severe enough to require some degree of oxygen supplementation and/or ventilatory support. Of 53 patients with sufficient data for analysis, 32 (68%) showed significant improvement in oxygen support status with use of remdesivir; the overall mortality was 13% over a median follow-up of 18 days, including 18% among those who were receiving invasive ventilation and 5% among those who were receiving noninvasive oxygen support. The authors observed that while there was no randomized control group and the patients in this study are not directly comparable, the observed mortality was considerably less than that reported contemporaneously in other COVID-19 case series and reports [26].

On October 22, 2020, the FDA approved remdesivir for use in adult and pediatric patients 12 years of age and older (weighing at least 40 kg) for the treatment of COVID-19 when hospitalization is required [90]. In April 2022, this approval was expanded to include children 28 days of age and older weighing at least 3 kilograms [177]. The approval was supported by an analysis of three randomized, controlled clinical trials that showed remdesivir shortens the time to recovery and decreases progression of respiratory illness in adult patients hospitalized with COVID-19 [90]. The data analysis included final results from an NIH-sponsored study, a double-blind, placebo-controlled remdesivir trial involving hospitalized patients with moderate-to-severe COVID-19 [35]. In this study, a total of 1,062 patients were randomized to receive intravenous remdesivir or placebo for 10 days. The primary outcome was time to recovery, defined by discharge from hospital or resolution of need for clinical care (hospitalization for infection-control purposes only). The median time to recovery was 10 days for the remdesivir group, compared with 15 days for the placebo group. In an analysis of secondary outcomes, patients who received remdesivir were more likely than those who received placebo to have clinical improvement at day 15. The proportion of serious adverse events related to respiratory failure and the need for higher levels of respiratory support were lower among patients in the remdesivir group. Kaplan-Meier estimates of mortality showed a trend in favor of the treatment group: 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% versus 15.2% by day 29 [35].

The NIH Treatment Guidelines Panel (NIH Panel) recommends remdesivir for treatment of COVID-19 in hospitalized patients with SpO2 <94% on ambient air or those who require supplemental oxygen, and in patients who need any form of mechanical ventilatory support [57]. The recommended duration of treatment and the advisability of combining remdesivir with a glucocorticoid vary in relation to severity of illness and level of ventilatory support. For patients who require supplemental oxygen but have no need for delivery of oxygen through a high-flow device, the recommended regimen is remdesivir 200 mg IV for one day, followed by 100 mg daily for four days or until hospital discharge, whichever comes first. The duration of remdesivir therapy may be extended up to 10 days when there is no substantial clinical improvement by day 5.

A three-day course of remdesivir has received FDA approval for use in nonhospitalized COVID-19 patients in settings where intravenous therapy and close patient monitoring are feasible. In a randomized, placebo-controlled clinical trial among nonhospitalized adults (mean age: 50 years) with symptomatic COVID-19 and at least one risk factor for disease progression, a three-day course of remdesivir resulted in an 87% lower risk of hospitalization or death than placebo [165]. COVID-19-related hospitalizations and deaths from any cause occurred in 2 patients (0.7%) in the remdesivir group and 15 patients (5.3%) in the placebo group.

Oral Anti-SARS-CoV-2 Agents

Two oral antiviral drugs, molnupiravir and nirmatrelvir-ritonavir, have received FDA EUA for early treatment of nonhospitalized patients with mild-to-moderate COVID-19 who are at risk of disease progression. Mulnupiravir is the prodrug of a ribonucleoside with broad antiviral activity against RNA viruses. Uptake by viral RNA-dependent RNA polymerases causes mutations that are lethal to the virus. In clinical trials, 800-mg molnupiravir twice daily for five days reduced the rate of hospitalization or death among patients with COVID-19 by 30% compared with placebo [57]. Molnupiravir is not recommended for use in pregnant patients due to concerns about potential fetal toxicity. The NIH Panel recommends using molnupiravir only when nirmatrelvir-ritonavir, remdesivir, and selective monoclonal antibody therapy are not available or cannot be used, because molnupiravir has lower efficacy than the other options [57].

Nirmatrelvir is a protease inhibitor active against a constitutive protein (protease) essential for virus replication. It has demonstrated antiviral activity against all human coronaviruses [57]. Nirmatrelvir is used in combination with ritonavir, a pharmacokinetic booster required to increase nirmetrelvir concentration into therapeutic range. Because ritonavir is a potent P450 3A4 inhibitor, nirmatrelvir-ritonavir has significant potential drug-drug interactions; the patient’s concomitant medications should be reviewed before clinical use. The available formulation (Paxlovid) uses nirmatrelvir 300 mg plus ritonavir 100 mg orally twice daily for five days in those older than 12 years of age and weighing more than 40 kg. Treatment should be initiated as soon as possible and within five days of symptom onset. Paxlovid is indicated for early treatment of select patients who are at high risk of severe disease and complications from COVID-19 [57]. In a randomized, placebo-controlled clinical trial of nirtrelvir-riyonavir among symptomatic, unvaccinated, nonhospitalized adults at risk for severe disease, the incidence of progression to severe COVID-19 (hospitalization or death) was 89% lower in the treatment group than in the placebo group [166]. The incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths.

There is some evidence of a COVID-19 recurrence following treatment with nirmatrelvir-ritonavir [176]. Limited information currently available from case reports suggests that persons treated with ritonavir-boosted nirmatrelvir who experience COVID-19 rebound have had mild illness; there are no reports of severe disease. There is currently no evidence that additional treatment is needed in cases where COVID-19 rebound is suspected. Patients with a COVID-19 recurrence should be advised to re-isolate for at least five days to prevent further transmission of the virus.

Hydroxychloroquine

In-vitro studies show that chloroquine phosphate and hydroxychloroquine sulphate (commonly used to treat malaria) interfere with the replication cycle of coronaviruses, including SARS-CoV-2, and thus may offer some therapeutic efficacy for treatment of COVID-19 [21]. Randomized controlled clinical trials of hydroxychloroquine are underway in the United States. Based on small case studies and anecdotal reports of possible efficacy, many clinicians have been inclined to administer hydroxychloroquine to patients with COVID-19 who are so ill as to require hospitalization and having risk factors for severe disease (i.e., age older than 65 years, underlying medical conditions, and/or signs of viral pneumonia). On March 28, 2020, the FDA issued an EUA that allowed chloroquine phosphate or hydroxychloroquine sulphate to be used for the treatment of patients hospitalized with COVID-19 when clinical trials are not available or participation is not feasible [36]. However, this letter was revoked in June 2020 [58]. If used, hydroxychloroquine is generally preferred as it is better tolerated. The suggested dosage regimen is hydroxychloroquine sulphate administered orally in a loading dose of 400 mg twice daily (for one day) then 200 mg twice daily for four days [22]. Potential adverse effects include cardiac conduction QT-prolongation and a number of drug-drug interactions.

An observational study examined the association between hydroxychloroquine use and clinical outcomes, analyzing data from 1,376 consecutive patients with COVID-19 admitted to a clinical center in New York City between March 7 and April 8, 2020 [37]. To assess potential benefit or detrimental effect, the primary end point selected was a composite of intubation or death in a time-to-event analysis, comparing outcomes in patients who received hydroxychloroquine with those who did not. A total of 811 patients (59%) were treated with hydroxychloroquine for a median of five days, 60% of whom also received azithromycin. After adjusting for severity of illness, the investigators found no significant difference in the rate of the composite end point of intubation or death over a median follow-up of 22.5 days. Thus, the risk of intubation or death was not significantly different among hospitalized patients with COVID-19 who received hydroxychloroquine than among those who did not [37].

Randomized, controlled clinical trials to assess efficacy of hydroxychloroquine in patients hospitalized with COVID-19 have not shown a benefit. A multicenter study of hospitalized patients with mild-to-moderate COVID-19 found that hydroxychloroquine, alone or in combination with azithromycin, was no more effective than standard care in improving clinical status at 15 days [70]. Preliminary analysis of data from a multicenter, randomized trial in the United Kingdom found no reduction in 28-day mortality among those treated with hydroxychloroquine when compared with the control group [71]. Hydroxychloroquine use was associated with increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation. An NIH-sponsored, controlled clinical trial was halted (after the fourth interim analysis) because hydroxychloroquine was found unlikely to be beneficial to hospitalized patients with COVID-19 [72]. As of November 2021, multiple randomized, controlled trials have failed to demonstrate any significant benefit for hydroxychloroquine in outpatient treatment of mild COVID-19 or as primary or secondary prophylaxis against SARS-CoV-2 infection.

On June 15, 2020, the FDA revoked the EUA that allowed for chloroquine and hydroxychloroquine donated to the Strategic National Stockpile to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was not available or feasible [58]. This decision was based on an ongoing analysis of emerging data indicating that these drugs are unlikely to be effective for patients hospitalized with COVID-19. As of July 2020, the NIH Panel recommends against the use of hydroxychloroquine or chloroquine for the treatment of COVID-19 except in a clinical trial [57].

Ivermectin

Ivermectin is an antiparasitic drug approved by the FDA for the treatment of several tropical diseases (e.g., onchocerciasis, helminthiases, scabies) and under investigation for the prevention of malaria transmission. Ivermectin is poorly absorbed from the intestinal tract, which enhances its effectiveness against parasitic infections confined largely to the intestinal tracts of humans and large mammals (e.g., sheep, cattle, horses). Reports from in vitro studies suggest that ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host's antiviral response. In addition, ivermectin docking may interfere with the attachment of the SARS-CoV-2 spike protein to the human cell membrane. Although ivermectin inhibits SARS-CoV-2 replication in vitro (cell culture), the effect is dose-dependent, meaning that inhibition is observed when the concentration of ivermectin is raised to a certain level. Furthermore, the ivermectin concentration required for in vitro inhibition of SARS-CoV-2 is 50 to 60 times higher than can be achieved in humans by standard oral doses of the drug. Pharmacokinetic and pharmacodynamic studies suggest that achieving the plasma concentrations necessary for the antiviral efficacy detected in vitro would require administration of doses up to 100-fold higher than those approved for use in humans.

In 2021, ivermectin dispensing by retail pharmacies increased dramatically, as did the use of available over-the-counter veterinary formulations not intended for human consumption. The number of ivermectin prescriptions dispensed in the United States increased from 3,600 per week at the pre-pandemic baseline to more than 88,000 per week in August 2021 [167]. During the same period, state poison control centers across the country reported a fivefold increase in consultations for human exposures to ivermectin [167,168]. Misuse of prescription ivermectin by excess dosage or duration can have adverse effects. Veterinary formulations intended for use in horses and cattle are often highly concentrated and unsafe for ingestion by humans. Clinical signs of ivermectin toxicity include gastrointestinal upset, confusion, ataxia, hypotension, disturbances of vision, hallucinations, seizures, and coma.

Ivermectin is not authorized or approved by FDA for prevention or treatment of COVID-19. Clinical studies regarding the use of ivermectin to treat or prevent COVID-19 have been conflicting, and many studies had incomplete information and significant methodological limitations. Among 400 patients with mild COVID-19, a double-blind, randomized, placebo-controlled trial of ivermectin 300 mg/kg twice daily for five days found that ivermectin had no significant effect on time to resolution of symptoms compared with placebo [169]. A larger, double-blind, randomized, placebo-controlled trial of early ivermectin treatment for COVID-19 (679 patients in each comparator group) found that ivermectin did not lower incidence of admission to hospital (progression of disease) or duration of time required for emergency department observation [170]. In a randomized, placebo-controlled trial among patients hospitalized with mild-to-moderate COVID-19, treatment with ivermectin on admission had no beneficial effect on the rate of disease progression (21.6%) compared with standard care (17.3%) [171]. The rates of COVID-19-associated ICU admission, mechanical ventilation, and mortality were not significantly different for the ivermectin group than the control group. Due to the lack of reliable and accurate data, the NIH Panel does not recommend either for or against the use of ivermectin for the treatment of COVID-19 [57].

Baricitinib

In May 2022, the FDA issued an EUA for baricitinib to treat COVID-19 in hospitalized pediatric patients 2 to 17 years of age requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO [175]. The recommended dosage of baricitinib under the EUA is 4 mg once daily for patients 9 years of age and older or 2 mg once daily for patients 2 to 8 years of age. Treatment should continue for 14 days or until hospital discharge, whichever occurs first [175].

Before initiating therapy, baseline glomerular filtration rate, liver enzyme level, and complete blood count should be assessed, as modifications in approach are necessary with abnormalities in any of these values. Baricitinib is not recommended for patients with active tuberculosis, who are on dialysis, have end-stage renal disease, or have acute kidney injury [175].

Other Agents

Several other approaches to antiviral therapy have been explored for the treatment of COVID-19, with poor results. The NIH guidelines for the treatment of COVID-19 recommend against the use of nitazoxanide, lopinavir/ritonavir, and other HIV protease inhibitors to manage or prevent COVID-19 outside of clinical trials [57].

Approaches to Disease Modification

Severe SARS-Cov-2 infection results in progressive interstitial-alveolar pneumonia and respiratory failure. The disease process is closely linked to activation of the innate immune system and dysregulation of adaptive immune responses, with release of proinflammatory cytokines and chemokines. Death from COVID-19 is often preceded by signs of a hyperimmune inflammatory response ("cytokine storm") that leads to ARDS, multi-organ dysfunction, and circulatory collapse. Laboratory markers of heightened inflammation include elevated C-reactive protein, ferritin, and interleukin-6. Novel approaches to disease management seek to modify disease progression and prevent or ameliorate pulmonary and systemic complications of cytokine storm, in hope of reducing mortality from COVID-19.

COVID-19 Convalescent Plasma

Passive immunization with plasma obtained from surviving patients has been used in the past to treat life-threatening infections absent specific therapy. There is emerging evidence that intravenous transfusion of convalescent plasma with high-titer antibody directed against SARS-CoV-2 is effective in reducing mortality in hospitalized patients with COVID-19 pneumonia. In a preliminary, uncontrolled case series of five critically ill Chinese patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in clinical status, including resolution of ARDS in four patients at 12 days after transfusion [27].

Convalescent plasma treatment has been widely utilized in the United States since early April 2020 under the Mayo Clinic's Expanded Access Protocol (EAP). A report from the Mayo EAP involving 35,322 registered patients found that plasma infusion is relatively safe and may reduce COVID-19 mortality when administered early after hospitalization [76]. A subset analysis showed a gradient of mortality in relation to IgG antibody levels in transfused plasma. The risk of dying from COVID-19 was lower among patients who received convalescent plasma units containing high titer anti-SARS-CoV-2 antibody than among those who received plasma containing low antibody levels. The pooled relative risk reduction among patients transfused with high antibody level plasma units versus low-level antibody plasma was 35% at 7 days and 23% at 30 days. The Mayo EAP report is an analysis of registry data and not a randomized controlled study.

