GKY17 • Nurses 2017

Table of Contents

GKY17 • Nurses 2017

How to Receive Credit

NetCE 2 Hour Course #96340 • Mental Health Issues Common to Veterans and Their Families

96340 • Mental Health Issues Common to Veterans and Their Families

1. INTRODUCTION

2. SCREENING FOR MILITARY SERVICE

3. MENTAL HEALTH ISSUES

4. REINTEGRATION AND READJUSTMENT

5. REFERRAL

6. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 3 Hour Course #98710 • Zika Virus Disease

98710 • Zika Virus Disease

1. INTRODUCTION

2. HISTORICAL BACKGROUND AND EPIDEMIOLOGY

3. ZIKA VIRUS TRANSMISSION

4. ZIKA VIRUS DISEASE

5. DIAGNOSIS

6. CLINICAL MANAGEMENT ISSUES

7. PREVENTION

8. VECTOR CONTROL

9. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

10. SUMMARY

Works Cited

NetCE 10 Hour Course #98930 • Irritable Bowel Syndrome

98930 • Irritable Bowel Syndrome

1. INTRODUCTION

2. EPIDEMIOLOGY

3. ETIOLOGY, PATHOGENESIS, AND PATHOPHYSIOLOGY

4. CLINICAL PRESENTATION AND DIAGNOSTIC WORKUP

5. TREATMENT

6. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

7. CONCLUSION

8. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

GKY17 • Nurses 2017

Alice Yick Flanagan, PhD, MSW

Mark Rose, BS, MA, LP

Carol Shenold, RN, ICP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

GKY17 • Nurses 2017

Expiration Date: 07/31/2019

How to Receive Credit

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96340 • Mental Health Issues Common to Veterans and Their Families

Alice Yick Flanagan, PhD, MSW

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2017 NetCE, All rights reserved.

The effects of deployment to military combat on the individual and the family system are wide-reaching and can be severe. Military personnel may confront numerous potentially traumatizing experiences, including military-specific events and those experienced by civilians. Research suggests the most common traumatic events experienced during active duty are witnessing someone badly injured or killed or unexpectedly seeing a dead body. These exposures can have a serious impact on veteran mental health, with higher rates of PTSD, depression, suicide, and intermittent explosive disorders than the general public. These effects extend to the family, with increased risks for domestic violence, divorce, and child abuse. Including screening items to identify veterans and their families and improve the care provided. In addition, steps should be taken to refer or treat these patients using evidence-based interventions with proven efficacy for veterans.

Table of Contents

96340 • Mental Health Issues Common to Veterans and Their Families

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. SCREENING FOR MILITARY SERVICE

3. MENTAL HEALTH ISSUES

POST-TRAUMATIC STRESS DISORDER

DEPRESSION AND SUICIDE

SUBSTANCE ABUSE

MILITARY SEXUAL TRAUMA

DOMESTIC VIOLENCE

INTERMITTENT EXPLOSIVE DISORDER

4. REINTEGRATION AND READJUSTMENT

IMPACT ON THE FAMILY SYSTEM

5. REFERRAL

RESOURCES

6. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

96340 • Mental Health Issues Common to Veterans and Their Families

Education Category. Psychiatric / Mental Health

Release Date. 05/01/2017

Expiration Date. 04/30/2020

Course Overview

The effects of deployment to military combat on the individual and the family system are wide-reaching and can be severe. Military personnel may confront numerous potentially traumatizing experiences, including military-specific events and those experienced by civilians. Research suggests the most common traumatic events experienced during active duty are witnessing someone badly injured or killed or unexpectedly seeing a dead body. These exposures can have a serious impact on veteran mental health, with higher rates of PTSD, depression, suicide, and intermittent explosive disorders than the general public. These effects extend to the family, with increased risks for domestic violence, divorce, and child abuse. Including screening items to identify veterans and their families and improve the care provided. In addition, steps should be taken to refer or treat these patients using evidence-based interventions with proven efficacy for veterans.

Audience

This course is designed for physicians, nurses, psychologists, social workers, therapists, counselors, and other healthcare professionals who may treat veterans or their family members.

Course Objective

The purpose of this course is to provide health and mental health professionals with an appreciation of the impact of military service on patient health as well as the skills necessary to effectively identify and intervene for these patients.

Learning Objectives

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

1. Outline the demographics of the U.S. current and former military personnel and the need to screen for military service in health and mental health care.

2. Describe risk factors for and the presentation of post-traumatic stress disorder (PTSD) in military veterans.

3. Discuss the impact of depression and suicide in veterans.

4. Evaluate the impact of other various mental health issues common in veterans and their families, including violence and intermittent explosive disorder.

5. Identify issues that may arise during reintegration and readjustment following deployment and the need for appropriate referral to services available to veterans and their families.

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.

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

Faculty Disclosure

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

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

Division Planners

John M. Leonard, MD

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

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

The effects of deployment to military combat on the individual and the family system are wide-reaching and can be severe. According to the U.S. Department of Defense, there were more than 3.5 million current military personnel and almost 24 million veterans in 2015 [1,2]. The Army has the largest number of active duty members, followed by the Navy, the Air Force, and the Marine Corps [1]. Military service presents its own set of risk and protective factors for a variety of mental health issues, including post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), depression and suicide, substance abuse, and interpersonal violence. In particular, transitioning from combat back to home life can be particularly trying for veterans and their families.

2. SCREENING FOR MILITARY SERVICE

As the number of military conflicts and deployments has increased since 2001, the need to identify and provide better treatment to veterans and their families has become a greater priority. The first step in providing optimal care is the identification of veterans and veteran families during initial assessments, with an acknowledgement that veterans may be any sex/gender and are present in all adult age groups [2].

Unfortunately, veterans and military families often do not voluntarily report their military service in healthcare appointments. In 2015, the American Medical Association updated its recommendations for social history taking to include military history and veteran status [3]. In addition, the American Academy of Nursing has designed the Have You Ever Served? Initiative to encourage health and mental health professionals to ask their patients about military service and related areas of concern [4]. This program provides pocket cards, posters, and resource links for professionals working with veterans and their families. Recommended questions for intake include [4]:

- Have you or has someone close to you ever served in the military?

- When did you serve?

- Which branch?

- What did you do while you were in the military?

- Were you assigned to a hostile or combative area?

- Did you experience enemy fire, see combat, or witness casualties?

- Were you wounded, injured, or hospitalized?

- Did you participate in any experimental projects or tests?

- Were you exposed to noise, chemicals, gases, demolition of munitions, pesticides, or other hazardous substances?

3. MENTAL HEALTH ISSUES

POST-TRAUMATIC STRESS DISORDER

Military personnel may confront numerous potentially traumatizing experiences, including military-specific events and those experienced by civilians. Research suggests the most common traumatic events experienced during active duty are witnessing someone badly injured or killed or unexpectedly seeing a dead body. Events most likely to result in the development of PTSD include witnessing atrocities, accidentally injuring or killing another person, and other interpersonal traumas, such as rape, domestic violence, and being stalked, kidnapped, or held captive [5,6].

Exposure to multiple traumatic events is not uncommon during deployment, and exposure to real or threatened death and serious physical injury that can lead to PTSD is likely. Fundamental beliefs about self, the world, and humanity can become severely challenged by the nature of wartime traumatic events, such as exposure to the death of civilians and destruction of communities on an unimaginable scale with little preparation. Veterans may themselves have committed acts of violence they deem with hindsight as atrocities, shattering previously held beliefs about the self [5].

More than 2 million members of the U.S. Armed Forces have now served in the Iraq and Afghanistan wars beginning in 2001 and 2003, respectively. In these conflicts, more than 6,000 soldiers died, close to 43,000 were wounded (ranging from shrapnel injuries to amputation and TBI), and more than 100,000 witnessed one or more traumatic events involving horrific injuries or loss of life in members of their unit [7]. Many have returned home with psychologically damaging memories. Combat veterans have often described feeling unable to relate to civilians, including their families, and of having lost the ability for true connectedness except with their comrades, which leads to a sense of loneliness and isolation [7].

With innocent civilians used as human shields, children used as "bait" for attacks, calm moments erupting into death and devastation in seconds, and violations of the rules of engagement, the nature of the Iraq and Afghanistan wars impose on the returning veteran an unnatural recalibration of security and sanity. Among returning war veterans, the most common problems involve somatic, emotional, cognitive, behavioral, interpersonal, and psychosocial components. Somatic concerns appear as primary and middle (sleep-maintenance) insomnia, fatigue, headaches, tinnitus, impotence, restlessness, and chronic pain. Emotional and psychologic complaints may involve nightmares, racing thoughts (particularly at bedtime), generalized and social anxiety, anger and irritability, impulsive hostility, emotional numbing, hypervigilance, complicated grief, and despair [7].