On August 23, 2020, the FDA granted an EUA to COVID-19 convalescent plasma for treatment of patients hospitalized with COVID-19 [73]. This decision was based on historical evidence derived from the use of plasma in prior outbreaks of respiratory virus infection, small case series, and non-randomized clinical trials conducted during the current outbreak. As of December 2020, the only double-blind, placebo-controlled clinical trial of convalescent plasma did not demonstrate a reduction in mortality or improvement in other clinical outcomes [93]. In this study, 333 patients with severe COVID-19 pneumonia were randomized in a 2:1 ratio to receive convalescent plasma (228 subjects) or placebo (105 subjects). Of the total, 68% were men and 65% had a coexisting condition at entry into the trial. The median time from onset of COVID-19 symptoms to enrollment was eight days. More than 90% were receiving oxygen and glucocorticoids at the time of entry into the trial. The infused convalescent plasma had a median titer of 1:3,200 of total SARS-CoV-2 antibodies. At 30 days, the clinical status of patients in the convalescent plasma group did not differ significantly from that of patients in the placebo group. The proportion of ICU admissions and invasive ventilatory support requirements were similar in both groups. Overall mortality was 11.43% in the placebo group and 10.96% in the convalescent plasma group. In a subset analysis, no differences favoring convalescent plasma were noted in a group of 39 patients who received the intervention within 72 hours of symptom onset [93]. Of note, all patients in this study had signs of severe pneumonia; thus, no firm conclusion can be drawn as to the potential efficacy of COVID-19 convalescent plasma initiated earlier in the disease. At present, IDSA and NIH guidelines recommend that convalescent plasma therapy be used only in the context of a clinical trial [10,57].

Although convalescent plasma therapy has no clear benefit for hospitalized patients with COVID-19 pneumonia, treatment with high-titer convalescent plasma early in the course of illness has been shown to reduce the risk of progression to severe disease. Evidence for this comes from a randomized, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV-2 administered to older adults within 72 hours after onset of mild COVID-19 symptoms. In the cohort of patients who received high-titer plasma therapy, 13 of 80 (16%) patients progressed to severe respiratory disease, compared with 25 of 80 patients (31%) who received placebo [109]. This corresponds to a relative risk reduction of 48%. The study population consisted of adults 75 years of age or older, or between 65 and 74 years of age with at least one coexisting condition.

The FDA provides a COVID-19 convalescent plasma fact sheet with guidance for healthcare providers [73]. Patients recovering from COVID-19 who wish to donate convalescent plasma can also find information at the FDA website [28]. Persons who have fully recovered from COVID-19 are candidates for plasma donation. COVID-19 convalescent plasma can only be collected from recovered individuals if they are eligible to donate blood. A potential donor must have had a prior diagnosis of COVID-19 documented by a laboratory test and meet other donor criteria. Complete resolution of symptoms for at least 28 days is required before an individual may donate plasma, or alternatively have had no symptoms for at least 14 days prior to donation and have a negative lab test for active COVID-19 disease [28]. Persons interested in becoming donors should contact the American Red Cross or ask the local blood center about options to donate convalescent plasma in their area.

On April 10, 2020, the FDA granted EUA for an extracorporeal blood purification system to treat adult patients with COVID-19 admitted to an ICU with confirmed or imminent respiratory failure [29]. This device filters the blood for removal of cytokines and other inflammatory mediators associated with cytokine storm, then returns filtered blood to the patient.

Monoclonal Antibody to SARS-CoV-2

Modern immunologic techniques enable the identification of pathogen-specific memory B cells and recovery of immunoglobulin genes that can be expressed to produce monoclonal antibodies [85]. The clinical application of monoclonal antibodies has been relatively safe. FDA-approved monoclonal antibody products are available to treat or prevent respiratory-syncytial virus, anthrax, and Clostridioides difficile. Several laboratories have used B cells from patients recovering from COVID-19 to produce neutralizing monoclonal antibodies to SARS-CoV-2. These antibodies are directed against surface spike glycoprotein, preventing entry of virus into host cells. Passive immunization with monoclonal antibodies has potential for preventing COVID-19 in vulnerable people and for early augmentation of the immune response (to block disease progression) in COVID-19 patients at risk for severe illness. Given the long half-life of immunoglobulin (approximately three weeks), a single infusion of monoclonal antibodies to SARS-CoV-2 should suffice for either prevention or treatment of COVID-19 [85]. In a phase 2 randomized clinical trial involving outpatients with mild or moderate COVID-19, a single infusion of bamlanivimab (a monoclonal neutralizing antibody) was associated with rapid decline in viral load and reduced need for further medical attention [94]. Subsequent COVID-related hospitalization or visit to an emergency room was required in 1.6% of patients in the monoclonal antibody group, compared with 6.3% in the placebo group.

As of March 2022, three monoclonal antibody products (bamlanivimab plus etexevemab, casirivimab plus imdevimab, and sotrovimab) have received EUAs from the FDA for the treatment of nonhospitalized patients with mild-to-moderate COVID-19 who are at high risk of progressing to severe disease. In placebo-controlled clinical trials for these agents, anti-SARS-CoV-2 monoclonal antibodies reduced the risk of hospitalization or death by 70% to 85% [57]. At present, sotrovimab is recommended over the other two products because in vitro studies indicate that only sotrovimab exhibits acceptable activity against the Omicron variant, the predominant SARS-CoV-2 variant in all regions of the United States as of May 2022 [57]. Outpatient monoclonal antibody therapy is reserved for at-risk symptomatic patients and should be administered soon after confirmation of SARS-CoV-2 infection, within 7 to 10 days of symptom onset. Patients with symptomatic COVID-19 who meet one of the following criteria are eligible for treatment:

- Body mass index >35

- Diabetes

- Chronic kidney disease

- Immunosuppressive disease or current immunosuppressive treatment

- Age 65 years or older or 55 years or older with underlying cardiovascular disease, hypertension, or chronic lung disease

Specific guidance that addresses patient selection criteria, authorized dosage, and treatment precautions, is provided at the NIH Panel website [57,96].

Dexamethasone

Preliminary results of a large multicenter therapeutic trial show that dexamethasone (a glucocorticoid) improves survival in patients hospitalized with COVID-19 who require some degree of respiratory support [63]. In this ongoing study platform, patients are randomly assigned to a group of different therapies and efficacy is assessed using a single end-point: mortality within 28 days after randomization. A total of 2,104 patients were assigned to receive dexamethasone at a dose of 6 mg daily, and 4,321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1,110 patients (25.7%) in the usual care group died within 28 days after randomization. The observed differences in mortality varied according to the level of respiratory support patients required upon entry to the study. Among patients receiving mechanical ventilation, the 28-day mortality was significantly lower in the dexamethasone group (29.3%) than that in the usual care group (41.4%). Among patients receiving supplemental oxygen without mechanical ventilation, the observed benefit was less pronounced but also significant, 23.3% in the dexamethasone group and 26.2% in the usual care group. There was no demonstrable benefit from dexamethasone treatment in patients who did not require oxygen.

The NIH Panel recommends using dexamethasone (at a dose of 6 mg per day for up to 10 days) for the treatment of COVID-19 in patients who are mechanically ventilated and in patients who require supplemental oxygen but not mechanical ventilation [57]. If dexamethasone is not available, equivalent doses of another glucocorticoid may be used, such as prednisone 40 mg/day or methylprednisolone 32 mg/day. Dexamethasone is the preferred glucocorticoid to use in pregnant women with COVID-19 who require respiratory support, because of the potential benefit of decreased maternal mortality and the known low risk of fetal adverse effects associated with short-course maternal dexamethasone therapy [57]. Patients receiving dexamethasone at the time of hospital discharge should be given a prescription to complete the specified 10-day course. The Panel recommends against using dexamethasone for the treatment of COVID-19 in patients who do not require supplemental oxygen.

Potential adverse effects of glucocorticoid use include hyperglycemia and opportunistic infection. Clinicians should be aware that Strongyloides hyperinfection syndrome has been reported as a complication of modest-dose and short-duration dexamethasone regimens [75]. Patients who may be at risk are those who have previously resided in South America, the Caribbean, the Middle East, Africa, or Asia. Clinical clues to subclinical or unrecognized Strongyloides infection include peripheral eosinophilia and unexplained gram-negative bacteremia [75].

Tocilizumab

Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, has been used to mitigate cytokine storm syndrome associated with COVID-19. A retrospective cohort study of hospitalized patients who required ICU support found that treatment with tocilizumab was associated with reduced mortality [74]. Of 630 patients selected for analysis, 358 (57%) died—102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. The primary multivariable Cox regression analysis showed an association between receiving tocilizumab and decreased hospital-related mortality. This association was also noted among subgroups requiring mechanical ventilation and with baseline C-reactive protein of 15 mg/dL or higher. In contrast to findings from this and other observational studies of COVID-19 pneumonia, randomized clinical trials have not reported a mortality benefit from tocilizumab therapy [91]. Tocilizumab has been reported to reduce the requirement for mechanical ventilation in some patient populations, thereby alleviating the demand on ICU-level care for management of severe COVID-19. A published editorial assessment concluded that newly released randomized trials suggest a potential role for tocilizumab in COVID-19 but do not show clear evidence of efficacy [91]. As of August 2021, the NIH Panel guidelines recommend adding IV tocilizumab for the treatment of hospitalized patients with evidence of systemic inflammation and who require delivery of oxygen through a high-flow device or either noninvasive or mechanical ventilation [57]. Tocilizumab should only be used in combination with dexamethasone, as trials have shown the clinical benefit of tocilizumab was seen among patients who were receiving this agent in combination with a glucocorticoid [57]. Clinicians may consider assessing the patient's response to dexamethasone before deciding whether adding tocilizumab is necessary.

COVID-19 VACCINES

The effort to develop vaccines against coronavirus began following the 2002–2004 SARS outbreak, but was halted when SARS-CoV began to disappear from the human population. These earlier preclinical studies did clarify the antigenic target for coronavirus and laid the groundwork for current SARS-CoV-2 vaccine development. Coronaviruses encode for one large surface glycoprotein, the spike protein, which is responsible for receptor binding and membrane fusion [97]. As noted, SARS-CoV-2 spike protein binds to ACE2 receptors on host cells and facilitates release of the viral genome into the cytoplasm for replication of new virions. Antibodies that bind to the spike protein prevent attachment and neutralize the virus [97]. On the basis of these observations, the spike protein is an antigenic target for development of vaccines against SARS-CoV-2.

As of December 2020, more than 180 potential vaccines were in preclinical studies worldwide, and several candidate vaccines had entered into clinical trials designed to assess immunogenicity and safety. The range of vaccine platforms includes inactivated-virus and live-virus vaccines, recombinant protein vaccines, vectored vaccines, and novel RNA and DNA vaccines [97]. Three vaccines showed promising early results and were advanced to phase 3 clinical trials in August 2020; two are messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech and Moderna, and the third is an adenovirus-vectored vaccine developed by Astra-Zeneca and the University of Oxford. Pfizer and the German company BioNTech have reported preliminary results of an ongoing phase 1 mRNA vaccine trial in 45 healthy adults 18 to 55 years of age. Participants received one of three vaccine doses (25, 100, or 250 mcg) given as two inoculations 28 days apart [64]. All participants developed an immune response. Following the second dose, antibody titers increased and serum neutralizing antibody activity was comparable to levels measured in a control panel of SARS-CoV-2 convalescent serum. Adverse events such as fatigue, myalgia, feverishness, and pain at injection site were reported in half the participants, more commonly after the second injection and at the highest dose. The study group concluded that immunogenicity and safety findings supported expansion of the trial to include older adults and advancement of this vaccine to later-stage clinical trials. In a follow-up report of 40 older adults (50% 56 to 70 years of age and 50% older than 70 years of age) administered the mRNA vaccine, the safety profile and immunogenicity were comparable to results in the younger cohort of participants [86]. Enrollment in a phase 3 trial began in late July 2020.

A report from the University of Oxford described early results of a clinical trial using a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCov-19) that expresses a full-length version of the SARS-CoV-2 spike protein [65]. In a phase 1/2 randomized controlled trial, 1,077 healthy adults received either the candidate vaccine or a meningococcal conjugate vaccine as control. Following a single dose, ChAdOx1 nCoV-19 elicited spike-specific T-cell responses that peaked on day 14 and measurable anti-spike IgG antibody by day 28. Strong humoral and cellular immune responses persisted at day 56 of the ongoing trial. Neutralizing antibody was detected in 32 (91%) of 35 participants after a single dose, and in 10 (100%) of 10 participants who received a booster dose. Adverse events such as discomfort at injection site, fever, malaise, and headache were common but mild or moderate and self-limiting. There were no serious adverse reactions. Progression into phase 2 and 3 trials is underway, recruiting older age groups with comorbidities, healthcare workers, and those at higher risk for SARS-CoV-2 exposure [65].

COVID-19 mRNA Vaccines

COVID-19 mRNA vaccine represents a new vaccine technology that has important public health advantages. The vaccine can be produced completely in vitro, which enables facile purification and rapid production of individual vaccine doses. The COVID-19 mRNA vaccine consists of a nucleoside-modified messenger RNA inside a lipid-laden nanoparticle. The vaccine mRNA encodes for SARS-CoV-2 surface spike protein. The lipid envelope not only facilitates vaccine delivery into host cells but also enhances stability and may augment the immune response. Following intramuscular inoculation, host myocytes utilize vaccine mRNA to express SARS-CoV-2 antigen on cell surfaces, which in turn elicits neutralizing antibody and cellular immune responses to SARS-CoV-2. The vaccine mRNA does not enter the host cell nucleus and cannot become part of the vaccinee's own DNA.

Preliminary results of phase 3 clinical trials demonstrate that both the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines are safe and 94% to 95% effective [98,99]. In the Pfizer-BioNTech vaccine trial, 43,448 adults were randomized to receive vaccine (21,720 participants) or placebo (21,728 participants) in two doses 21 days apart [98]. The primary outcomes were safety and the incidence of symptomatic COVID-19 at least seven days after the second dose. The interim analysis included the first 170 cases of symptomatic COVID-19 diagnosed in the study population and covered a median of two months of safety data. Of the total, eight cases of COVID-19 were observed in the vaccine group and 162 cases in the placebo group. This corresponds to a vaccine efficacy of 95.0%. Vaccine efficacy was similar across subgroups defined by age, sex, race, body mass index, and coexisting medical conditions. Ten cases of severe COVID-19 occurred with onset after the first dose, of which nine were in placebo recipients. Post-vaccination reactions included mild-to-moderate localized pain at the injection site and transient systemic reactions such as fatigue, fever, and headache. Systemic reactions occurred more commonly in younger vaccine recipients (16 to 55 years of age) and after the second dose [98]. The Moderna phase 3 vaccine trial results were equally favorable [99]. In this trial, 30,420 adult participants were randomly assigned to receive either two doses of vaccine or placebo 28 days apart. Of 196 confirmed cases of symptomatic COVID-19 with onset at least 14 days after the second inoculation, 185 cases were in the placebo group and 11 in the vaccine group, a vaccine efficacy of 94.1%. Severe COVID-19, including one fatality, occurred in 30 participants, all of whom were in the placebo group. Transient local and systemic post-vaccination reactions occurred commonly; no safety concerns were identified [99]. In mid-December 2020, following independent verification of safety and efficacy data, the FDA issued an EUA to the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines for use in adults and older adolescents.

COVID-19 Adenovirus Vector Vaccine

In February 2021, Johnson and Johnson (Janssen Pharmaceuticals) received an EUA for use of the Janssen COVID-19 vaccine in adults [110]. This is a recombinant, replication-incompetent adenovirus vector vaccine encoded for the SARS-CoV-2 prefusion spike glycoprotein. Based on interim data from an international phase 3 clinical trial, a single dose of Janssen COVID-19 vaccine is highly effective in preventing COVID-19-associated hospitalization and death [110]. The phase 3 study enrolled 43,783 participants across three regions, 44% from United States, 41% from Latin America, and 15% from South Africa. One-third of the participants were older than 60 years of age and 41% had underlying chronic health conditions. At 14 days following vaccination, the Janssen vaccine was 66% effective in preventing symptomatic COVID-19. After 28 days, the vaccine was 85% effective against severe disease and 93% effective in preventing hospitalization. Among participants in South African, where 95% of COVID-19 cases were caused by the B.1.351 variant, vaccine efficacy against severe disease was 89%. There were no COVID-19 deaths in the vaccine group compared with seven in the placebo group. Vaccine administration side effects were mild-to-moderate, and adverse events were rare and manageable; no anaphylaxis was encountered [110].

COVID-19 Protein Subunit Vaccine

In July 2022, the FDA issued an EUA for the Novavax COVID-19 Vaccine, Adjuvanted for individuals 18 years of age and older [178]. The vaccine contains purified SARS-CoV-2 spike protein and Matrix-M adjuvant. The vaccine was the subject of an ongoing randomized, blinded, placebo-controlled study conducted in the United States and Mexico. The effectiveness of the vaccine was assessed in clinical trial participants 18 years of age and older who did not have evidence of SARS-CoV-2 infection through six days after receiving the second vaccine dose. Among these participants, approximately 17,200 received the vaccine and approximately 8,300 received saline placebo. Overall, the vaccine was 90.4% effective in preventing mild, moderate, or severe COVID-19, with 17 cases of COVID-19 occurring in the vaccine group and 79 cases in the placebo group [178]. No cases of moderate or severe COVID-19 were reported in participants who received the vaccine, compared with nine cases of moderate COVID-19 and four cases of severe COVID-19 reported in placebo recipients. In the subset of participants 65 years of age and older, the vaccine was 78.6% effective. However, it is important to note that the clinical trial was conducted prior to the emergence of Delta and Omicron variants [178].

Vaccine Distribution

Because initial supplies of vaccine were limited, the Advisory Committee on Immunization Practices (ACIP) and the CDC have provided interim recommendations for allocation of COVID-19 vaccines, updated January 1, 2021 [100]. The recommended plan called for prioritization of vaccine distribution based upon risk of exposure to SARS-CoV-2 and potential for severe illness. In Phase 1a, healthcare workers and residents and staff of long-term care facilities were offered vaccination. The next priority group (Phase 1b) consisted of front-line essential workers (e.g., first-responders, teachers, Postal Service employees, grocery workers) and people older than 75 years of age. In Phase 1c, vaccine was offered to persons 65 to 74 years of age and 14 to 64 years of age with high-risk conditions, and other essential workers. Phase 2 included all other persons 16 years of age and older who were not offered the vaccine in Phase 1.

The ACIP has issued interim considerations for the use of Pfizer-BioNTech, Moderna, and Janssen (Johnson & Johnson) COVID-19 vaccines, available at the CDC website [101]. This guidance includes vaccine dose, timing of second inoculation, contraindications, anticipated side effects, and COVID-19 vaccination of pregnant persons and those with underlying medical conditions. Adolescents 16 to 17 years of age were included among those initially eligible to receive the Pfizer-BioNTech COVID-19 vaccine under the EUA. Following review of efficacy and safety data in spring 2021, Pfizer mRNA COVID-19 vaccine received FDA EUA for use in adolescents 12 to 18 years of age. In November 2021, FDA issued a EUA and CDC/ACIP recommended Pfizer COVID-19 vaccine use, at reduced dosage, in children 5 to 11 years of age. Providers should counsel vaccine recipients to expect local reactions (e.g., injection site pain, swelling, erythema, localized axillary lymphadenopathy) and systemic symptoms such as fever, fatigue, headache, or myalgias. Most post-vaccination symptoms are mild-to-moderate and resolve within one to three days of onset.

Data from clinical trials indicate that it is safe to offer vaccination to persons with evidence of a prior SARS-CoV-2 infection, and the CDC recommends doing so 90 days or more after infection [101]. Interestingly, the natural immunity that follows SARS-CoV-2 infection is greatly enhanced by vaccination. In one study, anti-spike antibody titers increased more than 140-fold from peak pre-vaccine levels following a single dose of mRNA vaccine [111]. In a small cohort of persons previously infected, a single dose of vaccine was also shown to substantially increase neutralizing activity against the important SARS-CoV-2 variants circulating in the United States [112].

COVID-19 Vaccine Booster Dose

Following initial rollout in December 2020, COVID-19 vaccines were nearly 100% effective against severe disease, hospitalization, and death, and about 95% effective in preventing SARS-CoV-2 infection. Six months later, and coinciding with emergence of the Delta variant in May/June 2021, protection against severe illness and hospitalization remained strong (92% to 95%) while efficacy against infection had declined to about 70%. An analysis of reported COVID-19 hospitalizations during the period January to May 2021, during which 100 million persons were vaccinated against SARS-CoV-2, found that 600 vaccinated adults had developed breakthrough COVID-19 severe enough to require hospitalization. Of this group, 74% were older than 65 years of age and 130 died (all deaths were patients 71 to 89 years of age) [154].

In fall 2021, the CDC noted that vaccine effectiveness against SARS-CoV-2 infection and mild illness was gradually diminishing among healthcare and other frontline workers, most likely because of decreased immune protection and greater infectiousness of the Delta variant. Small clinical trials demonstrated that booster doses of COVID-19 vaccines enhanced the anti-SARS-CoV-2 immune response in participants who were immunized months earlier [155]. In response, the CDC recommended everyone 5 years of age and older receive an interval-appropriate booster after completing the initial COVID-19 vaccine series. The recommended timing is six months after completion of Pfizer or Moderna mRNA vaccination or two months after Johnson & Johnson vaccination. The choice of vaccine booster is open, meaning that one may “mix and match” dosing for booster shots. One of the two mRNA vaccines is preferred. Effective April 1, 2022, the CDC has authorized a second booster dose of COVID-19 vaccine for persons older than 50 years of age and those at high risk of severe illness because of underlying medical conditions. Updated guidance and COVID-19 vaccine schedules are provided at the CDC website.

As of April 2022, COVID-19 vaccines have been in use in the United States for 16 months; more than 560 million COVID-19 vaccine doses have been administered and 217.6 million people are fully vaccinated, comprising 65.5% of the total population and 85.3% of those 65 years of age and older [124]. About 50% of those fully vaccinated have received an interval-appropriate booster dose. Vaccine efficacy in reducing the incidence of SARS-CoV-2 infection and protecting against severe outcomes (hospitalization and death) has been demonstrated in clinical trials and confirmed by real-world observational studies. One such study, which analyzed data from a multistate hospital network comprising 7,544 patients enrolled between March 11, 2021, and January 24, 2022, found that receipt of two or three doses of COVID-19 mRNA vaccine conferred 90% protection against COVID-19-related invasive mechanical ventilation or in-hospital death [172]. Vaccine effectiveness was consistent throughout the periods of Delta and Omicron predominance; protection against mechanical ventilation and death was higher (94%) among those who received a third (booster) dose during the period of Omicron predominance.

COVID-19 Vaccine Safety

COVID-19 Vaccines and Pregnancy, Lactation, and Fertility

As noted, observational data demonstrate that pregnant persons have an increased risk of severe illness and complications from COVID-19, including ICU admission and mechanical ventilation [107]. Related concerns include the possibility that COVID-19 during pregnancy may increase the risk for adverse pregnancy outcomes (e.g., pre-eclampsia, coagulopathy, preterm birth) [101]. Any currently authorized COVID-19 vaccine can be administered to pregnant or lactating people; the ACIP does not state a product preference [101,149].

Vaccination reduces the risk of getting COVID-19 and protects patient and fetus from severe consequences. Vaccination while pregnant has the added benefit of providing transplacental maternal antibody protection to the newborn for some months after delivery. Studies show that maternal neutralizing antibodies directed against SARS-CoV-2 are present in umbilical cord blood of newborn infants and in breast milk [138].

There was no expectation that COVID-19 vaccines would pose a risk to pregnant persons or the fetus based on current knowledge of human coronaviruses and the science of COVID-19 vaccine development. The authorized COVID-19 vaccines in use are non-replicating vaccines; they do not contain intact virus and cannot cause infection in either the mother or fetus [101]. No reproductive, fetal developmental, or safety concerns were demonstrated in preclinical vaccine studies in animals, nor were any adverse pregnancy-related outcomes, including fetal outcomes, determined to be related to previous use of an adenovirus vector platform in a large-scale Ebola virus vaccine trial [101].

The CDC has three national surveillance programs in place to monitor the safety and efficacy of COVID-19 vaccination in pregnant persons [139]. As of October 25, 2021, more than 169,000 participants enrolled in the CDC v-safe Health Checker indicated they were pregnant when vaccinated against COVID-19. The COVID-19 Vaccination Registry, a subset of 5,100 participants enrolled within 30 days of vaccination, provides direct contact and detailed surveillance, including access to medical records. To date there are no reports of increased risk of pregnancy loss, adverse effects on fetal growth and development, or other safety concerns among pregnant or lactating individuals. An analysis of outcomes among registry participants vaccinated before 20 weeks' gestation found no increased risk of miscarriage in association with COVID-19 vaccine use early in pregnancy [140]. A case-control analysis of outcomes from Norwegian registries on first-trimester pregnancies also found no evidence of an increased risk for early pregnancy loss after COVID-19 vaccination [141]. In general, there is no difference in the incidence of pregnancy loss, preterm birth, delayed gestational growth, congenital abnormalities, and neonatal death among pregnant persons who have received mRNA vaccine compared with the known background incidence of these events in unvaccinated pregnant persons.

The Academy of Breastfeeding Medicine does not recommend cessation of breastfeeding for individuals who are vaccinated against COVID-19 [142]. The Academy considers it unlikely that vaccine lipid would enter the blood stream and reach breast tissue, and if it did, even less likely that either the intact nanoparticle or mRNA would transfer into milk. In the unlikely event mRNA is present in milk, it would be digested by the child and be unlikely to have any biological effects. In a study of seven breastfeeding mothers who received either Pfizer or Moderna COVID-19 vaccine, analysis of 13 samples of breastmilk obtained 4 to 48 hours after vaccination found no detectable mRNA or any other vaccine-related particles in any of the samples tested [143].

On September 14, 2021, the Society for Maternal and Fetal Health and the American College of Obstetrics and Gynecology, along with 18 other professional organizations representing nurse practitioners, nurse-midwives, pediatricians, infectious disease specialists, and public health professionals, issued a joint Statement of Strong Medical Consensus for Vaccination of Pregnant Individuals Against COVID-19 [144]:

As the leading organizations representing experts in maternal care and public health professionals that advocate and educate about vaccination, we strongly urge all pregnant individuals—along with recently pregnant, planning to become pregnant, lactating, and other eligible individuals—to be vaccinated against COVID-19.

A conversation between the patient and clinical team may assist with decisions about the selection and timing of a COVID-19 vaccine during pregnancy, though a discussion with a healthcare provider is not required before vaccination [101]. When making a decision, patient and provider should consider the level of SARS-CoV-2 community transmission, the patient's personal risk of contracting COVID-19, the risks of COVID-19 to the patient and potential risks to the fetus, the efficacy and side effects of the vaccine, and current data about the COVID-19 vaccine use during pregnancy [101]. Pregnant persons who choose to receive COVID-19 vaccine are encouraged to enroll in the CDC's v-safe registry, established to follow outcomes among people who are vaccinated [113].

Concerning infertility, there is no scientific basis for COVID-19 vaccines having any impact on fertility, and no scientific evidence that these vaccines cause sterility in either women or men. Claims that vaccine-derived antibodies directed against SARS-CoV-2 spike protein would cross-react with uterine syncytin-1 protein and cause damage to the developing trophoblast, thereby preventing embryo implantation, are unfounded. A study comparing implantation and sustained pregnancy success rates among individuals receiving frozen embryo transfer found no differences among vaccine seropositive, infection seropositive, and seronegative participants. Rates of sustained embryo implantation for seronegative, vaccine seropositive, and infection seropositive patients were 52.3%, 65.7%, and 47.4%, respectively, and were consistent with pre-COVID-19 success rates [150]. Seropositivity to the SARS-CoV-2 spike protein, derived from either vaccination or infection, had no adverse effect on embryo implantation or early pregnancy development.

There are no studies showing COVID vaccination reduces sperm concentration or motility. Among 45 volunteers for baseline and post-vaccination measure of sperm parameters, no significant differences in semen volume, sperm counts, or sperm motility were found after two doses of mRNA COVID-19 vaccine [151]. On the other hand, male sexual dysfunction and related fertility issues have been reported as potential late complications of symptomatic COVID-19 [152].