Cognitive problems that may develop from combat trauma exposure include poor sustained and divided attention that partially reflects hypervigilance, poor concentration, impaired memory, rumination, and distorted thinking (e.g., jumping to conclusions, dichotomous decision-making). Common behavioral problems (often under-reported) include abuse of alcohol, illicit drugs, or prescription medications, and high-risk behaviors such as reckless driving or starting fights. Interpersonal concerns often involve feeling misunderstood, intolerance of others, distrust, isolation, and withdrawal. Frequent psychosocial concerns can involve spiritual crisis, domestic violence, child abuse, and general family dysfunction. The most common concerns of veterans seeking primary care are anger, sleep problems, and erectile dysfunction, and all are complicated if there is ongoing substance abuse [7,8].

Veterans frequently report sensitivity to triggers that stimulate sensory perception, such as sudden or loud sounds, noxious or unusual smells, high temperatures, foreign foods, or uneven terrain. Even less obvious triggers can produce anxiety, panic, fear, anger, and overall sympathetic nervous system arousal, including situations that appear unpredictable (e.g., crowds), beyond control (e.g., a room without an easy exit), or the precursor of potential danger (e.g., traffic or building complexes) [7].

Triggers can activate muscle memory of combat, including the readiness to fight, aggress, and escalate, and none of these are appropriate reactions in the civilian milieu. Combat immersion mode can become stuck in the "on" position, with the defensive or aggressive posture not easily turned off. For others, this heightened state of arousal is experienced as an adrenaline rush of battle that is reinforcing, driving some veterans to seek danger, risk, or excitement to maintain the "high" [7].

Epidemiology

Vietnam Veterans

The National Vietnam Veterans Readjustment Study interviewed 3,016 U.S. Vietnam-era veterans between 1986 and 1988 and found a lifetime PTSD prevalence of 30.9% in men and 26.9% in women. The past-year PTSD prevalence was 15.2% in men and 8.1% in women [9,10].

Gulf War Veterans

From 1995 to 1997, 11,441 U.S. Gulf War veterans were assessed with the PTSD Checklist, with a score ≥50 considered as meeting PTSD criteria. The prevalence of current PTSD was 12.1% [9,11].

Iraq and Afghanistan War Veterans

Several studies have published PTSD prevalence and incidence rates in Iraq and Afghanistan war veterans. Highly consistent rates have been found with grouping the studies by subpopulation, such as Army or Marine combat infantry units [12]. An early PTSD prevalence study in Iraq and Afghanistan war military personnel using stringent PTSD criteria found three-month post-deployment rates among infantry soldiers and Marines returning from high-intensity combat in Iraq of 12.9% and 12.2%, respectively. Soldiers deployed to Afghanistan who were exposed to very low-intensity combat showed a three-month post-deployment PTSD rate of 6.2%, compared with the pre-deployment baseline population rate was 5% [12,13]. Subsequent studies of Iraq and Afghanistan war-deployed soldiers found rates of acute stress disorder (ASD) or PTSD of 10% to 20% [12]. Prevalence was directly associated with combat frequency and intensity, with units exposed to minimal combat similar in prevalence to baseline rates in the population, and a linear increase up to 25% in units involved in the highest-intensity combat. Soldiers in Afghanistan showed lower PTSD prevalence earlier in the war, which increased to levels comparable with Iraq combatants from 2007 onward [12].

Soldiers assigned to active and National Guard combat infantry teams showed post-deployment PTSD rates of 15% after 3 months and 17% to 25% after 12 months [12,14]. A study of previously deployed Iraq and Afghanistan war veterans found a current PTSD rate of 13.8% [9].

Risk Factors

The strongest predictors of increased prevalence of post-deployment PTSD are combat frequency and intensity, which impose greater risk than the actual number of deployments in predicting adverse mental health outcomes [12]. Some evidence indicates that military recruits have a higher prevalence of childhood physical abuse, sexual abuse and neglect, and family dysfunction compared with community averages, with these factors contributing to the higher PTSD risk [15,16]. Practitioners should assess pre-military history, as these factors can also influence the therapeutic relationship and treatment planning [5].

Comorbid Conditions

Biomechanical Injury/Traumatic Brain Injury

Evidence Based Practice Recommendation

As PTSD may contribute to the overall burden of symptoms in some individuals following mild traumatic brain injury (TBI), particularly where problems persist for more than three months, the Scottish Intercollegiate Guidelines Network recommends that mental state should be routinely examined in patients with TBI.

https://www.guideline.gov/summaries/summary/43914

Last Accessed: April 10, 2017

Level of Evidence: C (A body of evidence including well-conducted case control or cohort studies, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from high-quality systematic reviews of case control or cohort studies)

In Iraq and Afghanistan war veterans, biomechanical trauma to the brain caused by explosions and blast waves is the most frequent physical injury [17]. When severe enough, the brain trauma is termed traumatic brain injury or TBI. Even mild TBI elevates patient risk of psychiatric conditions, including PTSD, depression, anxiety, substance abuse, or suicide. TBI is characterized by three symptom types [7,18]:

- Cognitive: Problems with memory, poor attention, and limited concentration

- Emotional/behavioral: Irritability, depression, anxiety, impulsivity, and isolation

- Somatic: Insomnia, headache, tinnitus, and dizziness

The chaos and possible amnesia surrounding the TBI event can interfere with obtaining a proper history of the injury, but the provider should make an effort to document injury severity and type, previous brain injury history, and the extent of symptom overlap between TBI and PTSD. Common overlapping symptoms include depression, anxiety, irritability/anger, trouble concentrating, fatigue, hyperarousal, and avoidance [7,18].

Risk of Suicide and Violence

Since 2007, the suicide rates in the Army and Marine Corps have surpassed general population rates [19]. Factors with the greatest association to suicide risk include depression, relationship strain, financial and vocational loss, and magnitude of life impairment. Clinical presentations with the highest prediction of potential future suicidal behavior are the presence of overwhelming negative thoughts and hopelessness over the future [20].

The potential for harm to others is another safety concern to address during assessment. Veterans with pronounced irritability, anger, and impulsivity may act aggressively toward others, and in one study, 63% of veterans seeking care for PTSD had been aggressive to their partners in the last year [7,21]. To gain a clearer picture of individual veteran risk of suicide or violence, the provider should assess the integrity of the veteran's support system, access to lethal means of self-harm, history of impulsivity and substance use, sleep adequacy, medication regimen, and outlook on the near and distant future [22].

Treatment

The overall objective of PTSD therapy is to treat the four core symptom clusters of intrusive re-experiencing, avoidance, hyperarousal, and negative alterations in cognitions and mood. Psychotherapy is the backbone of PTSD therapy, with pharmacotherapy used as an adjunct if necessary. Providers should be aware of the range of therapeutic options along with their advantages and disadvantages (e.g., time commitment, side effects, risks) and be able to explain these to the patient.

Therapies for PTSD are broadly divided into psychotherapies, pharmacotherapies, and adjunctive or supplemental treatment modalities. Providers and patients alike are faced with important decisions involving the type, number, frequency, and dose of psychotherapy and pharmacologic interventions [12].

As noted, TBI is often comorbid in combat veterans with PTSD. The effect of mild TBI on PTSD treatment response is less clear due to the absence of high-quality randomized controlled trials. Tentative suggestions support the use of standard cognitive-behavioral therapy, with minor modifications as needed. Therapists can encourage patients to manage mild TBI-related symptoms by using compensatory strategies such as personal digital assistants or scheduling cognitive breaks [23,24,25].

DEPRESSION AND SUICIDE

Although the true incidence of suicide among military war veterans is difficult to estimate due to the lack of national suicide surveillance data, the U.S. Department of Veterans Affairs (VA) estimates that 22% of all deaths from suicide in the United States are in military war veterans [26]. In addition, 12% of all U.S. Army suicides occur within 12 months of hospital discharge [27]. Despite preventive measures taken by the military, the number of suicides in this population continues to increase [28,29,30,31,32]. Although the majority of military suicides occur among young men shortly after their discharge from military service, military women 18 to 35 years of age commit suicide nearly three times more frequently than nonveteran women of the same age group [33,34].

Protective Factors

Several general protective factors against suicide may be more prevalent among veterans, including strong interpersonal bonds, responsibilities/duties to others, steady employment, sense of belonging/identity, and access to health care [26]. Historically, the selection bias for healthy recruits, employment, purposefulness, access to health care, and a strong sense of belonging were believed to be protective against suicide, but increasing rates have challenged this assumption [26]. In one study, having a service-connected disability was associated with a lower risk of suicide in veterans, likely due to greater access to VA health care and regular compensation payments [28]. It is interesting to note that many of these protective factors do not apply to discharged or retired veterans. Other potentially protective factors include older age, African American/black race, and admission to a nursing home [26].