Adverse Reactions to COVID-19 mRNA Vaccines

Early side effects, such as soreness at injection site, fatigue, and headache, occur in about 50% of vaccine recipients; feverishness is less common, and all side effects usually resolve in 12 to 36 hours. Immediate, severe allergic reactions (anaphylaxis) do occur rarely within 15 minutes after injection, as with influenza vaccine. Anaphylaxis was not observed during clinical trials, in part because potential participants who had experienced reactions to vaccines were excluded. However, according to a review of SARS-CoV-2 vaccine safety, several cases of anaphylaxis associated with the Pfizer mRNA vaccine were reported following vaccination of 2 million healthcare workers in the United States [102]. For most vaccines in common use, vaccine-associated anaphylaxis has been a rare event, at about one case per million injections. The estimated risk of anaphylaxis associated with use of the Pfizer mRNA vaccine is 1 in 100,000 inoculations—10 times higher [102]. The explanation for this is unclear. One component unique to mRNA vaccines is a polyethylene glycol (PEG) 200 lipid conjugate used to stabilize the nanoparticle carrier system. PEG is a stabilizing compound commonly used in medications and other products and has been implicated in IgE-mediated reactions and recurrent anaphylaxis [102]. This has raised concern that individuals sensitized by past exposure to PEG (or its polysorbate derivative) in commercial products may be at risk of anaphylactic reactions from mRNA vaccination. Anaphylaxis is an acute allergic reaction that can lead to upper airway obstruction, bronchospasm, and circulatory collapse. Prompt recognition and treatment with epinephrine is necessary to prevent life-threatening complications.

A detailed discussion of contraindications and precautions to be observed with mRNA vaccine administration is included in the guidance provided by the CDC [101]. The history of any one of the following reactions is considered a contraindication to vaccination with either the Pfizer-BioNTech or Moderna COVID-19 vaccines [101]:

- Severe allergic reaction (e.g., anaphylaxis) after a previous dose of an mRNA vaccine or any of its components

- Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any of its components (including PEG)

- Immediate allergic reaction of any severity to polysorbate (due to potential cross-reactive hypersensitivity with the vaccine ingredient PEG)

Persons with an immediate allergic reaction to the first dose of an mRNA vaccine should not receive additional doses of either of the mRNA COVID-19 vaccines [101]. Healthcare providers who participate in mRNA vaccine administration should be familiar with signs and symptoms of hypersensitivity reactions and have access to medications and supplies needed for assessing and managing anaphylaxis. The CDC has provided interim guidance on preparation for the potential management of anaphylaxis after COVID-19 vaccination [103].

Delayed-onset local reactions have been reported after mRNA vaccination in some individuals beginning a few days through the second week after the first dose [101,114]. The suspected cause is delayed-type or T-cell-mediated hypersensitivity, and reactions resolve within a few days. In a small series report, the recurrence rate following the second dose was less than 50% [114]. Vaccinees with only a delayed-onset local reaction (e.g., erythema, induration, pruritis) around the injection site do not have a contraindication or precaution to the second dose of vaccine. The CDC recommends these individuals receive the second dose using the same vaccine product as the first dose at the recommended interval, preferably in the opposite arm [101].

Immune Thrombotic Thrombocytopenia and Adenovirus-Vectored Vaccines

On April 13, 2021, after more than 6.8 million doses of the Janssen COVID-19 vaccine had been administered in the United States. the FDA placed a pause on use of this vaccine while the CDC investigated six reports of severe intravascular clotting events that occurred within two weeks following vaccination [127]. In these cases, a rare form of blood clot (cerebral venous sinus thrombosis) combined with thrombocytopenia was observed between the 6th and 13th day after vaccination. All cases were women 18 to 48 years of age, one of whom died. The pause was for purposes of further analysis and so health professionals could become familiar with the diagnostic and management implications. Treatment of this type of clotting disorder is different from treatment that might typically be administered to patients with thrombosis. Usually, the anticoagulant drug heparin is used to treat blood clots. However, in this setting the administration of heparin may be dangerous, and alternative therapies are needed [127]. The risk of cerebral venous thrombosis following Jenssen COVID-19 vaccination is approximately 1 in 1,000,000 vaccinees.

AstraZenica COVID-19 vaccine, the other primate adenovirus-vectored vaccine used in Europe, has also been linked to thrombotic events in vaccinees. In two separate reviews (11 cases from Germany and Austria, and 5 cases from Norway), patients presented 5 to 16 days after vaccination with thrombocytopenia and signs of vascular thrombosis at unusual sites [128,129]. In patients with one or more thrombotic events, there were 13 instances of cerebral venous thrombosis, 4 of splanchnic-vein thrombosis, 2 of pulmonary embolism, and 4 involving other sites. The patient age range was 22 to 54 years, and 13 of 16 cases were women. The timing of events and character of clinical features were similar to that observed in cases of severe autoimmune heparin-induced thrombocytopenia, suggesting an antibody-mediated thrombotic thrombocytopenia triggered by the vaccine. All patients in each series had high levels of antibodies directed against antigenic complexes of platelet factor 4 (PF4). None of the patients had previously received heparin. This disorder is thought to represent vaccine-induced immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4 [128,129].

These reports, and the action taken by the FDA and the CDC, have important implications for health professionals. The few cases among millions of vaccine doses administered indicates the incidence is rare and the risk low. The risk may be highest in women younger than 50 years of age. Vaccinees who are beyond three weeks from date of vaccination are not considered at risk for thrombotic complications. Individuals who develop any of the following new-onset symptoms within three weeks of vaccination should be evaluated for severe headache, abdominal pain, swelling or pain in the leg, chest pain, or shortness of breath. The evaluation should include a platelet count and imaging studies appropriate to clinical exam findings. Patients with thrombocytopenia and suspicion of a thrombotic event should not be treated initially with a heparin product. A diagnostic screening immunoassay for antibodies against PF4-heparin, or an enzyme-linked immunosorbent assay for antibodies against PF4-polyanion should be ordered. Hematology consultation is advisable. Potential treatment options include high-dose immunoglobulins and certain non-heparin anticoagulants [128,130].

Another rare adverse event reported after Janssen COVID-19 vaccination is Guillain-Barré syndrome (GBS). As of June 30, 2021, approximately 12.6 million doses of Janssen COVID-19 vaccine had been administered in the United States, with 100 reports of GBS with disease onset 3 to 42 days after vaccination [145]. The median age of reported cases was 57 years, and 61 were male. The GBS reporting rate for all recipients was 7.8 cases per million doses administered; among men 50 to 64 years of age, the rate is 15.6 cases per million doses [145].

Myocarditis/Pericarditis and mRNA COVID-19 Vaccines

Myocarditis and pericarditis have been reported more frequently than expected following receipt of either the Pfizer or Moderna mRNA COVID-19 vaccine, usually within seven days after the second dose of vaccine. The majority were male adolescents or young adult, and most cases were mild, responded well to treatment, and improved rapidly without evident long-term effects. Because a background level of seasonal myocarditis/pericarditis is associated with several common viral infections, at issue is whether and how many additional (excess) cases are precipitated by COVID vaccination. Following a nationwide vaccination program, a one-to-one comparison study with 800,000 subjects each in the vaccinated and control groups found that mRNA COVID-19 vaccine was associated with an excess risk of myocarditis (2.7 events per 100,000 persons) [146]. SARS-CoV-2 infection in the same time period was associated with a higher incidence of myocarditis (11 events per 100,000 persons). In a follow-up report, the estimated incidence of vaccine-associated myocarditis among males 16 to 29 years of age was 10 events per 100,000 vaccinees; among females 16 to 29 years of age, 0.3 events per 100,000 vaccinees; and among males 30 years of age of older, 2 events per 100,000 [153].

Data from a network of 40 healthcare systems (subserving 15 million people) found the risk of cardiac complications (myocarditis/pericarditis) was significantly higher after SARS-CoV-2 infection than after mRNA COVID-19 vaccination in all age groups evaluated. For example, among males 12 to 17 years of age, the incidence rate of myocarditis/pericarditis was 50 to 65 cases per 100,000 after infection, 2 to 3 cases per 100,000 after the first dose of vaccine, and 22 to 36 after the second dose; among males 18 to 29 years of age, the corresponding incidence rates (cases per 100,000) were 55 to 100 after infection, to -8 after the first and 7 to 15 after the second dose of vaccine. Among young children 5 to 11 years of age, the incidence of myocarditis/pericarditis was considerably lower. After infection, the rate was 13 to 18 cases per 100,000 among males and 5 to 11 cases per 100,000 among females; after COVID-19 vaccination, the rate was 0 to 4 cases per 100,000 among males and 0 cases among females [173]. These findings show that the risk of myocarditis/pericarditis in adolescent and young adult males is 5 to 8 times higher after SARS-CoV-2 infection than after mRNA COVID-19 vaccination.

On July 22, 2021, the ACIP reviewed updated benefit-risk analyses after Janssen and mRNA COVID-19 vaccination and concluded that the benefits of COVID-19 vaccination outweigh the risks for rare serious adverse events after COVID-19 vaccination [145]. In reaching this conclusion, the ACIP reviewed population-level considerations, including that COVID-19 cases were rising in the United States, the predominance of the highly transmissible Delta variant, and the importance of providing options for the type of COVID-19 vaccines offered in relation to epidemiologic considerations. The Department of Health and Human Services, American Academy of Pediatrics, American Heart Association, and other health professional organizations issued a joint statement concurring with the ACIP findings and recommended COVID-19 vaccination of all eligible persons [147].

DURATION OF IMMUNITY AND REINFECTION

More than two years into the COVID-19 pandemic, there is limited information on duration of immunity following SARS-CoV-2 infection and COVID-19 vaccination. Despite the scope of the pandemic and burgeoning number of COVID-19 cases, reports of reinfection were uncommon before the emergence of SARS-CoV-2 variants. Natural immunity to SARS-CoV-2 appears to be quite durable for protection against reinfection by the original infecting strain, but less robust or predictable for protection against reinfection by variant strains of the virus.

As with most viral infections, pathogen-specific IgG antibody assays in the weeks following onset of COVID-19 are useful for diagnostic purposes but not for measuring the durability of immunity provided by (unmeasured) neutralizing antibody and memory T-cell immune responses, which often persist for months to years. In a population-based study designed to assess durability of humoral immune responses to SARS-CoV-2, serum samples from 1,107 seropositive persons were collected up to four months after diagnosis of COVID-19. Antiviral Ig-antibody titers increased during the first two months and had not declined four months after infection [116]. In a longitudinal study of healthcare workers at the University of Oxford Hospitals undergoing periodic SARS-CoV-2 testing, the presence of antibodies in persons with previous asymptomatic or symptomatic COVID-19 substantially reduced the risk of reinfection [117]. Workers were offered nasopharyngeal SARS-CoV-2 PCR testing every two weeks and antibody testing at two-month intervals. Among 11,364 workers who were initially seronegative, 223 subsequently acquired SARS-CoV-2 infection, evidenced by a positive PCR. Among 1,265 workers who were seropositive, 2 subsequently developed an asymptomatic reinfection, evidenced by a positive PCR. During eight months surveillance, no symptomatic SARS-CoV-2 reinfections were detected among workers who had serologic evidence of prior SARS-CoV-2 infection [117].

Population-based studies also indicate that reinfection with SARS-CoV-2 is uncommon and occurs in less than 1% of individuals who have previously tested positive by SARS-CoV-2 PCR. Using a PCR-test data set from 4 million inhabitants of Denmark, researchers analyzed infection rates across separate surges of COVID-19 to estimate the degree of protection afforded by natural immunity against SARS-CoV-2 reinfection more than seven months later [118]. Among 11,068 persons who tested PCR-positive during the first COVID-19 surge (March to May 2020), 72 (0.65%) tested positive again during the second surge (September to December 2020). By comparison, the rate of infection among uninfected persons who became PCR-positive during the second surge was 3.27%. Thus, the estimate of protection against SARS-CoV-2 reinfection was 80.5%. However, protection against reinfection among persons older than 65 years of age was lower (47%). The authors note the limitations of this study, including absence of information about severity of infection and the possibility individuals infected during the first COVID-19 surge may have altered subsequent behavior affecting exposure risk. These estimates of protection do highlight the importance of administering SARS-CoV-2 vaccines to previously infected individuals, especially the elderly [118].

Durable protective immunity after SARS-CoV-2 infection or COVID-19 vaccination consists of a repertoire of immune responses referred to collectively as "immunological memory" [119]. Measurable components of immune memory include pathogen-specific antibody level, memory B cells, CD4+ T cells, and/or memory CD8+ T cells. Immune memory against SARS-CoV-2 provides the basis of protection against reinfection and determines the quality and duration of vaccine efficacy. An analysis of 254 blood samples from 188 COVID-19 cases, including some samples up to eight months after infection, found that substantial immune memory involving all four types of immune response was retained in 95% of subjects over the six- to eight-month period of observation [119]. Antibodies against SARS-CoV-2 spike and receptor binding domains declined over eight months, and memory B cell activity increased between one month and eight months after infection. Circulating antibody titers were not predictive of memory T-cell activity. The authors concluded that simple serologic tests for SARS-CoV-2 antibodies do not reflect the quality and durability of immune memory to the virus [119].

COVID-19 vaccines also produce durable cellular immunity against SARS-CoV-2 infection. Studies show persistence of memory B cells and strong CD4+ T cell immune responses at least six to eight months after mRNA COVID-19 vaccination [156]. Furthermore, vaccine-induced cellular immune responses impacting cell binding with SARS-CoV-2 variants are superior to infection-induced natural immunity. This may explain in part the epidemiologic evidence that COVID-19 vaccination provides greater protection against subsequent Delta variant COVID-19 than prior SARS-CoV-2 infection. An analysis of hospitalizations for COVID-19-like illness during January–September 2021 found the adjusted odds of laboratory-confirmed COVID-19 were five-fold higher among unvaccinated patients with documented previous SARS-CoV-2 infection than among mRNA COVID-19 vaccinated patients with no previous SARS-CoV-2 infection [157].

Natural immunity augmented by COVID-19 vaccination against SARS-CoV-2 may provide the strongest, most durable protection against subsequent COVID-19. In a retrospective cohort study, using data from national health registries subserving the entire population of Sweden, investigators analyzed the impact of natural immunity on risk of SARS-CoV-2 reinfection and COVID-19 hospitalization, and potential further benefit from COVID-19 vaccination (hybrid immunity). Natural immunity from SARS-CoV-2 infection was associated with a 95% lower risk of reinfection and 87% lower risk of COVID-19 hospitalization up to 20 months follow-up. One- and two-dose hybrid immunity was associated with a lower risk of SARS-CoV-2 reinfection than natural immunity up to nine months follow-up. One-dose hybrid immunity conferred a 94% lower risk of subsequent COVID-19 hospitalization than natural immunity alone, though differences in absolute numbers were small [174].

7. GLOBAL PUBLIC HEALTH CONCERNS AND WHO RESPONSE

WHO DAILY SITUATION REPORT

Beginning in January 2020, and in association with travel to and from China, cases of confirmed SARS-CoV-2 infection began to be reported from multiple countries around the world, including the United States. In the initial weeks of the outbreak, cases reported in countries outside China were occurring primarily in returning travelers who had visited Wuhan City or nearby locales in central China. Soon, however, the extent of person-to-person transmission unrelated to travel became increasingly clear from contact tracing and rapid community spread. By November 2021, 224 countries and territories around the world had been impacted by the COVID-19 pandemic, SARS-CoV-2 infections were on the increase in 53 countries, and the global case report total exceeded 250 million, with more than 5 million deaths [120].

The WHO monitors developments and tracks the progress of the epidemic, providing daily Situation Reports at its website [8]. In an effort to curb the spread of infection, the WHO and national agencies have developed public health measures and clinical criteria to guide the evaluation and management of persons with significant exposure and/or compatible illness.

Advice to the Public

The WHO has posted standard recommendations for the general public designed to reduce exposure to, and transmission of SARS-CoV-2 [11]. In addition, the CDC has developed guidelines for the public on how to best protect themselves and others [24]:

- Wash hands often with soap and water for at least 20 seconds, especially after having been in a public place or after coughing, sneezing, or blowing your nose. If soap and water are not readily available, a hand sanitizer that contains at least 60% alcohol may be used.

- Avoid touching eyes, nose, and mouth with unwashed hands.

- Avoid close contact with people who are sick, and stay home as much as possible

- Put distance (at least 6 feet) between yourself and other people.

- Cover your mouth and nose with a cloth face cover when around others (i.e., in public). Note: This recommendation does not apply to children younger than 2 years of age, persons with breathing difficulties, or those who are unable to remove the mask unassisted.

- Cover coughs and sneezes.

- Clean and disinfect frequently touched surfaces daily, including tables, doorknobs, light switches, countertops, handles, desks, phones, keyboards, toilets, faucets, and sinks.

WHO and CDC guidance on the use of a face covering, whether by prefabricated mask or fashioned from cloth, is predicated on the growing evidence that asymptomatic and presymptomatic individuals infected with SARS-CoV-2 can transmit the virus to others in close proximity [54]. Therefore, anyone out in public should consider that he or she could, unwittingly, be an agent of transmission to others. The simple act of coughing, sneezing, talking, singing, or forceful breathing can release virus-laden droplets and respiratory particles into the air and onto nearby environmental surfaces. Multi-layered cloth masks block 50% to 70% of fine droplets and particles and limit the forward spread of those not captured [104]. Although the primary function of a face covering is to prevent inadvertent transmission to others ("source control"), it may also provide a degree of barrier protection for the one wearing it. The CDC recommends wearing cloth face coverings in public settings in which other social distancing measures are difficult to maintain (e.g., grocery stores, pharmacies), especially in areas experiencing significant community-based transmission. Detailed guidance on the construction, proper usage, and cleaning of cloth face coverings is provided on the CDC website [12].

As public health restrictions are lifted, professional and social interactions in the community present more opportunities for spread of SARS-CoV-2. The risk of transmission varies in proportion to how closely a person interacts with an infected individual and for how long. In a scientific brief updated November 20, 2020, the CDC summarized the experimental and epidemiologic data supporting community masking to reduce the spread of SARS-CoV-2 and concluded that the prevention benefit of masking is derived from the combination of source control and personal protection for the mask wearer [104]. Studies confirm that wearing face masks or double-layer cloth face coverings reduces the risk of transmission for medical personnel, patients, and the general public when in social and community settings, especially when social distancing is not possible [66,67]. A CDC report of a contact investigation involving a hair salon where universal face covering was practiced is illustrative. Two stylists with COVID-19 symptoms had worked closely with 139 clients over an eight-day period before learning of the COVID-19 diagnosis, yet there was no evidence of secondary transmission [67]. None of the clients developed COVID-19 symptoms and of 67 individuals tested for SARS-CoV-2, all were negative. Both stylists and 98% of of the clients interviewed had followed posted company policy and city ordinance requiring face coverings by employees and clients in businesses providing personal care services.

The CDC issued an order, effective February 1, 2021, requiring passengers to wear a mask on all public conveyances (e.g., airplanes, ships, ferries, subways, buses, taxis, ride-shares) when traveling into, within, or out of the United States [121]. Masks are required upon entering or while on the premises of a transportation hub and when waiting, boarding, and disembarking from public conveyances. People must wear masks that completely cover the mouth and nose.

Although highly effective in preventing severe illness, hospitalization, and death, COVID-19 vaccines are not 100% effective at preventing SARS-CoV-2 breakthrough infection. Most breakthrough infections in immunized individuals are asymptomatic or mild, having little public health import unless local transmission rates are high. In order to reduce such risks, the CDC website provides updated public health recommendations for vaccinated people [131]. As of October 2021, the CDC recommends fully vaccinated persons wear a mask indoors in public if local SARS-CoV-2 transmission is sustained or high, and get tested for COVID-19 if experiencing symptoms or within five to seven days after exposure to someone with known or suspected COVID-19. Vaccinated people may resume domestic and international travel and refrain from testing before and after travel and from self-quarantine after travel [131].

8. TRANSMISSION: PUBLIC HEALTH IMPLICATIONS

The rapidity with which the outbreak spread locally in China provided early evidence that human-to-human transmission from close contact with persons having mild, nonspecific symptoms is the primary means by which SARS-CoV-2 spreads within the community. Epidemiologic studies suggest that infected droplet nuclei expelled during coughing, sneezing, loud talking, or singing is the primary mode of transmission. Sustained close personal contact (being within 6 feet for at least 15 minutes) with an infected person increases the risk of transmission. Limiting the time and lengthening the distance reduces the risk [87]. Recovery of replication-competent virus from the upper respiratory tract begins to decline after onset of symptoms. For patients with mild-to-moderate COVID-19, replication-competent virus has not been recovered after 10 days following symptom onset [88]. Recovery of replication-competent virus between 10 and 20 days after symptom onset has been documented in some patients with severe COVID-19.

Unlike the 2003 SARS-CoV, whereby replication occurred mostly in the lower respiratory tract and virus shedding is temporally associated with symptom onset, SARS-CoV-2 is characterized by high levels of replication and virus shedding was the upper respiratory tract, even during the pre-symptomatic phase of infection [38]. Newly infected individuals are most infectious one to two days before and for a few days after the onset of symptoms. This means that persons with asymptomatic and pre-symptomatic SARS-CoV-2 infection may have high viral loads in nasopharyngeal secretions that render them efficient vectors of person-to-person transmission. Therefore, a strategy for prevention that relies solely on symptom-based detection and isolation of COVID-19 cases is likely to have limited effectiveness. In a study of skilled nursing facility residents infected with SARS-CoV-2 from a healthcare worker, half were asymptomatic or pre-symptomatic at the time of contact tracing evaluation and testing [15].

These considerations have important public health implications. Close personal contact implies touching and the sharing of common utensils; it is also defined by a proximity of 6–8 feet—the distance respiratory droplets travel after coughing or sneezing. As noted, the risk of infection is greatest for persons who have prolonged, unprotected close contact (i.e., within 6 feet for 15 minutes or longer) with someone recently diagnosed with SARS-CoV-2 infection, regardless of whether the patient has symptoms [89]. A CDC contact investigation demonstrated that even brief periods of unprotected close contact, if repeated and cumulative (exceeding 15 minutes) over the course of a day, significantly increases the risk [92]. This highlights the importance of avoiding congregate settings (e.g., assisted living facilities, college dormitories, family gatherings, indoor dining and bars) because of the increased likelihood of repetitive or sustained close contact. People can reduce the community spread of SARS-CoV-2 by practicing social distancing, wearing face coverings in public, and washing their hands.

On October 21, 2020, the CDC definition of "close contact" was revised for purposes of contact investigation [59]. Close contact describes someone who was within 6 feet of an infected person for a cumulative total of 15 minutes within a 24-hour period starting from two days before illness onset (or, for asymptomatic patients, two days prior to test specimen collection) until the time the patient is isolated. The cumulative 15-minute exposure refers to any combination of individual exposures (e.g., three 5-minute exposures) over a 24-hour period. Factors to consider when assessing close contact include proximity, duration of exposure, whether the individual has symptoms (as the period around onset of symptoms is associated with highest levels of viral shedding), whether the infected person was likely to generate aerosols (e.g., was coughing, shouting, singing), and other environmental factors (e.g., crowding, adequacy of ventilation, whether exposure was indoors or out of doors) [59].

Several emerging reports and epidemiologic studies indicate that children younger than 10 years of age may play only a small role in transmission of SARS-CoV-2. An investigation of 36 childhood COVID-19 cases in China found that 89% acquired the infection from exposure to an older household family member [50]. A population-based surveillance study in Iceland, drawing from a nationwide random sample, found that of 848 children younger than 10 years of age, none tested positive for SARS-CoV-2, whereas 100 of 12,232 (0.8%) adolescents and adults tested positive [51]. Contact tracing in relation to a cluster of COVID-19 among family and friends in France revealed that despite several days of potential exposure to a symptomatic pediatric case, there was no evidence of secondary transmission among 172 school contacts [52]. One possible explanation for these observations is the finding that gene expression of ACE2 in nasal epithelium is age-dependent; it is significantly lower in young children and increases as one develops into adulthood [53]. Lower ACE2 expression in children relative to adults could impact transmission dynamics and may help explain why COVID-19 is less prevalent in children.

Assumptions about childhood transmission of COVID-19 have been tempered somewhat since emergence of the highly transmissible SARS-CoV-2 Delta and Omicron variants in 2021. Compared with original strain infection, nasal and pharyngeal virus shedding is significantly higher; persons with Delta or Omicron infection are two and four times more infectious, respectively. Consequently, transmission now occurs more readily among children and from child to adult. Because most children were unvaccinated, symptomatic childhood infection has increased and with it the need for hospitalization. COVID-19-associated hospitalization rates among children and adolescents in the United States increased five-fold from June 2021 to mid-August 2021 [148]. Hospitalization rates were 10 times higher among unvaccinated than among vaccinated adolescents.

The stability of SARS-CoV-2 on environmental surfaces has been studied in an effort to assess whether surface contamination (fomites) could play a role in virus transmission. After application of aerosols containing a standard dose of SARS-CoV-2, viable virus was detected up to 72 hours on plastic and stainless steel, though the virus titer was greatly reduced; on cardboard, no viable SARS-CoV-2 was measured after 24 hours [19]. These data should be interpreted with caution, as it is unclear to what extent environmental detection of virus in much reduced titer at a given interval, experimentally, can be equated with actual risk of transmission from common environmental surfaces. In an April 2021 scientific brief, a CDC analysis of quantitative microbial risk assessment studies concluded the risk of SARS-CoV-2 infection via the fomite transmission route is less than 1 in 10,000, which means that each contact with a contaminated surface has less than a 1 in 10,000 chance of causing an infection [122].

The public health strategy of mitigation (preventing spread within communities) has become paramount in order to decisively limit spread and blunt the COVID-19 epidemic curve, pending development and distribution of effective vaccines. These measures include the following: suspension or cancellation of events having large public gatherings, such as cinema, theatre, concerts, and collegiate and professional sports competition; closure of schools and cancellation of classes at colleges and universities; the practice of social distancing in smaller venues such as restaurants and churches; the wearing of masks or cloth face coverings at indoor commercial venues and social gatherings. By slowing the degree and pace of virus transmission, effective mitigation helps to protect those most vulnerable and to ensure that the clinical case load does not overwhelm local hospital and critical care resources.

VARIANT STRAINS OF SARS-COV-2

In late 2020, variant strains of SARS-CoV-2 began to appear in countries with high COVID-19 case rates. Widespread circulation of SARS-CoV-2 combined with spontaneous mutations in the genome increases the probability that mutations affecting transmissibility will lead to emergence of a variant strain. As indicated, the CDC’s national genomic surveillance program identifies SARS-CoV-2 variants and tracks the proportion and distribution of COVID-19 cases attributable to variants [123,124]. SARS-CoV-2 variants circulating in the United States are characterized as variants of concern (VOC) or variants of interest (VOI). In spring 2021, three VOCs accounted for 40% of COVID-19 cases in the United States: B.1.1.7, B.1.351, P.1, and California (B.1.351, 427/429) [123]. The defining characteristics of VOC include increased transmission (B.1.1.7), increased disease severity (B.1.1.7), and decreased neutralization by monoclonal antibody therapeutics (P.1, B.1.351, 427/429). By June/July 2021, these variants had been superseded by a single highly transmissible VOC: B.1.617.2 (Delta) variant [132].

Delta Variant

Compared with the original SARS-CoV-2 strain, Delta variant is more infectious, spreads faster, and causes more severe illness in unvaccinated people than previous variants [132]. First detected in December 2020, the Delta variant spread rapidly to 43 countries across six continents. In spring 2021, the COVID-19 surge in the United States had receded to the lowest point of the pandemic; the seven-day moving average of daily new cases was 12,000. By mid-July, the daily average of new cases had again surged to more than 60,000, of which 98% were caused by the SARS-CoV-2 Delta variant [132].

During the period of Delta predominance, breakthrough infection (usually asymptomatic or mild) occurred in vaccinated persons, but the majority of hospitalizations and deaths caused by Delta variant COVID-19 were in unvaccinated people. During the summer COVID-19 surge in Los Angeles County, unvaccinated individuals were five times more likely to acquire Delta variant infection and 29 times more likely to be hospitalized than persons who had been fully vaccinated [158]. The principal risk of secondary household and community transmission was also attributable to unvaccinated people, who were much more likely to become infected and thus shed the virus. Fully vaccinated individuals with breakthrough Delta infection did spread virus to others, but to a lesser degree and for a shorter period of time [132]. An investigation of virologic characteristics among healthcare workers with Delta variant breakthrough COVID-19 found that illness was uniformly mild; shedding of virus from the nose and throat was either unmeasurable or rapidly dissipated within one to three days [115].

Omicron Variant

In mid-November 2021, a new SARS-CoV-2 strain (the Omicron variant) emerged in South Africa among children, college students, and international travelers. Within 10 to 14 days’ time, cases of Omicron variant COVID-19 were identified in 50 countries, indicating a high level of transmission. Early clinical reports indicated that Omicron-associated COVID is mild (characterized mainly by nasal congestion, cough, and fatigue). with rates of hospitalization less than half that seen with the Delta variant. Cases of SARS-CoV-2 Omicron were first reported in the United States in December; by end of that month, Omicron had replaced Delta as the predominant variant and principal cause of COVID-19 in the United States [123,124].

Omicron is unique because of the number of genomic mutations and substitutions identified--50 overall and more than 30 in the spike protein, some of which are known to be associated with reduced susceptibility to monoclonal antibody therapeutics or reduced neutralization by convalescent and vaccinee sera [123]. Omicron is highly transmissible and spreads two to four times more rapidly than the original SARS-CoV-2 and Delta variant. COVID-19 cases tend to be less severe, though this can be misleading, as many patients are children or vaccinated adults, groups expected to experience mild illness. Health providers should expect the Omicron COVID-19 clinical profile to be similar to that associated with previous strains; the risk of serious illness is lower but still significant for unvaccinated persons, especially the elderly and those with underlying health conditions.