Risk Factors

Evidence Based Practice Recommendation

When assessing military service persons in transition for risk of suicide, the Department of Veterans Affairs recommends providers should inquire about changes in the patient's life and be aware of other indicators of change (retirement physical, overseas duty screening, etc.) and be willing to discuss and consider methods to strengthen social support during the transition time if there are other risk factors present.

https://www.guideline.gov/summaries/summary/47023

Last Accessed: April 10, 2017

Level of Evidence: Expert Opinion/Consensus Statement

Veterans often possess many risk factors for attempting or completing suicide. These include combat exposure (particularly deployment to a combat theater and/or adverse deployment experiences), combat wounds, PTSD and other mental health problems, comorbid major depression, TBI, poor social support, feelings of not belonging or of being a burden to others or society, acquired ability to inflict lethal self-injury, and access to lethal means [34,35,36,37]. There is conflicting evidence of the role of PTSD in suicide risk, with some studies finding PTSD diagnosis to be protective while others indicating it increases risk. Other possible risk factors include [26]:

- Disciplinary actions

- Reduction in rank

- Career-threatening change in fitness for duty

- Perceived sense of injustice or betrayal (unit/command)

- Command/leadership stress, isolation from unit

- Transferring duty station

- Administrative separation from service/unit

With military service members, the command element should also be involved in education, safety planning, treatment planning, and implementation of duty limitations. Additional areas to address are medical, psychosocial, socioeconomic, or spiritual needs of the patient [26].

Treatment

The VA has made the following recommendations when creating a treatment plan for veterans and active service members at risk for suicide [26]:

- Providers must take reasonable steps to limit the disclosure of protected health information to the minimum necessary to accomplish the intended purpose.

- Providers should involve command in the treatment plan of service members at high acute risk for suicide to assist in the recovery and the reintegration of the patient to the unit. For service members at other risk levels, the provider should evaluate the risk and benefit of involving command and follow service department policies, procedures, and local regulations.

- When performing a medical profile, the provider should discuss with command the medical recommendation and the impact on the service member's limitations to duty and fitness for continued service.

- Provider should discuss with service members the benefit of having command involved in their plan and assure them their rights to protected health information with some exceptions regarding to the risk for suicide.

- As required by pertinent military regulations, communicate to the service member's chain of command regarding suicidal ideation along with any recommended restrictions to duty, health and welfare inspection, security clearance, deployment, and firearms access. Consider redeployment to home station any service member deployed to a hazardous or isolated area.

- Service members at high acute risk for suicide who meet criteria for hospitalization and require continuous (24-hour) direct supervision should be hospitalized in almost all instances. If not, the rationale should specifically state why this was not the preferred action, with appropriate documentation.

- During operational deployment conditions or other extreme situations during which hospitalization or evacuation is not possible, "unit watch" may be considered as appropriate in lieu of a high level care setting (hospitalization), and service department policies, procedures, and local regulations should be followed.

Because of the high risk of suicide during the period of transition, providers should pay particular attention to ensure follow-up, referral, and continuity of care during the transition of service members at risk for suicide to a new duty station, after separation from unit, or separation from military service.

Prevention

Assessment of suicide risk and protective factors in military personnel is vital, particularly at times of transition (e.g., deployment, separation from service/unit). It is important to include life planning, referral information, and resources for patients who experience suicidal ideation, and there are military-specific resources available for current or former members of the military. The Veterans Crisis Line, at 800-273-8255, is free to all active service members, including members of the National Guard and Reserve, and veterans, even if they are not registered with the VA or enrolled in VA health care [38].

Suicide Survivors: Treatment and Resources

Family members and friends affected by the death of a loved one through suicide are referred to as "suicide survivors." Conservative estimates suggesting a ratio of six survivors for every completed suicide indicate that an estimated 6 million Americans became suicide survivors in the past 25 years [39].

The death of a loved one by suicide can be shocking, painful, and unexpected for survivors. The ensuing grief can be intense, complex, chronic, and nonlinear. Working through grief is a highly individual and unique process that survivors experience in their own way and at their own pace. Grief does not always move in a forward direction, and there is no time frame for grief. Survivors should not expect their lives to return to their previous state and should strive to adjust to life without their loved one. The initial emotional response may be overwhelming, and crying is a natural reaction and an expression of sadness following the loss of a loved one [40].

Survivors often struggle with trying to comprehend why the suicide occurred and how they could have intervened. Feelings of guilt are likely when the survivor believes he or she could have prevented the suicide. The survivor may even experience relief at times, especially if the loved one had a psychiatric illness. The stigma and shame that surrounds suicide may cause difficulty among the family members and friends of survivors in knowing what to say and how to support the survivor and might prevent the survivor from reaching out for help. Ongoing support remains important to maintain family and other relationships during the grieving process [40].

Many survivors find that the best help comes from attending a support group for survivors of suicide in which they can openly share their own story and their feelings with fellow survivors without pressure or fear of judgment and shame. Support groups can be a helpful source of guidance, understanding, and support through the healing process [40]. The American Foundation for Suicide Prevention maintains an international directory of suicide bereavement support groups on their website at http://www.afsp.org.

SUBSTANCE ABUSE

Among all military service members, the overall prevalence rate for heavy alcohol use in the past 12 months is 8.4% [41]. A Department of Defense report indicates that the heaviest rates of drinking were among Marines (15.5%), followed by the Navy (9%), Army (8.6%), Coast Guard (7.5%), and Air Force (3.8%) [41]. When comparing illicit substance use among civilian and military populations, civilian past-year usage is higher (8.9%) compared with military servicemen and women (1.3%). This lower rate of illicit substance use is due in part to the military's random testing procedures and zero-tolerance policies [41]. Binge drinking has spiked since the wars in Iraq and Afghanistan started; in 2008, almost half of active-duty military members reported binge drinking [42]. In that same time, the use of prescription pain medications (particularly opioids) have also increased; between 2001 and 2009, the number of prescriptions written by military physicians increased fourfold [42]. Because drugs and alcohol can inhibit negative feelings and disconcerting memories, it may be used to self-medicate, particularly among those who have witnessed or experienced suffering related to war and deployment.

Substance and alcohol abuse can cause tremendous harm, strain, and burden on the family system. It inevitably impacts communications, roles, finances, routines, parenting, employment, and other dimensions of family life [43]. The Stress-Strain-Coping-Support model has been employed to understand how substance and alcohol abuse impact the family [44]. This framework postulates that a family member using substances or alcohol causes stress and strain on the entire family; family members may exhibit stress or strain through a variety of physical, emotional, and psychologic symptoms; family members frequently try to determine what is wrong and what they can do to fix the problem; and the way family members cope and respond to the situation is often influenced by how others in their immediate social support system respond [44].

For military families, deployment and reintegration trigger additional stressors that can lead to substance and alcohol abuse. For example, servicemen and women returning from deployment have a higher prevalence rate of new-onset drinking problems compared with nondeployed active-duty personnel [45]. In a study examining veterans returning from Iraq, 13.9% of the veterans were determined to have probable PTSD, 39% probable alcohol misuse, and 3% probable substance abuse [46]. Military members who have been in combat and who have PTSD are more likely use substances and alcohol to cope [47]. However, one study found that a clinical diagnosis of PTSD was a less important predictor of alcohol, substance, or aggressive behavioral problems than the presence of symptoms of a stress response [47].

MILITARY SEXUAL TRAUMA

The VA defines military sexual trauma as "sexual assault or repeated, threatening sexual harassment that occurred while the veteran was in the military" [48]. This can include rape (nonconsenting, forced, or coerced sexual activity); unwanted sexual touching or grabbing; threatening, offensive remarks about a person's body or sexual activities; and/or threatening or unwelcome sexual advances [48]. In 2015, the Department of Defense received 6,083 reports of sexual assault involving service members [49]. In a survey of 60,000 veterans who served during the Operations Enduring Freedom and Iraqi Freedom eras, approximately 41% of women and 4% of men reported experiencing military sexual trauma [50]. Female Marines and Navy veterans were at an increased risk compared with female Air Force veterans, and both men and women who experienced combat exposure during deployment had increased risk for sexual trauma compared with those who did not [50]. In general, deployment was a protective factor for male veterans, but not for female veterans. In a separate study of 13,262 female military members, significant risk factors for sexual stressors included younger age, recent separation or divorce, service in the Marine Corps, positive screen for a baseline mental health condition, moderate/severe life stress, and prior sexual stressor experiences [51].

Although military sexual assault is relatively common, victims remain reluctant to report their experiences [52]. It is recommended that all health and mental health professionals ask their veteran patients about experiences of sexual assault, even if they served many years previously. The following questions may be included in history-taking [4]:

- During military service, did you receive uninvited or unwanted sexual attention, such as touching, pressure for sexual favors, or sexual remarks?

- Did anyone ever use force or threat of force to have sexual contact with you against your will?

- Did you report the incidents to your command and/or military or civilian authorities?

Clinical care providers should be alert for, and responsive to, the emotional trauma sustained by the sexual assault victim. In the hours following an assault, these patients exhibit a range of emotional responses, including fear, panic, shame, anger, mistrust, and denial. They are in need of emotional support, comfort, and the assurance of protection. Often, there is a need for reassurance that the victim is not at fault, no matter the circumstances surrounding the assault. Rape crisis counseling and social services should be enlisted early to assist in the care of the patient and to develop a discharge plan that addresses emotional needs, support systems, safety issues, and follow-up care.

The military also provides services for victims of sexual trauma. The VA provides free services to help veterans overcome sexual trauma, even for veterans who do not qualify for other VA care or who have not reported the incident(s) [53]. The Department of Defense offers anonymous crisis and support help for victims via its Safe Helpline at (877) 995-5247 or https://www.safehelpline.org.