It was expected that the Omicron variant might evade immune protection gained from prior SARS-CoV-2 infection or COVID-19 vaccination. There is a three- to eightfold increased risk of Omicron reinfection among people who have had prior COVID-19. Studies show the initial two-dose mRNA vaccines (Pfizer, Moderna) lose their effectiveness against Omicron infection after four to six months (though protection against severe illness and hospitalization is largely preserved). Evasion of vaccine immunity is reversed following a booster dose in people who previously received the primary COVID-19 vaccine series; an interval-appropriate third (booster) dose increases neutralizing antibody levels 25- to 60-fold, reduces risk of breakthrough infection by 75%, and provides more than 90% protection against severe illness and hospitalization.

Rapid, wide-spread circulation has led to emergence of Omicron subvariants, one of which (BA.2) is more transmissible than the parent variant and slowly becoming the predominant version. Apart from heightened transmissibility, severity of illness appears to be unchanged and the benefit derived from previous natural and boosted vaccine immunity appears to be as robust as that against the parent variant.

The emergence of Delta and Omicron demonstrates that SARS-CoV-2 variants can impact transmission, disease severity, risk of reinfection, and vaccine efficacy. At issue is the extent to which adaptive immunity (CD4+ and CD8+ T cell responses) in COVID-19 convalescent patients and vaccinees recognize (target) conserved epitopes on SARS-CoV-2 variants of concern. Fortunately, studies to date have demonstrated that SARS-CoV-2 T cell epitopes are not appreciably affected by the mutations found in newly described variants [125,126]. Overall, CD4+ and CD8+ T cell responses in convalescing COVID-19 patients or COVID-19 mRNA vaccinees remain effective against VOC presently circulating in the United States, including Delta and Omicron variants.

CDC MONITORING AND GUIDANCE FOR HEALTHCARE PROFESSIONALS

As of May 2022, more than 82 million cases and more than 1 million deaths from COVID-19 have been reported in the United States and territories [124]. Ethnic populations appear to be disproportionately affected. The CDC monitors COVID-19 epidemiologic data and provides updated clinical guidance for healthcare providers, laboratories, health facilities, and public health professionals [124]. Included are recommendations for the evaluation of persons/patients under investigation, laboratory specimen transport, and protection of healthcare workers. Recommendations for patient assessment and care in hospitals and other healthcare facilities emphasize the importance of strict adherence to patient isolation and barrier precautions, including the proper use of personal protective equipment (PPE).

Selected materials from the CDC website, including recommendations for travelers, interim guidance for healthcare professionals, infection control, and healthcare worker safety, are reproduced in the following sections. Please note that language and/or cultural barriers may impede assessment and education on the topic, and interpreters and translated materials are recommended, when appropriate.

COVID-19 Data Tracker

The CDC website maintains a COVID-19 Data Tracker and Weekly Review [124]. This site tracks the number of reported cases of SARS-COV-2 infection in the United States, prevalence of variant strains, rates of COVID-19 hospitalization, and vaccination status of the population. As of May 15, 2022, the seven-day moving average of daily new cases was 90,337 (2.4% increase). The CDC estimates the Omicron lineage (e.g., BA.1, BA.2) accounted for 100% of new cases. The seven-day daily average of new hospitalizations was 2,698 (8.3% increase). The seven-day moving average of daily new deaths remained stable over the prior week. Overall, about 581.8 million vaccine doses have been administered and about 221 million people (66.7% of the population) is fully vaccinated. Vaccination trends by age group show that 96.9% of people 65 or older have received at least one dose and 84.9% are fully vaccinated. About 102.3 million people (46.4% of the eligible population) have received an additional or booster dose of COVID-19 vaccine [124].

The CDC Data Tracker also monitors COVID-19 vaccine effectiveness. COVID-19 case rates and deaths among fully vaccinated and unvaccinated people are reported to the CDC from multiple jurisdictions. During the recent Omicron surge, adults who were vaccinated and boosted were 7 times less likely to be hospitalized and 21 times less likely to die from COVID-19 compared with those who were unvaccinated [124].

CDC Guidance on Travel During COVID-19

The CDC provides updated information and guidance on domestic and international travel based on SARS-CoV-2 vaccination status [13]. The CDC recommends delaying travel until fully vaccinated. Both vaccinated and unvaccinated individuals who must travel should observe the following precautions [13]:

- Avoid contact with sick people.

- Avoid touching your eyes, nose, or mouth with unwashed hands.

- Wash hands often with soap and water for at least 20 seconds or use an alcohol-based hand sanitizer that contains at least 60% to 85% alcohol.

- Avoid traveling if you are sick.

- Wear a cloth face covering in terminals and other public venues.

- Cover coughs and sneezes.

- Pick up food at drive-throughs, curbside restaurant service, or stores.

Unvaccinated persons should get a SARS-CoV-2 nasopharyngeal swab test one to three days before the trip, repeat the viral test three to five days after travel and self-quarantine for seven days after travel (or 10 days if testing is omitted). Returning travelers from any destination are encouraged to observe standard precautions, monitor health, and follow state, territorial, tribal, and local recommendations or requirements after travel [13].

As of May 2022, the CDC recommends that persons who are up to date with COVID-19 vaccination can travel with low risk to themselves and others [13]. Up-to-date COVID-19 vaccination status is defined as having received the initial primary series and an interval-appropriate booster dose. Such persons can travel safely within the United States without the need for pre-travel testing or post-travel self-quarantine if they continue to take COVID-19 precautions while traveling.

Recommended Criteria to Guide Evaluation of Patients Under Investigation for COVID-19

CDC guidance specifies who should be tested for COVID-19 and encourages clinicians to use clinical judgment in determining whether a patient with signs and symptoms compatible with COVID-19 should be tested [14]. Symptoms to be considered include fever, chills, cough, sore throat, muscle aches, shortness of breath, new loss of taste or smell, and vomiting or diarrhea. As noted, SARS-CoV-2 can cause asymptomatic, pre-symptomatic, and minimally symptomatic infection, leading to virus shedding that may result in transmission to others who are particularly vulnerable to severe disease and death. Special attention should be paid to older adults and to patients with underlying conditions or immunosuppressed states. Even mild signs and symptoms of COVID-19 should be evaluated among potentially exposed healthcare personnel because of their extensive contact with vulnerable patients in healthcare settings.

The CDC has established priorities for COVID-19 diagnostic testing [14]. High priority for testing applies to hospitalized patients with compatible clinical features, healthcare facility workers and those who work in congregate living settings with symptoms, and residents in long-term care facilities (including prisons and shelters) with symptoms. Priority designation for testing applies to any person in the community with symptoms of potential COVID-19. In addition, persons without symptoms may be prioritized by health departments or clinicians for reasons such as public health monitoring, sentinel surveillance, or screening purposes.

Clinicians should work with their local and state health departments to coordinate testing through public health laboratories or work with commercial or clinical laboratories using SARS-CoV-2 diagnostic tests granted an Emergency Use Authorization by the FDA. Patients should be evaluated and discussed with public health departments on a case-by-case basis if their clinical presentation or exposure history is equivocal.

Other considerations that may guide testing include epidemiologic factors (e.g., close contact with an individual who in the past 14 days has tested positive for SARS-CoV-2) and the occurrence of local transmission or a cluster of COVID-19 within a specific community setting (e.g., nursing home, manufacturing facility) [14]. Close contact is defined as one of the following:

- Being within approximately 6 feet (2 meters), or within the room or care area, of a novel coronavirus case for a prolonged period of time while not wearing recommended personal protective equipment or PPE (e.g., gowns, gloves, certified disposable N95 respirator, eye protection); close contact can include caring for, living with, visiting, or sharing a healthcare waiting area or room with a novel coronavirus case.

- Having direct contact with infectious secretions of a novel coronavirus case (e.g., being coughed on) while not wearing recommended personal protective equipment.

Any patient with fever and severe acute lower respiratory illness (e.g., pneumonia, ARDS) requiring hospitalization and without alternative explanatory diagnosis (e.g., influenza) should be evaluated for COVID-19, even if no source of exposure has been identified [14].

A symptomatic patient should be provided a surgical mask and placed on respiratory isolation, preferably in an airborne isolation negative pressure room. Caregivers should observe enhanced precautions (i.e., wear gloves, gown, eye protection device [other than prescription eye glasses], and N95 respirator). For information on the management of patients with COVID-19, see https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html.

Diagnostic Testing

The CDC recommends that healthcare providers should immediately notify both infection control personnel at their healthcare facility and their local or state health department in the event of a newly diagnosed or suspected case of COVID-19.

Confirmation of COVID-19 is performed using the RT-PCR assay for SARS-CoV-2 on respiratory specimens (which can include nasopharyngeal or oropharyngeal aspirates or washes, nasopharyngeal or oropharyngeal swabs, bronchoalveolar lavage, tracheal aspirates, or sputum) and serum. The FDA has worked to expedite the availability of tests through emergency authorization of commercial laboratories that have developed SARS-CoV-2 testing capability. Information on specimen collection, handling, and storage is available at https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html. After initial confirmation of COVID-19, additional testing of clinical specimens can help inform clinical management, including discharge planning. Additional guidance for collection, handling, and testing of clinical specimens is available at the CDC website [12].

Infection with both SARS-CoV-2 and with other respiratory viruses has been reported, and detection of another respiratory pathogen does not rule out COVID-19 [15].

Interim Clinical Guidance for Management of Patients with Confirmed COVID-19

Interim clinical guidance and additional resources for clinicians caring for patients with COVID-19 is provided and updated at the CDC and NIH websites, selected aspects of which are reproduced in this section [15].

As noted, the clinical presentation of COVID-19 can range from asymptomatic to critically ill, and older patients and those with comorbidities are considered at greater risk for more severe disease. Among patients who developed severe disease, the median time to dyspnea was 5 to 8 days, the median time to ARDS was 8 to 12 days, and the median time to ICU admission was 10 to 12 days. Clinicians should be aware of the potential for some patients to rapidly deteriorate one week after illness onset. Among all hospitalized patients, 26% to 32% of patients were admitted to the ICU [15]. Only 3% to 17% of all patients with COVID-19 develop ARDS, but this increases to 20% to 42% for hospitalized patients and 67% to 85% for patients admitted to the ICU. Mortality among patients admitted to the ICU ranges from 39% to 72%, depending on the study [15]. The median length of hospitalization among survivors was 10 to 13 days.

Clinical management entails prompt implementation of recommended infection prevention and control measures and supportive management of complications, including advanced organ support if indicated [15]. Healthcare personnel should care for patients in an airborne infection isolation room. Isolation Precautions should be used when caring for the patient. For more detailed recommendations, see the CDC's Interim Infection Prevention and Control Recommendations for Patients with Suspected or Confirmed Coronavirus Disease 2019 (COVID-19) in Healthcare Settings at https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.html. The NIH and the Infectious Diseases Society of America provide updated COVID-19 management guidelines, including specific recommendations for the use of remdesivir and dexamethasone in hospitalized patients [10,57].

Management of COVID-19 in the Ambulatory Care Setting

Patients with a mild clinical presentation may not initially require hospitalization [15]. However, clinical signs and symptoms may worsen with progression to lower respiratory tract disease in the second week of illness; all patients should be monitored closely. As noted, possible risk factors for progressing to severe illness may include, but are not limited to, older age, obesity (body mass index >35), and underlying chronic comorbidities (e.g., lung disease, cancer, heart failure, cerebrovascular disease, renal disease, liver disease, diabetes, immunocompromising conditions, pregnancy).

Approximately 80% of patients with symptomatic SARS-CoV-2 infection have mild COVID-19 (having no viral pneumonia or hypoxemia) and do not require medical intervention or hospitalization [57]. Such patients can be managed in the ambulatory setting. Patients with moderate COVID-19 (having signs of viral pneumonia but without hypoxemia) or severe COVID-19 (those having dyspnea, hypoxemia, or lung infiltrates) require in-person evaluation and ongoing observation for progression of pulmonary disease. It is important to identify those patients at risk for progression to severe disease and therefore candidates for early therapeutic intervention.

Several therapeutic options are now available for nonhospitalized patients with mild COVID-19 who are at risk for disease progression, including anti-SARS-CoV-2 monoclonal antibody, parenteral remdesivir, and oral anti-SARS-CoV-2 agents. Factors to consider in selecting the best treatment option for a given patient are clinical efficacy and availability of the treatment option, feasibility of parenteral administration (for remdesivir or monoclonal antibody), potential drug-drug interactions (particularly those associated with use of nirmatrelvir-ritonavir), and the local prevalence of SARS-CoV-2 VOCs [57]. As of May 2022, Omicron is the predominant SARS-CoV-2 variant and sotrovimab is the only monoclonal antibody product with acceptable activity against this variant. Administration of remdesivir requires three consecutive days of intravenous infusion. Selection of nirmatrelvir-ritonavir necessitates reviewing the patient’s concurrent medications and supplements to evaluate potential drug-drug interaction. Molnupiravir, which has a lower efficacy than the other treatment options, should only be used when other options are not available [57].

The CDC advises that the decision to monitor a patient in the inpatient or outpatient setting should be made on a case-by-case basis. Important considerations are the patient's clinical status, reliability of clinical monitoring, and need and options for home isolation to reduce risk of secondary transmission. For more information, see the CDC's Criteria to Guide Evaluation of Patients Under Investigation (PUI) for COVID-19 at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-criteria.html.

The CDC recommends that for most patients with confirmed SARS-CoV-2 infection the decision to discontinue transmission-based precautions should be made using a symptom-based strategy [88]. In general, patients with mild-to-moderate COVID-19 who are not immunocompromised may discontinue isolation once five to seven days have passed since onset of illness, respiratory symptoms have improved, and at least 24 hours have passed since resolution of fever (without the use of fever-reducing medications). For patients who were asymptomatic throughout their infection, precautions may be discontinued when at least five days have passed since the date of their first positive viral diagnostic test. Symptomatic and asymptomatic persons should continue to wear a well-fitted mask (for five additional days) when around others at home and in public. Additional considerations apply to patients who have sustained severe or critical illness and to those who are significantly immunocompromised [88].

9. OTHER AVAILABLE RESOURCES

CDC Information for Healthcare Professionals about Coronavirus (COVID-19)

https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html

CDC Information for Healthcare Professionals about COVID-19 Vaccination

https://www.cdc.gov/vaccines/covid-19/index.html

CDC Coronavirus Disease 2019 (COVID-19) Resources for Health Departments

https://www.cdc.gov/coronavirus/2019-ncov/php/index.html

World Health Organization Coronavirus Disease 2019 (COVID-19) Pandemic

https://www.who.int/emergencies/diseases/novel-coronavirus-2019

Johns Hopkins University and Medicine Coronavirus Resource Center

https://coronavirus.jhu.edu

NIH Coronavirus Disease 2019 (COVID-19) Treatment Guidelines

https://www.covid19treatmentguidelines.nih.gov

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management

Works Cited

1. Periman S. Another decade, another coronavirus. N Engl J Med. 2020;382:760-762.

2. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382: 727-733.

3. Centers for Disease Control and Prevention. More Resources About COVID-19. Available at https://www.cdc.gov/coronavirus/2019-ncov/more/index.html. Last accessed May 16, 2022.

4. Munster VJ, Koopmans M, van Doremalen N, et al. A novel coronavirus emerging in China: key questions for impact assessment. N Engl J Med. 2020;382:692-694.

5. Azhar EI, El-Kafrawy SA, Farraj SA, et al. Evidence for camel-to-human transmission of MERS Coronavirus. N Engl J Med. 2014;370:2499-2505.

6. Drosten C, Meyer B, Muller MA, et al. Transmission of MERS-Coronavirus in household contacts. N Engl J Med. 2014;371:828-835.

7. Assiri A, McGeer A, Peri TM, et al. Hospital outbreak of Middle East Respiratory Syndrome Coronavirus. N Engl J Med. 2013;369:407-416.

8. World Health Organization. Coronavirus Disease (COVID-19) Pandemic. Available at https://www.who.int/emergencies/diseases/novel-coronavirus-2019. Last accessed May 16, 2022.

9. Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.

10. Infectious Disease Society of America. COVID-19 Resource Center. Available at https://www.idsociety.org/covid-19-real-time-learning-network. Last accessed May 16, 2022.

11. World Health Organization. Coronavirus Disease (COVID-19) Advice for the Public. Available at https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public. Last accessed May 16, 2022.

12. Centers for Disease Control and Prevention. Coronavirus Disease (COVID-19) in the U.S. Available at https://www.cdc.gov/coronavirus/2019-ncov/index.html. Last accessed May 16, 2022.

13. Centers for Disease Control and Prevention. Travel During the COVID-19 Pandemic. Available at https://www.cdc.gov/coronavirus/2019-ncov/travelers/travel-during-covid19.html. Last accessed May 16, 2022.

14. Centers for Disease Control and Prevention. Overview of Testing for SARS-CoV-2. Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html. Last accessed May 16, 2022.

15. Centers for Disease Control and Prevention. Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19). Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html. Last accessed May 16, 2022.

16. U.S. Food and Drug Administration. FDA Takes Significant Step in Coronavirus Response Efforts, Issues Emergency Use Authorization for the First 2019 Novel Coronavirus Diagnostic. Available at https://www.fda.gov/news-events/press-announcements/fda-takes-significant-step-coronavirus-response-efforts-issues-emergency-use-authorization-first. Last accessed May 16, 2022.

17. Guan W-J, Ni Z-Y, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708-1720.

18. Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus disease (COVID-19) in China. Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41(2):145-151.

19. van Doremalen N, Bushmaker T, Morris DH, et al. To the editor: aerosolized and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020;382:1564-1567.

20. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19. N Engl J Med. 2020; 382:1787-1799.

21. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020;71(15):732-739.

22. Devaux CA, Rolain JM, Colson P, et al. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020;55(5):105938.

23. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-1242.

24. Centers for Disease Control and Prevention. How to Protect Yourself and Others. Available at https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Last accessed May 16, 2022.

25. Centers for Disease Control and Prevention. Interim Infection Prevention and Control Recommendations for Healthcare Personnel During the Coronavirus Disease 2019 (COVID-19) Pandemic. Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.html. Last accessed May 16, 2022.

26. Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe COVID-19. N Engl J Med. 2020;382:2327-2336.

27. Shen C, Wang Z, Zhao F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020;323(16):1582-1589.

28. U.S. Food and Drug Administration. Donate COVID-19 Plasma. Available at https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/donate-covid-19-plasma. Last accessed May 16, 2022.

29. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Blood Purification Device to Treat COVID-19. Available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-blood-purification-device-treat-covid-19. Last accessed May 16, 2022.

30. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-280.

31. Puelles VG, Lütgehetmann M, Lindenmeyer MT, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med. 2020; 383:590-592.

32. Pei G, Zhang Z, Peng J, et al. Renal involvement and early prognosis in patients with COVID-19 pneumonia. J Am Soc Neph. 2020;31(6):1157-1165.

33. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323:1061-1069.

34. Clerkin KJ, Fried JA, Raikhelkar J, et al. Coronavirus disease 2019 (COVID-19) and cardiovascular disease. Circulation. 2020;141:1648-1655.

35. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19: final report. N Engl J Med. 2020;383:1813-1826.

36. U.S. Food and Drug Administration. Emergency Use Authorization for Use of Chloroquine Phosphate or Hydroxychloroquine Sulphate for Treatment of 2019 Coronavirus Disease. Available at https://www.fda.gov/media/136534/download. Last accessed May 16, 2022.

37. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020;382:2411-2418.

38. Gandhi M, Yokie DS, Havlir DV. Asymptomatic transmission, the Achilles' heel of current strategies to control COVID-19. N Engl J Med. 2020;382:2158-2160.

39. Cannegieter S, Klok FA. COVID-19-associated coagulopathy and thromboembolic disease: commentary on an interim expert guidance. Res Pract Thromb Haemost. 2020;4(4):439-445.

40. COVID-19 coagulopathy: an evolving story. Lancet. 2020;7(6):E425.

41. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844-847.

42. Helms J, Tacquard C, Severac F, et al. for the CRICS TRIGGERSEP Group. High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-1098.

43. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research. 2020;191:145-147.

44. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of COVID-19 in New York City. N Engl J Med. 2020;382:2372-2374.

45. Centers for Disease Control and Prevention. Information for Pediatric Healthcare Providers. Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/pediatric-hcp.html. Last accessed May 16, 2022.

46. New York State Department of Health. Novel Coronavirus (COVID-19): Multisystem Inflammatory Syndrome in Children (MIS-C). Available at https://coronavirus.health.ny.gov/multisystem-inflammatory-syndrome-children-mis-c. Last accessed May 16, 2022.

47. Riphagen S, Gomez X, Gonzalez-Martinez C, et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):P1607-P1608.

48. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicenter of the SARS-CoV-2 epidemic: an observational study. Lancet. 2020;395(10239):P1771-P1778.

49. Centers for Disease Control and Prevention. Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C). Available at https://www.cdc.gov/mis/mis-c/hcp/index.html. Last accessed May 16, 2022.

50. Qui H, Wu J, Hang L, et al. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational study. Lancet. 2020;20(6):P689-P696.

51. Gudbjartsson D, Helgason A, Jonsson H, et al. Spread of SARS-CoV-2 in the Icelandic population. N Engl J Med. 2020;382: 2302-2315.

52. Danis K, Epaulard O, Bénet T, et al. Cluster of coronavirus disease 2019 (Covid-19) in the French Alps, 2020. Clin Infect Dis. 2020;71(15):825-832.

53. Bunvavanich S, Do A, Vicencio A. Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA. 2020;323(23):2427-2429.

54. Centers for Disease Control and Prevention. Considerations for Wearing Masks. Available at https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/cloth-face-cover-guidance.html. Last accessed May 16, 2022.

55. Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus disease 2019 case surveillance—United States, January 22–May 30, 2020. MMWR. 2020;69(24):759-765.

56. Solomon IH, Normandin E, Bhattacharyya S, et al. Neuropathological features of Covid-19. N Engl J Med. 2020;383:989-992.

57. National Institutes of Health. COVID-19 Treatment Guidelines. Available at https://www.covid19treatmentguidelines.nih.gov. Last accessed May 16, 2022.

58. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine. Available at hhttps://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and. Last accessed May 16, 2022.

59. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19): Health Departments, Appendices. Available at https://www.cdc.gov/coronavirus/2019-ncov/php/contact-tracing/contact-tracing-plan/appendix.html. Last accessed May 16, 2022.

60. Burke RM, Killerby ME, Newton S, et al. Symptom profiles of a convenience sample of patients with COVID-19—United States, January–April 2020. MMWR. 2020;69:904-908.

61. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 2020;383:334-346.

62. Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York state. N Engl J Med. 2020;383:347-358.

63. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19—preliminary report. N Engl J Med. 2021;384:693-704.

64. Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine against SARS-CoV-2—preliminary report. N Engl J Med. 2020;383:1920-1931.

65. Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomized controlled trial. Lancet. 2020;396(10249):P467-P478.

66. Brooks JT, Butler JC, Redfield RR. Universal masking to prevent SARS-CoV-2 transmission—the time is now. JAMA. 2020;324(7):635-637.

67. Hendrix MJ, Wade C, Findley K, Trotman R. Absence of transmission of SARS-CoV-2 after exposure at a hair salon with universal face mask policy—Springfield, Missouri. MMWR. 2020;69(28):930-932.

68. Carfi A, Bernabei R, Landi F, et al. Persistent symptoms in patients after acute COVID-19. JAMA. 2020;324:603-605.

69. Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020. MMWR. 2020;69:993-998.

70. Cavalcanti AB, Zampieri FG, Rosa RC, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19.N Engl J Med. 2020;383:2041-2052.

71. Horby P, Mafham M, Linsell L, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-center, randomized, controlled trial. Available at https://www.medrxiv.org/content/10.1101/2020.07.15.20151852v1. Last accessed May 16, 2022.

72. National Institutes of Health. NIH Halts Clinical Trial of Hydroxychloroquine. Available at https://www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine. Last accessed May 16, 2022.

73. U.S. Food and Drug Administration. Fact Sheet for Healthcare Providers: Emergency Use Authorization (EUA) of COVID-19 Convalescent Plasma for Treatment of COVID-19 in Hospitalized Patients. Available at https://www.fda.gov/media/141478/download. Last accessed May 16, 2022.

74. Biran N, Andrew I, Ahn J, et al. Tocilizumab among patients with COVID-19 in the intensive care unit: a multicenter observational study. Lancet Rheumatology. 2020;2(10):e603-e612.

75. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid-related Strongyloides hyperinfection. JAMA. 2020;324(7):623-624.

76. Joyner MJ, Senefeld JW, Klassen SA, et al. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. Available at https://www.medrxiv.org/content/10.1101/2020.08.12.20169359v1. Last accessed May 16, 2022.

77. Tartof SY, Qian L, Hong V, et al. Obesity and mortality among patients diagnosed with COVID-19: results from an integrated health care system. Ann Int Med. 2020;M20-3742.

78. Kass DA. COVID-19 and obesity: a big problem? Ann Int Med. 2020;M20-5677.

79. Centers for Disease Control and Prevention. Overview of Testing for SARS-CoV-2 (COVID-19). Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/testing-overview.html. Last accessed May 16, 2022.

80. U. S. Food and Drug Administration. Coronavirus Disease 2019 (COVID-19) Emergency Use Authorization for Medical Devices: In Vitro Diagnostics EUAs. Available at https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/vitro-diagnostics-euas#individual-antigen. Last accessed May 16, 2022.

81. Fournier J, Casanovas-Massana A, Campbell M, et al. To the editor: Saliva or nasopharyngeal swab specimens for detection of SARS-CoV-2. N Engl J Med. 2020;383:1283-1286.

82. Hanson KE, Barker AP, Hillyard DR, et al. Self-collected anterior nasal and salivary specimens versus healthcare worker-collected nasopharyngeal swabs for the molecular detection of SARS-CoV-2. J Clin Microbiol. 2020;58(11):e01824-e01830.

83. Centers for Disease Control and Prevention. Interim Guidelines for COVID-19 Antibody Testing. Available at https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antibody-tests-guidelines.html. Last accessed May 16, 2022.

84. U.S. Food and Drug Administration. Coronavirus Disease 2019 (COVID-19) Emergency Use Authorization for Medical Devices: EUA Authorized Serology Test Performance. Available at https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/eua-authorized-serology-test-performance. Last accessed May 16, 2022.

85. Marovich M, Mascola JR, Cohen MS. Monoclonal antibodies for prevention and treatment of COVID-19. JAMA. 2020;324:131-132.

86. Anderson EJ, Rouphael NG, Widge AT, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults.N Engl J Med. 2020;383:2427-2438.

87. Chu DK, Aki EA, Duda S, et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systemic review and meta-analysis. Lancet. 2020;395:1973-1987.

88. Centers for Disease Control and Prevention. Ending Isolation and Precautions for People with COVID-19: Interim Guidance. Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html. Last accessed May 16, 2022.

89. Centers for Disease Control and Prevention. Clinical Questions about COVID-19: Questions and Answers: COVID-19 Risk. Available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/faq.html#COVID-19-Risk. Last accessed May 16, 2022.

90. U.S. Food and Drug Administration. FDA Approves First Treatment for COVID-19. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19. Last accessed May 16, 2022.

91. Parr JB. Time to reassess tocilizumab's role in COVID-19 pneumonia. JAMA Intern Med. 2021;181(1):12-15.

92. Pringle JC, Leikauskas J, Ransom-Kelly S, et al. COVID-19 in a correctional facility employee following multiple brief exposures to persons with COVID-19—Vermont, July–August 2020. MMWR. 2020;69(43):1569-1570.

93. Simonovich VA, Burgos Pratx LD, Scibona P, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia.N Engl J Med. 2021;384:619-629.

94. Chen P, Nirula A, Heller B, et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med. 2021;384:229-237.

95. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Monoclonal Antibody Bamlanivimab. Available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-monoclonal-antibody-bamlanivimab. Last accessed May 16, 2022.

96. U.S. Food and Drug Administration. Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of Casirivimab and Imdevimab. Available at https://www.fda.gov/media/145611/download. Last accessed May 16, 2022.

97. Krammer F. SARS-CoV-2 vaccines in development. Nature. 2020;586:516-527.

98. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383:2603-2615.

99. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384: 403-416.

100. Dooling K, Marin M, Wallace M, et. al. The Advisory Committee on Immunization Practices' updated interim recommendation for allocation of COVID-19 vaccine—United States, December 2020. MMWR. 2021;69:1657-660.

101. Centers for Disease Control and Prevention. COVID-19 Vaccination: Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently Authorized in the United States. Available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html. Last accessed May 16, 2022.