DOMESTIC VIOLENCE

It has been argued that because the military culture legitimizes violence, it places military family members at risk for various forms of violence [54]. Furthermore, the stressors associated with military lifestyle, such as the lack of social support systems, adjustments to a new region, or encountering different cultures, can heighten risk factors for domestic violence [55]. Often, military needs take priority over family issues. These factors contribute to stress, which can lead to domestic violence [56]. One study suggested that combat produces stress and antisocial behaviors among veterans, and these antisocial behaviors can affect marriage [57].

The U.S. Department of Defense has taken a proactive stance on domestic violence. In 2007, the Department of Defense instituted a policy that holds military-affiliated abusers accountable for their behaviors [58]. A unit commander is obligated and authorized to respond to domestic violence situations in order to safeguard victims and can discipline the alleged perpetrator. If the abuser is not a military member, there is no military recourse, but if the perpetrator is a member of the military, a commander can issue disciplinary actions such as restricting access to the post, forfeit of pay, extra duties, and/or reduction in grade [58].

Because state laws for mandatory reporting vary, in the 1980s the U.S. Army established its own definitions and policies for domestic violence [59]. When an incident of abuse (child abuse or spouse abuse) is reported, the Case Review Committee, which falls under the purview of the commander of the medical treatment facility, reviews the case to determine if it is substantiated or unsubstantiated. When the review is complete, the information is forwarded to the Army Family Advocacy Program [60]. The Army Family Advocacy Program is mandated to focus on identification, reporting, prevention, and treatment of child abuse and domestic violence. As part of the Army Family Advocacy Program's mission, the U.S. Army has a central registry that collects and maintains all cases of reported child abuse and domestic violence. Child abuse information has been collected since 1975, and domestic violence cases since 1983 [59].

In terms of prevention and intervention, the Family Advocacy Program provides a range of prevention strategies, including support groups for new parents, education programs for married couples to learn how to deal with stress, parenting classes, communicating and coping instruction, and anger management courses [61]. Training is also targeted to professionals such as law enforcement agents and social workers. Interventions include crisis intervention, marital counseling, emergency medical care, safety plan development, drug and alcohol treatment, support groups, case management, and anger control management groups.

As with domestic violence in the civilian population, military victims face a host of barriers in disclosing abuse. In addition to shame and embarrassment, fear of reprisals, feelings of isolation, and lack of available services, many military victims find when they do report abuse, military personnel are not sensitive to their needs [62].

Given the barriers to disclosure, it is difficult to assess the prevalence of domestic violence among military families. However, a few studies provide a glimpse of the scope of this problem. According to the Army's Central Registry, a total of 61,827 initial substantiated cases, 5,772 subsequent incidents, and 3,921 reopened cases were reported between 1989 and 1997 [59]. Victim rates varied between 8 and 10.5 per 1,000 married persons. More than two-thirds of the victims were female, and almost half of the referrals were from law enforcement agencies. The majority (93%) involved physical violence resulting in minor injuries. Some Department of Defense data indicate that 19 out of 1,000 wives of Navy and Air Force personnel and 21 out of 1,000 wives of Army personnel were abused in the last year [63]. Newer studies suggest rates of interpersonal violence in the military are anywhere from 13.5% to 58% [64].

Deployment and moving are potential risk factors. In a 2013 study, 2% of married deployed personnel had perpetrated physical or emotional spousal abuse during the study period [65]. Rates of moderate and severe abuse and abuse involving alcohol were significantly higher in the post-deployment period.

Some studies show that female veterans are at increased risk of physical and sexual violence from their intimate partners (33%) compared with nonveteran counterparts (23.8%) [66]. Research indicates that female veterans who experienced previous childhood sexual abuse are three times more likely to be victims of spousal abuse, and those who experienced an unwanted incidence of sexual victimization during military service were more likely to have experienced interpersonal violence in the last year [67,68]. Being in the Army (versus other military branches) is also a risk factor for past-year victimization [67].

In another study, a total of 716 married military service men stationed in a U.S. Army post in Alaska participated in a survey. Almost one-third of the men (31.6%) reported engaging in some act of aggression against their partner in the last 12 months. Nine percent disclosed having engaged in at least one moderate-to-severe act of aggression [69].

Race is another factor. When researchers examined white and African American spouse abuse cases documented in the Army Central Registry, rates were higher among all age brackets for African Americans. It is not clear what specific factors are influencing these different rates, but a systematic bias may exist in the referral process [60]. It is also possible that referrals are made to the Family Advocacy Program due to stereotypical perceptions that African American families are more violent. The authors recommended further longitudinal studies to examine cultural specific factors that contribute to these rates.

It has also been speculated that exposure to the trauma of combat and the development of post-traumatic stress symptoms provokes military veterans to be violent at home [56]. Furthermore, when these veterans do obtain treatment, either voluntarily or as mandated, many do not complete their treatment regimens [56].

In a similar vein, a study examined the extent by which recent military deployment predicted domestic violence against 368 wives whose husbands were deployed and 528 wives whose husbands were not deployed [70]. Wives who reported post-deployment domestic violence tended to be younger. The authors found that military deployment was not related to domestic violence during the first 10 months of the post-deployment period. However, when there was a history of pre-deployment domestic violence, the risk of post-deployment domestic violence was greater. Thus, age and previous history of domestic violence are important indicators to consider when developing prevention efforts [70].

The risk factors for domestic violence in military families are multi-faceted. The role of stress emanating from family, military life, culture, and environment and combat stress should be further researched to understand its influence on domestic violence.

INTERMITTENT EXPLOSIVE DISORDER

Intermittent explosive disorder is included under the general category of disruptive, impulse-control, and conduct disorders in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [71]. Approximately 2.7% of the general public meets the diagnostic criteria for this disorder, but it is much more common among military veterans. In one study of nondeployed U.S. Army personnel, 11.2% of participants met the criteria for intermittent explosive disorder in the past 30 days; it was the most prevalent mental disorder, surpassing PTSD and attention deficit hyperactivity disorder [72].

Intermittent explosive disorder is characterized by recurrent behavioral outbursts (manifested as verbal aggression, damage or destruction of property, and/or physical assault) representing an inability to control aggressive impulses [71]. The magnitude of this aggression is greatly out of proportion to the stressor or provocation, is not premeditated, and causes distress or impairment to the individual.

In many cases, intermittent explosive disorder occurs with comorbid depressive disorders, PTSD, and/or substance use disorder [73,74]. This can complicate diagnosis and treatment for some patients. In general, patients seek help only after they have committed significant violence or to address a comorbid disorder; the time from onset of symptoms to treatment is often more than a decade [75]. The recommended treatment approach is cognitive-behavioral therapy with or without pharmacotherapy [75,76]. There may be difficulty engaging persons with impulse-control disorders, like intermittent explosive disorder, in psychotherapy. If medication is necessary, selective serotonin reuptake inhibitors (SSRIs), specifically fluoxetine, are the agents of choice [76]. Patients should continue to be monitored throughout treatment, with assessment of aggressive and/or violent outbursts. There is some evidence that the number of outbursts may decrease over time, although aggressiveness as a trait persists.

4. REINTEGRATION AND READJUSTMENT

As noted, times of transition are particularly stressful for veterans and military families, and special care should be taken during these periods to fully assess and support patients. Although the majority of returning military members have readjusted well to post-deployment life, 44% report difficulties after they return [77].

Military personnel returning from deployment are required to complete the Post-Deployment Health Assessment [78]. This medical screener is composed of 10 mental health questions and must be completed by a medical provider within 30 days of returning from military assignment [78]. In addition, the mental health departments in the Army and Navy use the Post-Deployment Psychological Screener, which consists of 22 questions assessing for symptoms for depression, PTSD, communication issues, interpersonal problems, alcohol abuse, and anger [78]. PTSD is commonly assessed due to the many distressing events that military personnel experience in combat. However, avoidance behaviors such as substance and alcohol abuse, withdrawing from others, and dissociating should be assessed as well [79].

IMPACT ON THE FAMILY SYSTEM

During the post-deployment or reintegration phase, the service member returns and the entire family is involved in helping him/her integrate back into the system [80]. There is usually a honeymoon phase, but awkwardness and tension often follow [81]. Family roles may have changed during this time, and the returning member will need time to adjust. For example, new parenting strategies may have surfaced in order to deal with being a "single parent" during the deployment. Upon homecoming, the military member should not expect family dynamics to have remained the same, but he/she may report feeling like a guest in his/her own home [82]. Some may not recognize their child, especially if the child was recently born or just an infant when they left. Similarly, children may not recognize the returning parent or express wariness of this returning stranger. As a result, the military parent may experience distress and hurt [83].

Some military families will encounter challenges during the post-deployment phase, including substance abuse, PTSD, and domestic violence. In fact, it is estimated that the rate of relationship and family problems is four times higher during this phase than the other phases [84]. In a study involving 19,227 active U.S. soldiers from brigade combat teams who served in Iraq or Afghanistan between 2003 and 2009, problems of marital quality and separation/divorce intentions increased during the reintegration period [85].

5. REFERRAL

All health and mental health professionals involved in the care of veterans and their families should be committed to providing culturally competent and responsive care and should be engaged with available military resources. Referral to available resources is a vital part of the continuum of care for these patients. The military offers reintegration programs for veterans and their families. One such program is Coaching Into Care, a national telephone service of the VA created to help veterans, their family members, and other loved ones find the appropriate services at local VA facilities and/or in the community. It is staffed by licensed psychologists and social workers who can empower and support family members seeking to help veterans adjust to civilian life [86]. Military OneSource Site is a free service provided by the Department of Defense to military members and their families to help with a broad range of concerns, including possible mental health problems. Peer support groups are also a useful tool. If a veteran and/or military family is living in an isolated area or lacks access to local VA services, the VA offers the Vet Center Call Center, a 24-hour call center staffed by combat veterans and families members of combat veterans.

RESOURCES

Department of Defense Safe Helpline

1-877-995-5247

Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury Outreach Center

1-866-966-1020

http://dcoe.mil

National Suicide Prevention Lifeline

1-800-273-TALK

Coaching Into Care

1-888-823-7458

http://www.mirecc.va.gov/coaching

Military OneSource

1-800-342-9647

http://www.militaryonesource.mil

U.S. Army's Intervene, Act, and Motivate (I. A.M.) STRONG

http://www.sexualassault.army.mil

After Deployment

http://afterdeployment.dcoe.mil

Give an Hour

https://www.giveanhour.org

Disabled American Veterans (DAV)

https://www.dav.org

Veteran Combat Call Center

1-877-WAR-VETS

http://www.vetcenter.va.gov

VA Caregiver Support

1-855-260-3274

http://www.caregiver.va.gov

Yellow Ribbon Program

http://www.benefits.va.gov/gibill/yellow_ribbon.asp

6. CONCLUSION

Many service members returning from conflict report that their experiences were rewarding, and they readjust to life off the battlefield with few difficulties. Others, however, return with varied complex mental health conditions and find that readjusting to life at home, reconnecting with family, finding work, or returning to school is an ongoing struggle [77]. As such, it is vital that mental health and healthcare professionals work with veterans and families to identify risk factors, facilitate the identification of inner resources and resiliencies, and intervene to effectively treat and/or refer to further treatment.

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Evidence-Based Practice Recommendations Citations

1. Scottish Intercollegiate Guidelines Network. Brain Injury Rehabilitation in Adults: A National Clinical Guideline. Edinburgh: Scottish Intercollegiate Guidelines Network; 2013. Summary retrieved from National Guideline Clearinghouse at https://www.guideline.gov/summaries/summary/43914. Last accessed April 10, 2017.

2. Assessment and Management of Risk for Suicide Working Group. VA/DoD Clinical Practice Guideline for Assessment and Management of Patients at Risk for Suicide. Washington, DC: Department of Veterans Affairs, Department of Defense; 2013. Summary retrieved from National Guideline Clearinghouse at https://www.guideline.gov/summaries/summary/47023. Last accessed April 30, 2014.

98710 • Zika Virus Disease

John M. Leonard, MD

Carol Shenold, RN, ICP

www.netce.com

Copyright © 2016 NetCE, All rights reserved.

The potential for a localized or regional outbreak of Zika virus disease in the United States is significant given the level of travel exposure, opportunities for Zika virus migration, and the prevalence of Aedes aegypti mosquitoes along the southern and southeastern rim of the country. This course will review the history of Zika virus migration and the important clinical and public health aspects of Zika virus disease, including the epidemiology, modes of transmission, clinical manifestations, approach to diagnosis, and strategies for prevention and control of Zika virus infection.

Table of Contents

98710 • Zika Virus Disease

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. HISTORICAL BACKGROUND AND EPIDEMIOLOGY

3. ZIKA VIRUS TRANSMISSION

MOSQUITO-BORNE TRANSMISSION

SEXUAL TRANSMISSION

VERTICAL TRANSMISSION

4. ZIKA VIRUS DISEASE

CLINICAL MANIFESTATIONS

5. DIAGNOSIS

MOLECULAR DIAGNOSTIC TESTING

SEROLOGIC TESTING

CONGENITAL ZIKV DISEASE

CASE DEFINITION AND NOTIFICATION

6. CLINICAL MANAGEMENT ISSUES

GENERAL TREATMENT

CARE OF THE PREGNANT PATIENT

7. PREVENTION

TRAVEL TO ENDEMIC AREAS

PREVENTION OF SEXUAL TRANSMISSION

ZIKV VACCINE

8. VECTOR CONTROL

NOVEL APPROACHES TO VECTOR CONTROL

9. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

10. SUMMARY

Works Cited

98710 • Zika Virus Disease

Education Category. Infection Control / Internal Medicine

Release Date. 08/01/2016

Expiration Date. 07/31/2019

Course Overview

The potential for a localized or regional outbreak of Zika virus disease in the United States is significant given the level of travel exposure, opportunities for Zika virus migration, and the prevalence of Aedes aegypti mosquitoes along the southern and southeastern rim of the country. This course will review the history of Zika virus migration and the important clinical and public health aspects of Zika virus disease, including the epidemiology, modes of transmission, clinical manifestations, approach to diagnosis, and strategies for prevention and control of Zika virus infection.

Audience

This course is designed for physicians, physician assistants, and nurses in all settings who may identify and act to prevent Zika virus disease.

Course Objective

The purpose of this course is to enhance the knowledge and skill of physicians, nurses, and other health professionals who may be called upon to address the concerns of international travelers, provide advice to women of childbearing age, or assess febrile rash illness in persons recently returned from endemic areas.

Learning Objectives

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

1. Describe the historical background and dynamics of the emerging Zika virus epidemic in the Americas and its potential impact on public health.

2. Discuss and advise patients as to the risks of Zika virus transmission via various routes.

3. Recognize and manage a patient presenting with characteristic clinical and epidemiologic features of acute Zika virus disease.

4. Discuss the salient features of microcephaly, including the incidence, causative factors, and clinical and pathologic findings unique to congenital Zika virus infection.

5. Select the appropriate laboratory diagnostic tests for Zika virus in relation to a patient's clinical profile and the time elapsed since exposure or onset of symptoms.

6. Using your knowledge of Zika virus disease, devise a management plan for persons with known or suspected infection.

7. Using knowledge of Zika virus shedding by infected men and the risk of sexual transmission, counsel infected men and couples on the importance and recommended duration of safe sex practice.

8. Using knowledge of vector transmission and the behavior of Aedes aegypti mosquitoes, devise an effective strategy for avoiding bites, limiting exposure, and eliminating mosquito-breeding habitat.

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.

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, John M. Leonard, MD, 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 V. Jurica, MD, MPH

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

Division Planners Disclosure

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

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

Zika virus (ZIKV) is the latest in a series of related human arboviral pathogens that has migrated out of Africa and Asia into the Americas over the past two decades [1,2,3]. Arboviruses are transmitted by blood-feeding arthropod vectors, principally mosquitoes and ticks, and are maintained in cycles of transmission between a competent vector and any susceptible vertebrate species in the environs. Like yellow fever, dengue, and chikungunya viruses, the vector for ZIKV is the Aedes mosquito, and epidemics within susceptible population groups are sustained by a mosquito-human-mosquito transmission cycle.

Until recently, ZIKV disease was rarely reported and of little known consequence; circulation of the virus was largely confined to a mosquito-nonhuman primate-mosquito transmission cycle in forested terrain across a portion of east Africa and the adjacent Asian Pacific [1]. In 2007, the first outbreak of human ZIKV disease appeared on Yap Island in Micronesia. This was followed in 2013 by a large-scale epidemic in French Polynesia. Subsequent outbreaks were reported on other Pacific islands as ZIKV migrated in epidemic fashion across the Pacific and into the Americas. With the aid of a highly competent vector (the A. aegypti mosquito) having ready access to large, susceptible population groups, successive outbreaks of ZIKV disease have spread rapidly throughout South and Central America and the Caribbean, including Puerto Rico (Figure 1) [49].

Figure 1: COUNTRIES AND TERRITORIES WITH DOCUMENTED LOCAL TRANSMISSION OF ZIKA VIRUS INFECTION, REGION OF THE AMERICAS, 2015-2016

Source: [49]

Primary ZIKV infection is most often asymptomatic or causes a relatively mild, self-limited illness. However, infection during pregnancy is often complicated by transmission of virus to the developing fetus, resulting in arrested neurologic development, microcephaly, and related congenital anomalies. There is also growing evidence linking ZIKV infection with post-infectious Guillain-Barré syndrome. In February 2016, following the report of a marked increase in newborn infant microcephaly some months following a large ZIKV outbreak in Brazil, the World Health Organization (WHO) declared ZIKV disease a public health emergency of international concern [6]. A short time later, the Centers for Disease Control and Prevention (CDC) elevated its response to level 1, the highest for the agency [7]. Because of the link between exposure to ZIKV during pregnancy and microcephaly, pregnant women and those who may become pregnant are advised to avoid travel to regions of ongoing ZIKV transmission, and all travelers are urged to take enhanced precautions in areas where ZIKV is circulating.