102. Castells MC, Phillips EJ. Maintaining safety with SARS-CoV-2 vaccines. N Engl J Med. 2021;384:643-649.

103. Centers for Disease Control and Prevention. COVID-19 Vaccination, Interim Considerations: Preparing for the Potential Management of Anaphylaxis after COVID-19 Vaccination. Available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/managing-anaphylaxis.html. Last accessed May 16, 2022.

104. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19) Scientific Brief: Community Use of Cloth Masks to Control the Spread of SARS-CoV-2. Available at https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/masking-science-sars-cov2.html. Last accessed May 16, 2022.

105. Freeman EE, McMahon DE, Lipoff JB, et al. Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries. J Am Acad Dermatol. 2020;83:486-492.

106. Freeman EE, McMahon DE, Lipoff JB, et al. The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries. J Am Acad Dermatol. 2020;83:1118-1129.

107. Zambrano LD, Ellington S, Strid P, et al. Update: characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status—United States, January 22–October 3, 2020. MMWR. 2020;69:1641-1647.

108. Havervall S, Rosell A, Phillipson M. Symptoms and functional impairment assessed 8 months after mild COVID-19 among health care workers. JAMA. 2021;325(19):2015-2016.

109. Libster R, Marc GP, Wappner D, et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med. 2021;384:610-618.

110. Oliver SE, Gargano JW, Scobie H, et al. The Advisory Committee on Immunization Practices' interim recommendation for use of Janssen COVID-19 vaccine—United States, February 2021. MMWR. 2021;70:329-332.

111. Manisty C, Otter AD, Treibel TA, et al. Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals. Lancet. 2021;397:1057-1058.

112. Lustig Y, Nemer I, Kliker L, et al. Neutralizing response against variants after SARS-CoV-2 infection and one dose of BNT162b2. N Engl J Med. 2021;384(25):2453-2454.

113. Centers for Disease Control and Prevention. V-Safe After Vaccination Health Checker. Available at https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafe.html. Last accessed May 16, 2022.

114. Blumenthal KG, Freeman EE, Saff RR, et al. Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2. N Engl J Med. 2021;384:1273-1277.

115. Shamier MC, Tostmann A, Bogers S, et al. Virologic Characteristics of SARS-CoV-2 Vaccine Breakthrough Infections in Health Care Workers. Available at https://www.medrxiv.org/content/10.1101/2021.08.20.21262158v1. Last accessed May 16, 2022.

116. Gudbjartsson DF, Norddahl GL, Melsted P, et al. Humoral immune response to SARS-CoV-2 in Iceland. N Engl J Med. 2020;383:1724-1734.

117. Lumley SF, O'Donnell D, Stoesser NE, et al. Antibody status and incidence of SARS-CoV-2 infection in health care workers. N Engl J Med. 2021;384:533-540.

118. Hansen CH, Michlmayr D, Gubbels SM, et al. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-positive individuals in Denmark in 2020: a population-level observational study. Lancet. 2021;397(10280):1204-1212.

119. Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed up to 8 months after infection. Science. 2021;371(6529):eabf4063.

120. Reuters. COVID-19 Global Tracker. Available at https://graphics.reuters.com/world-coronavirus-tracker-and-maps/. Last accessed May 16, 2022.

121. Centers for Disease Control and Prevention. Order: Wearing of Face Masks While on Conveyances and at Transportation Hubs. Available at https://www.cdc.gov/quarantine/masks/mask-travel-guidance.html. Last accessed May 16, 2022.

122. Centers for Disease Control and Prevention. COVID-19 Science Brief: SARS-CoV-2 and Surface (Formite) Transmission for Indoor Community Environments. Available at https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/surface-transmission.html. Last accessed May 16, 2022.

123. Centers for Disease Control and Prevention. SARS-CoV-2 Variant Classifications and Definitions. Available at https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html. Last accessed May 16, 2022.

124. Centers for Disease Control and Prevention. COVID Data Tracker Weekly Review. Available at https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html. Last accessed May 16, 2022.

125. Tarke A, Sidney J, Methot N, et al. Negligible impact of SARS-CoV-2 variants on CD4+ and CD8+ T cell reactivity in COVID-19 exposed donors and vaccinees. bioRxiv. 2021; [Epub ahead of print].

126. Redd AD, Nardin A, Kared H, et al. CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants. Open Forum Infectious Diseases. 2021; [Epub ahead of print].

127. U. S. Food and Drug Administration. Joint CDC and FDA Statement on Johnson & Johnson COVID-19 Vaccine. Available at https://www.fda.gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine. Last accessed May 16, 2022.

128. Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med. 2021;384(22):2092-2101.

129. Schultz NH, Sorvoll IH, Michelsen AE, et al. Brief report: thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384(22):2124-2130.

130. Hunter PR. Editorial: thrombosis after covid-19 vaccination. BMJ. 2021;373:n958.

131. Centers for Disease Control and Prevention. Interim Public Health Recommendations for Fully Vaccinated People. Available at https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated-guidance.html. Last accessed May 16, 2022.

132. Centers for Disease Control and Prevention. Delta Variant: What We Know About the Science. Available at https://www.cdc.gov/coronavirus/2019-ncov/variants/delta-variant.html. Last accessed May 16, 2022.

133. Le Page M, Thomson H, Vaughan A, Wilson C. Getting to grips with long COVID. New Sci. 2021;250:10-13.

134. Becker JH, Lin JJ, Doernberg M, et al. Assessment of cognitive function in patients after COVID-19 infection. JAMA Netw Open. 2021;4(10):e2130645.

135. Say D, Crawford N, McNab S, et al. Post-acute COVID-19 outcomes in children with mild and asymptomatic disease. Lancet: Child & Adolescent Health. 2021;5(6):e22-e23.

136. American Academy of Pediatrics. Children and COVID-19: State-Level Data Report. Available at https://www.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/children-and-covid-19-state-level-data-report. Last accessed May 16, 2022.

137. Centers for Disease Control and Prevention. COVID Data Tracker: Health Department-Reported Cases of Multisystem Inflammatory Syndrome in Children (MIS-C) in the United States. Available at https://covid.cdc.gov/covid-data-tracker/#mis-national-surveillance. Last accessed May 16, 2022.

138. Gray KJ, Bordt EA, Atyeo C, et al. Coronavirus disease 2019 vaccine response in pregnant and lactating women: a cohort study. Am J Obstet Gynecol. 2021;225(3):303.e1-303.e17.

139. Centers for Disease Control and Prevention. V-safe COVID-19 Vaccine Pregnancy Registry. Available at https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafepregnancyregistry.html. Last accessed May 16, 2022.

140. Zauche LH, Wallace B, Smoots AN, et al. To the editor: receipt of mRNA vaccines and risk of spontaneous abortion. NEJM. 2021;385:1533-1535.

141. Magnus MC, Gjessing HK, Eide HN, et al. To the editor: COVID-19 vaccination during pregnancy and first-trimester miscarriage. NEJM. 2021;385:2008-2010.

142. Academy of Breastfeeding Medicine. ABM Statement: Considerations for COVID-19 Vaccination in Lactation. Available at https://abm.memberclicks.net/abm-statement-considerations-for-covid-19-vaccination-in-lactation. Last accessed May 16, 2022.

143. Golan Y, Prahi M, Cassidy A, et al. Evaluation of messenger RNA from COVID-19 BTN162b2 and mRNA-1273 vaccines in human milk. JAMA Pediatr. 2021;10:1069-1071.

144. The American College of Obstetricians and Gynecologists. Statement of Strong Medical Consensus for Vaccination of Pregnant Individuals Against COVID-19. Available at https://www.acog.org/news/news-releases/2021/08/statement-of-strong-medical-consensus-for-vaccination-of-pregnant-individuals-against-covid-19. Last accessed May 16, 2022.

145. Rosenblum HG, Hadler SC, Moulia D, et al. Use of COVID-19 vaccines after reports of adverse events among adult recipients of Janssen (Johnson & Johnson) and mRNA COVID-19 vaccines (Pfizer-BioNtech and Moderna): update from the Advisory Committee on Immunization Practices—United States, July 2021. MMWR. 2021;70:1094-1099.

146. Barda N, Dagan N, Shiomo YB, et al. Safety of the BNT162b2 mRNA COVID-19 vaccine in a nation-wide setting. N Eng J Med. 2021;385:1078-1090.

147. U.S. Department of Health and Human Services. Statement Following CDC ACIP Meeting from Nations Leading Doctors, Nurses, Pharmacists and Public Health Leaders on Benefits of Vaccination. Available at https://www.hhs.gov/about/news/2021/06/23/statement-following-cdc-acip-meeting-nations-leading-doctors-nurses-public-health-leaders-benefits-vaccination.html. Last accessed May 16, 2022.

148. Delahoy MJ, Ujamaa D, Whitaker M, et al. Hospitalizations associated with COVID-19 among children and adolescents—COVID-NET, 14 states, March 1, 2020–August 14, 2021. MMWR. 2021;70:1255-1260.

149. Seasely AR, Blanchard CT, Arora N, et al. Maternal and perinatal outcomes associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta (B.1.617.2) variant. Obstetrics & Gynecology. 2021;138(6):842-844.

150. Morris RS. SARS-CoV-2 spike protein seropositivity from vaccination or infection does not cause sterility. Amer Soc Reproduct Med, F & S Rep. 2021;2(3):253-255.

151. Gonzalez DC, Nassau DE, Khodamoradi K, et al. Sperm parameters before and after COVID-19 mRNA vaccination. JAMA. 2021;326:273-274.

152. Hezavehei M, Shokoohian B, Nasr-Esfahani MH, et al. Possible male reproduction complications after Coronavirus pandemic.Cell J. 2021;23:382-388.

153. Witberg G, Barda N, Hoss S, et al. Myocarditis after Covid-19 vaccination in a large health care organization. N Engl J Med. 2021;385:2132-2139.

154. Centers for Disease Control and Prevention. COVID-19 vaccine breakthrough infections reported to CDC—United States, January 1–April 30, 2021. MMWR. 2021;70:792-793.

155. Centers for Disease Control and Prevention. COVID-19 Vaccine Booster Shots. Available at https://www.cdc.gov/coronavirus/2019-ncov/vaccines/booster-shot.html. Last accessed May 16, 2022.

156. Goel RR, Painter MM, Apostolidis SA, et al. mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern. Science. 2021;374(6572):abm0829.

157. Bozio CH, Grannis SJ, Naleway AL, et al. Laboratory-confirmed COVID-19 among adults hospitalized with COVID-19-like illness with infection-induced or mRNA vaccine-induced SARS-CoV-2 immunity—nine states, January–September 2021. MMWR. 2021;70(44):1539-1544.

158. Griffin JB, Haddix M, Danza P, et al. SARS-CoV-2 infections and hospitalizations among persons aged >16 years, by vaccination status—Los Angeles County, May 1–July 25, 2021. MMWR. 2021;70(34):1170-1176.

159. Richter DR, Guasti L, Koehler F, et al. Late phase of COVID-18 pandemic in general cardiology: a position paper of the ESC Council for Cardiology Practice. ESC Heart Failure. 2021;8:3483-3494.

160. Xie Y, Xu E, Bowe B, et al. Long-term cardiovascular outcomes of COVID-19. Nat Med. 2022;28:583-590.

161. Xie Y, Al-Aly Z. Risks and burdens of incident diabetes in long COVID: a cohort study. Lancet Diabetes & Endocrinology. 2022; [Epub ahead of print].

162. Bradley RE, Ponsford MJ, Scurr MJ, et al. Therapeutic vaccination: a case report. J Clin Immun. 2022;42:32-35.

163. Marks KJ, Whitaker M, Agathis NT, et al. Hospitalization of infants and children aged 0-4 years with laboratory-confirmed COVID-19—COVID-NET, 14 states, March 2020–February 2022. MMWR. 2022;71(11):429-436.

164. Zambrano LD, Newhams MM, Olson SM, et al. Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA vaccination against multisystem inflammatory syndrome in children among persons aged 12-18 years—United States, July–December 2021. MMWR. 2022;71(2):52-58.

165. Gottlieb RL, Vaca CE, Peredes R, et al. Early remdesivir to prevent progression to severe Covid-19 in outpatients. N Engl J Med. 2022;386:305-315.

166. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med. 2022; [Epub ahead of print].

167. Centers for Disease Control and Prevention, Rapid Increase in Ivermectin Prescriptions and Reports of Severe Illness Associated with Use of Products Containing Ivermectin to Prevent or Treat COVID-19. Available at https://emergency.cdc.gov/han/2021/han00449.asp. Last accessed May 16, 2022.

168. Yemple C, Hoang R, Hendrickson RG. Toxic effects of ivermectin use associated with prevention and treatment of Covid-19. N Engl J Med. 2021;385:2197-2198.

169. Lopez-Medina E, Lopez P, Hurtado IC, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19. JAMA. 2021;325:1426-1435.

170. Reis G, Silva E, Silva D, et al. Effect of early treatment with ivermectin among patients with Covid-19. N Engl J Med. 2022; [Epub ahead of print].

171. Lim SCL, Hor CP, Tay KH, et al. Efficacy of ivermectin treatment on disease progression among adults with mild to moderate COVID-19 and comorbidities: the I-TECH randomized clinical trial. JAMA Intern Med. 2022; [Epub ahead of print].

172. Tenforde MW, Self WH, Gaglani M, et al. Effectiveness of mRNA vaccination in preventing COVID-19-associated invasive mechanical ventilation and death—United States, March 2021–January 2022. MMWR. 2022;71(12):459-465.

173. Block JP, Borhmer TK, Forrest CB, et al. Cardiac complications after SARS-CoV-2 infection and mRNA COVID-19 vaccination—PCORnet, United States, January 2021–January 2022. MMWR. 2022; [Epub ahead of print].

174. Nordstrom P, Ballin M, Nordstrom A. Risk of SARS-CoV-2 reinfection and COVID-19 hospitalization in individuals with natural and hybrid immunity: a retrospective study, total population cohort study in Sweden. Lancet Infect Dis. 2022; [Epub ahead of print].

175. U.S. Food and Drug Administration. Fact Sheet for Healthcare Providers Emergency Use Authorization (EUA) of Baricitinib. Available at https://www.fda.gov/media/143823/download. Last accessed May 20, 2022.

176. Centers for Disease Control and Prevention. COVID-19 Rebound After Paxlovid Treatment. Available at https://emergency.cdc.gov/han/2022/pdf/CDC_HAN_467.pdf. Last accessed May 31, 2022.

177. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Approves First COVID-19 Treatment for Young Children. Available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-approves-first-covid-19-treatment-young-children. Last accessed July 18, 2022.

178. U.S. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Emergency Use of Novavax COVID-19 Vaccine, Adjuvanted. Available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-emergency-use-novavax-covid-19-vaccine-adjuvanted. Last accessed July 18, 2022.