As of December 2016, within the United States, cases of ZIKV disease have been primarily reported in returning travelers and in women having intimate sexual contact with men infected while traveling to regions with ongoing mosquito transmission. Because of ongoing ZIKV circulation in many nearby regions of the hemisphere, the number of ZIKV disease cases among travelers visiting or returning to the United States is expected to increase. ZIKV disease and ZIKV congenital infection have been added to the list of nationally notifiable conditions, and the CDC Arboviral Disease Branch provides periodic updates of confirmed ZIKV cases reported in the United States and its territories [8]. As of December 7, 2016, a total of 4,575 cases have been reported; 1 case was laboratory-acquired, 4,389 were acquired in association with travel to endemic areas outside the country, and 185 cases were locally acquired, mainly in or around Miami in Florida [8]. One locally acquired case has been confirmed in south Texas [8]. Puerto Rico has been particularly affected, and data suggest that 25% of the population may be infected by the end of 2016 [50]. The potential for a localized or regional outbreak of ZIKV disease in the United States is significant given the level of travel exposure, opportunities for ZIKV migration, and the prevalence of A. aegypti mosquitoes along the southern and southeastern rim of the country [9].

This course will review the history of ZIKV migration and the important clinical and public health aspects of ZIKV disease, including the epidemiology, modes of transmission, clinical manifestations, approach to diagnosis, and strategies for prevention and control of ZIKV infection. The purpose is to enhance the knowledge and skill of physicians, nurses, and other health professionals who may be called upon to address the concerns of international travelers, provide advice to women of childbearing age, or assess febrile rash illness in persons recently returned from endemic areas.

2. HISTORICAL BACKGROUND AND EPIDEMIOLOGY

ZIKV is a single-stranded RNA virus closely related to dengue and belonging to the family of flaviviruses [10]. Like other flaviviruses that infect humans, ZIKV is transmitted by the bite of an infected mosquito.

ZIKV was first identified in 1947, after being isolated from an ill rhesus monkey caged in the Zika Forest of Uganda as part of a sentinel surveillance program for yellow fever [1]. One year later, the virus was isolated from A. africanus mosquitoes recovered from the same forest. In subsequent decades, documentation of human ZIKV infection was provided by population-based serologic studies of arbovirus infection in parts of Africa and Asia, combined with occasional case reports of human ZIKV isolation in association with febrile illness. By 1981, ambient human seropositivity for ZIKV had been reported from Nigeria, Uganda, other nearby African countries, and parts of Asia, including India, Malaysia, the Philippines, and Indonesia [4].

In April 2007, on Yap Island, Federated States of Micronesia in the western Pacific, physicians became aware of an outbreak of mild dengue-like illness characterized by rash, conjunctivitis, and arthralgia. The ensuing investigation was the first population-based epidemiologic study of a human ZIKV epidemic [11]. The outbreak lasted four months; 49 confirmed and 57 suspected cases were identified. ZIKV RNA was detected in serum samples obtained from patients during the acute phase of illness. No dengue or other arbovirus RNA was detectable. A household survey and serologic study conducted on a select sample of the population revealed that 414 of 557 participants (74%) were positive for immunoglobulin M (IgM) antibody to ZIKV, indicating recent infection. Clinical illness attributable to ZIKV infection was reported in 19% of participants who were seropositive. Investigators estimated that 5,005 of 6,892 Yap residents (73%) 3 years of age or older were infected with ZIKV during the outbreak; moreover, approximately 80% of infections had been asymptomatic or too mild to prompt medical attention. The A. hensilii mosquito was judged to be the vector, though no virus or viral RNA could be detected in any pools of trapped mosquitoes [11].

In 2013–2014, an outbreak of ZIKV infection was reported from French Polynesia, a territory consisting of 67 islands arranged in five archipelagoes located in the South Pacific. Between October 2013 and February 2014, the regional sentinel surveillance network recorded 8,262 suspected cases of ZIKV disease [12]. Of 746 samples sent for laboratory confirmation, 396 (53%) were confirmed by reverse transcription polymerase chain reaction (RT-PCR). An estimated 28,000 cases of ZIKV-like illness were seen during the course of the epidemic (about 11% of the population of French Polynesia). The A. aegypti mosquito was considered to be the principal vector. The clinical features were similar to those seen in the Yap outbreak, except that an unexpected cluster of Guillain-Barré syndrome cases and other neurologic complications were encountered during the course of the outbreak [12]. Subsequent outbreaks in 2014–2015 were reported on other Pacific islands, including New Caledonia, Easter Island, Cook Islands, and Samoa.

In early spring 2015, ZIKV was identified as the cause of an outbreak of febrile rash illness in Bahia State, Brazil, the first indication that the virus had migrated to the Americas. In the months that followed, Brazil reported a progressive, widespread outbreak of ZIKV disease among adults and children in 29 Brazilian states, followed in turn by an unexpected and significant increase in the number of reported infants born with microcephaly [6]. By December 2015, the number of suspected cases of ZIKV disease had reached 56,318. Brazilian authorities estimate that 500,000 to 1,500,000 persons were infected with ZIKV during the first 18 months of the outbreak. As of November 2016, outbreaks of ZIKV disease and evidence of continuing mosquito-borne transmission had been reported from 73 countries and territories, primarily in Latin America and the Caribbean [42].

New and important aspects of ZIKV disease and transmission have emerged from investigations of the current epidemic. It is now established that primary ZIKV infection during pregnancy is often transmitted to the developing fetus and leads to excess fetal loss, microcephaly, and related congenital abnormalities [13,14]. There is growing realization that ZIKV infection is linked to the observed increases in the incidence of post-infectious Guillain-Barré syndrome, now reported in several countries [15]. Finally, sexual transmission of ZIKV by men with recent symptomatic infection has been documented, adding a further element of complexity to strategies for prevention in women who are pregnant or may become pregnant [16].

3. ZIKA VIRUS TRANSMISSION

In epidemic settings and endemic areas, ZIKV infection is primarily vector-borne, transmitted by the bite of an infected Aedes mosquito. In addition, other modes of transmission are now known to be important in human ZIKV disease. These include sexual transmission from an infected male to female and male partners; transplacental transmission from mother to fetus during pregnancy, leading to congenital ZIKV disease; and perinatal transmission from a viremic mother to her newborn infant [16,17]. There is theoretical concern that blood transfusion and tissue/organ transplantation could also serve as vehicles of transmission. Therefore, the U.S. Food and Drug Administration has recommended universal screening of donated whole blood and components for ZIKV in the United States and its territories [48].

MOSQUITO-BORNE TRANSMISSION

As noted, the A. aegypti mosquito is the principal vector of transmission for most human arbovirus infections, including yellow fever, dengue, chikungunya viruses and ZIKV [2,3]. A. aegypti is one of several species belonging to the Aedes genus (Stegomyia subgenus) of mosquitoes [10]. Aedes species are distributed in various combinations throughout tropical and subtropical regions of the world, having adapted in different ways to prevailing climate and habitat. In remote rainforests of Africa, where ZIKV circulates in a mosquito-nonhuman primate-mosquito transmission cycle, the principle vector is A. africanus. In heavily populated and urban areas of Latin America and the Caribbean, the vector of transmission for outbreaks of human ZIKV disease is A. aegypti and, to a lesser extent, A. albopictus.

There is also variability among Aedes species with respect to vector competence (i.e., the intrinsic ability of a vector to transmit a disease agent) and vectorial capacity (i.e., the overall effectiveness of a vector to sustain and propagate a disease outbreak in a given location) [3,4]. A. aegypti and A. albopictus appear to have comparable vector competence for ZIKV transmission; however, A. aegypti exhibits greater vector capacity among human population groups, perhaps because of its behavior and adaptation to an urban environment [18].

In times past, A. aegypti thrived on nonhuman hosts and laid its eggs in water collected in tree holes and the axils of forest plant leaves; in recent decades, this mosquito has adapted to an urban habitat and shows a preference for the human host over other mammals [19]. It flourishes in impoverished crowded areas with no piped water, inadequate trash disposal, and ineffective domicile barrier protection, such as afforded by screened doors and windows. A single female deposits its eggs at multiple sites, taking advantage of stagnant water found in cemetery vases, pet bowls, abandoned barrels, and automobile tires. Adult mosquitoes of both sexes feed on nectar and fruit, but females require blood protein in order to fully develop their eggs. Thus, only the female mosquito bites.

A. aegypti is an aggressive daytime biting mosquito, and feeding is most intense in the hours around dawn and dusk. The bite itself is barely perceptible. Female A. aegypti mosquitoes are stealth feeders, approaching victims from behind and biting on ankles and elbows—a "sneak attack" that avoids being noticed [19]. This mosquito does not feed sufficiently with a single bite; it is a "sip feeder" that bites multiple humans in the course of a blood meal, thereby optimizing the vector capacity of a single mosquito carrying the virus. The female prefers shady areas for rest and is adept at hiding in closets and under beds, later to emerge for a nocturnal blood meal.

With the exception of mountainous regions above 3,500 feet, the range of A. aegypti and A. albopictus includes all of Latin America and the Caribbean and extends into parts of the contiguous United States. While the prevailing range of A. aegypti within the United States is limited to south Texas along the Mexican border, south Florida, and coastal areas of the gulf and southern Atlantic states, climate conditions are favorable for periodic expansion into adjacent states [9]. The A. albopictus species is acclimated to a milder climate and has a broader range that extends from the eastern seaboard through the Southeast and a portion of the Midwest, and throughout the Southwest. Of public health concern is the following scenario: a local area of ZIKV circulation among A. aegypti mosquitoes and humans becomes established in the United States, from which A. albopictus emerges as a secondary vector with potential for a more widespread outbreak in other parts of the country.

SEXUAL TRANSMISSION

Epidemiologic investigation and published case reports have demonstrated that a man with symptomatic ZIKV infection can transmit the virus to his partner through intimate sexual contact, including vaginal, anal, and likely oral sex [16,20,21]. Within the United States and other countries having no ZIKV circulation, cases of well-documented ZIKV disease have been reported in women whose only risk exposure was sexual contact with a symptomatic male partner who had recently traveled from an area with ongoing ZIKV transmission. An illustrative case report is that of a woman, 24 years of age, living in France, who on February 16, 2016, became ill with fever, arthralgia, myalgia, and a pruritic rash [21]. Samples of urine and saliva collected on the third day of illness were positive for ZIKV RNA by RT-PCR, and the serum tested positive for acute phase ZIKV IgM antibody. There is no known ZIKV circulation in that part of Europe, and the patient had no history of travel to an endemic area. She did report having sexual contact (vaginal intercourse and oral sex) on several occasions in the week prior to onset of symptoms with a man who had just returned from a two-month stay in Brazil. He also had experienced a febrile rash illness with arthralgia during the four days prior to his departure for France on February 10. Urine and semen samples obtained 16 days after onset of his symptoms tested positive for ZIKV RNA by RT-PCR. ZIKV was isolated by culture from semen samples obtained on day 18 and on day 24 following onset of his illness [21].

The full spectrum of behaviors and circumstances by which ZIKV is transmitted sexually is not yet known. ZIKV has been detected in saliva, urine, semen, and breast milk following acute infection, but not in vaginal swab specimens collected from infected women [20]. In one reported case, ZIKV RNA was detected in semen up to 62 days after onset of symptoms, and replication-competent ZIKV has been isolated from semen at least two weeks after onset of illness [22]. One study found that ZIKV RNA shedding in semen was common and could continue for more than six months, but shedding of infectious ZIKV was less common and limited to a few weeks [51]. The duration of infectious ZIKV in semen remains unknown. Studies are underway to determine the incidence, duration, and pattern of virus shedding in men with symptomatic and asymptomatic ZIKV infection. For now, the CDC recommends that men who have been diagnosed with ZIKV consider using condoms or abstaining from sex for six months following infection [22].

All reported cases of sexual transmission have involved vaginal or anal sex with men shortly before, during, or shortly after a symptomatic illness consistent with ZIKV disease [22]. It is not known whether infected men who never develop symptoms can transmit ZIKV to their sex partners. Sexual transmission of ZIKV from infected women to their sex partners has not been reported. The consistent and correct use of latex condoms is known to reduce substantially the risk of acquiring sexually transmitted infections, including those caused by viruses.

VERTICAL TRANSMISSION

In the course of acute infection during pregnancy, ZIKV can be transmitted across the placenta to the developing fetus. Evidence for intrauterine fetal infection includes demonstration of ZIKV in the placenta and products of conception following spontaneous abortion, identification of ZIKV RNA in amniotic fluid by RT-PCR, and virologic and serologic studies of infants born with microcephaly. The true incidence and natural history of this phenomenon, including the importance of such factors as gestational age, level and duration of viremia, and immune enhancement by pre-existing heterologous anti-flavivirus antibodies, is currently unknown [23].

Two cases of intrapartum transmission of ZIKV from a newly infected, viremic mother to her newborn infant have been reported [4]. One infant was considered to be asymptomatic; the other child developed a rash and transient thrombocytopenia. Although ZIKV has been identified in breast milk, there have been no reports of transmission through breastfeeding.

4. ZIKA VIRUS DISEASE

CLINICAL MANIFESTATIONS

Acute Illness in Adults and Children

In epidemic settings, the majority of primary ZIKV infections are asymptomatic, and those who do become ill usually experience a self-limited, mild febrile illness with rash, conjunctivitis, myalgia, and arthralgia lasting three to six days. The incubation period for ZIKV is not well defined; it is considered to be similar to that of other mosquito-borne flaviviruses—usually less than one week and in the range of 3 to 10 days.

The first detailed description of the illness caused by acute ZIKV infection is a self-reported case study in 1964 of a young (28 years of age) European research worker at the East Africa Virus Research Institute in Uganda [24]:

"The illness began with a slight frontal headache in the evening, followed the next morning by an aching sensation in the back and thighs and the appearance of a maculopapular rash covering the face, neck, trunk, and upper arms. Throughout day 2, the rash, which was non-itching, spread gradually to involve all four extremities, including the palms of the hands and the soles of the feet. Toward midday the patient was febrile (99.4° F) and experiencing malaise accompanied by pain in the back and a frontal headache. By the evening of day 2, the temperature had returned to normal, the rash was beginning to fade from the back and neck, and the patient felt better apart from slight headache. On day 3, the patient felt no ill effects and the temperature remained normal. The rash persisted on the trunk and extremities, faded slowly throughout days 3 and 4, and disappeared completely on day 5. No other signs or symptoms were noted during the illness."

The patient had visited Zika Forest 21 days before the onset of illness and had been bitten by mosquitoes at a time when ZIKV was being isolated from mosquitoes collected in the forest. ZIKV was isolated from the patient's blood by mouse inoculation studies, and a rise in antibody to ZIKV was demonstrated. The clinical features of the infection—a mild, self-limited febrile illness with malaise, myalgias, headache, and exanthema—was likened to that seen with other arthropod-borne viruses such as West Nile and chikungunya [24].

A more complete description of the natural history of acute ZIKV infection is provided by clinical observations collected during the investigation of the four month-long epidemic on Yap Island in 2007 [11]. Based on results of a seroepidemiologic survey, only about 18% of 5,005 islanders estimated to have been infected developed symptoms attributable to ZIKV. In the course of this investigation, information regarding symptoms and signs was obtained from 31 of 49 confirmed cases (63%) of ZIKV disease. The most common clinical characteristics were macular or papular rash (90%), fever (65%), arthritis or arthralgia (65%), non-purulent conjunctivitis (55%), myalgia (48%), and headache (45%) [11]. Other symptoms included retro-orbital pain, edema, and vomiting. The median duration of rash was 6 days (range: 2 to 14) and arthralgia was 3.5 days (range: 1 to 14). There were no hospitalizations or deaths attributed to ZIKV illness in the course of this outbreak.

A similar pattern of illness was observed in a cohort study from Rio de Janeiro, wherein pregnant women who had experienced fever and rash illness within the previous five days were enrolled in a surveillance study designed to assess the cause of illness and to monitor subsequent maternal health and fetal development [25]. During the period from September 2015 through February 2016, 72 of 88 women enrolled tested positive for acute ZIKV infection by RT-PCR on blood, urine, or both. All women had rash, as this was an inclusion criterion; the prevailing pattern was a descending macular or maculopapular exanthema accompanied by pruritus in 94% of patients. Arthralgia was reported in 65% of ZIKV-positive women, conjunctival injection was seen in 58%, and lymphadenopathy (generalized or regional) was present in 41%. Fever was documented in only one-third of patients and, when present, was low-grade and of short duration. Nausea and vomiting were reported in 21%, and respiratory findings were evident in 7% [25].

From these observations there emerges a distinctive, though nonspecific, clinical ZIKV syndrome: an acute onset descending maculopapular rash (often with pruritus), conjunctival injection, arthralgia, myalgia, and transient low-grade fever. Lymphadenopathy may be present, but respiratory symptoms and signs are conspicuously uncommon. ZIKV disease should be considered in patients with any combination of these symptoms who have traveled to areas with ongoing transmission in the two weeks preceding onset of illness. Rare manifestations of acute ZIKV infection, based on isolated case reports, include meningoencephalitis, myelitis, thrombocytopenic purpura, and ocular complications [4,26,27].

Because dengue and chikungunya viruses have the same vector of transmission and share a similar geographic distribution and clinical profile with ZIKV, patients with suspected ZIKV disease should be evaluated and managed for these possibilities as well. Other considerations in the differential diagnosis include malaria, rubella, measles, parvovirus, adenovirus, enterovirus, leptospirosis, rickettsiosis, and group A streptococcal infections [5].

Neurologic Complications of ZIKV Disease

ZIKV is a neurotropic virus, which accounts for its association with post-infectious Guillain-Barré syndrome and with infant microcephaly and related neurologic abnormalities that follow intrauterine infection.

Guillain-Barré Syndrome

Guillain-Barré syndrome is an acute, progressive, immune-mediated motor axonal neuropathy characterized by flaccid paralysis. It is often triggered by infection. Most patients recover after many weeks or months but often require prolonged hospitalization, respiratory ventilation support, and management of other complications, all of which are costly and burdensome to any health system.

An unexpected increase in the number of patients presenting with Guillain-Barré syndrome has been observed in several countries experiencing large outbreaks and ongoing transmission of ZIKV. During the 2013–2014 ZIKV outbreak in French Polynesia, in the space of four months' time, 38 cases of Guillain-Barré syndrome were diagnosed among an estimated 28,000 persons who sought medical care for suspected ZIKV disease [12]. Based on annual reported cases of Guillain-Barré syndrome for the prior four years, the number expected in a four-month period was three or less. Among the ZIKV-associated cases, 73% were male and the mean age was 46 years; 15 patients were admitted to the intensive care unit, and 9 required mechanical ventilation. There were no deaths. To date, this association between ZIKV outbreaks and clusters of Guillain-Barré syndrome has been reported in eight countries: French Polynesia, Brazil, El Salvador, the French territory of Martinique, Colombia, Suriname, the Bolivarian Republic of Venezuela, and Honduras [4].

Microcephaly and Congenital ZIKV Disease

Microcephaly is a rare pediatric disorder often associated with other congenital anomalies and developmental complications. Microcephaly may be classified as prenatal (congenital) or postnatal (developing sometime after birth); only the former has been linked with ZIKV infection. The growth of the fetal brain in utero approaches maximum volume after 21 weeks' gestation, a process that influences the size of the newborn infant skull. Microcephaly is the clinical (or radiographic) finding of a head size unexpectedly small for a given stage of development; it is usually defined as an occipitofrontal head circumference below the third percentile for gestational age and sex [4]. Any injury that causes sequence disruption of normal fetal brain growth can lead to microcephaly. The common causative factors are genetic perturbations, maternal illness (e.g., infection), and exposure to teratogenic substances. The incidence of congenital microcephaly is estimated to be 2 to 10 cases per 10,000 live births [4].

The clinical course of children born with microcephaly is difficult to predict; when intrauterine infection is the cause, the severity and prognosis are determined in large part by gestational age of onset and the presence of additional neurologic deficits. Common childhood sequelae include developmental delay, hearing loss, vision defects, impaired intellectual ability, and seizures.

In November 2015, after alarming reports of an epidemic of microcephaly in northern Brazil, later attributed to maternofetal ZIKV infection, the Brazilian Ministry of Health set up a surveillance system for cases of microcephaly and other malformations possibly linked with ZIKV. As of June 4, 2016, 7,830 suspected cases had been reported, of which 40% were judged confirmed or probable cases of congenital ZIKV syndrome based on subsequent clinical and epidemiologic investigation [28]. For this six-month period, the number of newborns with microcephaly associated with confirmed ZIKV infection represents a 40-fold increase in monthly reports of microcephaly in Brazil prior to 2015. In the course of this case-by-case investigation, clinicians also discovered that 1 in 5 children with definite or probable congenital ZIKV infection presented with head circumference in the normal range. Thus, the sensitivity of microcephaly alone to detect cases of congenital ZIKV was 83%, increasing to 87% when history of maternal rash was included [28].

The true rate, or risk, of adverse fetal outcomes following maternal ZIKV infection has not been determined. In the Rio de Janeiro prospective cohort study, 42 of 72 pregnant women with definite ZIKV infection, contracted between week 6 and week 36 of gestation, were agreeable to fetal monitoring by serial ultrasonography [28]. Significant fetal abnormalities, including growth restriction, cerebral calcifications, microcephaly, and other brain malformations, were seen in 12 cases (29%). There were two fetal deaths after 30 weeks' gestation (4.8%) [25].

In comparison with other known causes of congenital infection (e.g., toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis), the microcephaly associated with ZIKV infection has a unique phenotype consistent with fetal brain disruption [4,29]. The severity of fetal brain injury and the characteristic clinical and pathologic features associated with congenital ZIKV are illustrated by the following case report. An expectant mother, 25 years of age, developed a febrile rash illness during the 13th week of gestation while living and working in northern Brazil. Ultrasonography performed at 14 and 20 weeks' gestation indicated normal fetal growth and anatomy. At 29 weeks, the patient reported reduced fetal movements and follow-up imaging showed early signs of fetal anomalies. Ultrasonography at 32 weeks' gestation confirmed intrauterine growth retardation, microcephaly, and numerous calcifications in various parts of the brain. Because of severe brain disease and a poor prognosis, the pregnancy was terminated by request at 32 weeks' gestation. Autopsy examination revealed microcephaly, widely open Sylvian fissures, small cerebellum and brain stem, almost complete agyria, and internal hydrocephalus of the lateral ventricles. Numerous calcifications of variable size were found in the cortex and subcortical white matter of the frontal, parietal, and occipital lobes. Microscopic examination of the brain showed extensive neuronal destructive change with multifocal filamentous neuronal calcifications, diffuse astrogliosis, and degeneration of the long descending tracts within the brain stem and spinal cord. Tissue samples were positive for ZIKV by RT-PCR assay and the complete genome of ZIKV was recovered from the fetal brain [30].

The distinctive characteristics of microcephaly associated with congenital ZIKV infection, evident on neuroimaging and by pathologic examination, are extensive intracranial calcifications, severe cortical atrophy and malformation, hypodensity of the white matter, cerebellar hypoplasia, and ventriculomegaly. Infection during pregnancy has also been linked to other adverse outcomes, including excess miscarriage and stillbirths, ocular defects, hearing loss, and impaired growth in infants.

In April 2016, after careful consideration of available data, epidemiologists at the CDC concluded that a causal relationship exists between prenatal ZIKV infection and microcephaly and other neurologic abnormalities [14,29]. Supporting evidence includes the timing of infection during prenatal development is consistent with the defects observed; a specific, rare phenotype involving microcephaly and associated brain anomalies in infants with confirmed congenital ZIKV infection; and identification of ZIKV in brain tissue of affected fetuses and infants.

5. DIAGNOSIS

The possibility of ZIKV disease should be considered in the patient with a compatible clinical syndrome (e.g., febrile rash illness with arthralgia and conjunctivitis) and epidemiologic risk factors, such as residence in or travel to an area of active ZIKV transmission within the previous two weeks, or sexual contact with a person known or suspected of recent ZIKV infection. Laboratory confirmation relies on molecular detection of the viral genome (via RT-PCR) in blood or body fluids and serologic assay for acute-phase ZIKV-specific IgM antibody.

The U.S. Food and Drug Administration has issued an emergency use authorization for two diagnostic tools for ZIKV: the Triplex Real-Time RT-PCR assay and the Zika MAC-ELISA for anti-ZIKV IgM [31]. These have been distributed to qualified laboratories that are certified to perform high-complexity tests in the United States. Clinicians should contact local and state health departments to facilitate diagnostic testing. The CDC provides updated guidance for the selection and timing of ZIKV diagnostic testing at http://www.cdc.gov/zika/hc-providers/types-of-tests.html.

MOLECULAR DIAGNOSTIC TESTING

In the first week after onset of symptoms, ZIKV disease can often be diagnosed by performing RT-PCR on serum. However, RT-PCR for detection of viral nucleic acid in blood is dependent on timing of the sample in relation to the onset, duration, and level of viremia. The viremia that follows ZIKV infection begins a few days before onset of symptoms and lasts about five to seven days. By the time a patient presents with symptoms, the window of opportunity may be short or the degree of viremia below detectable levels. During acute infection, ZIKV is shed in the urine and detectable viral RNA persists well into the second week. For this reason, the CDC recommends that serum and urine samples be submitted for RT-PCR in patients presenting up to 14 days after onset of illness [31]. A positive RT-PCR result on any sample confirms ZIKV infection, and no additional testing is indicated. A negative RT-PCR result does not exclude infection, and a serum sample should then be tested for anti-ZIKV IgM antibody.

SEROLOGIC TESTING

Serologic testing is useful in patients who present more than one week after onset of symptoms. ZIKV-specific IgM antibodies develop toward the end of the first week of illness and remain detectable for 12 weeks; neutralizing antibodies (IgG) become detectable in the second week and persist for many years [32]. Therefore, if serum and urine are negative by RT-PCR, serum IgM antibody testing for ZIKV should be performed. If the patient resides or has traveled in an endemic area where other flaviviruses are circulating, anti-dengue virus and anti-chikungunya virus IgM antibody testing should be requested as well.

The ZIKV IgM enzyme-linked immunosorbent assay (ELISA) is used for the qualitative detection of anti-ZIKV IgM antibodies in serum and cerebrospinal fluid; however, positive test results can be difficult to interpret because of cross-reactivity with related flaviviruses, which precludes identification of the specific infecting virus [32]. This is especially problematic in persons residing in endemic areas or previously vaccinated against flaviviruses. When the IgM ELISA test result is presumed positive, equivocal, or inconclusive, the serum sample must be forwarded to the CDC (or a CDC-designated laboratory) for confirmation by plaque-reduction neutralization testing (PRNT). PRNT measures virus-specific neutralizing antibodies and is able to discriminate between cross-reacting antibodies in primary flavivirus infections [32].

CONGENITAL ZIKV DISEASE

If intrauterine ZIKV infection is suspected during the course of pregnancy and amniocentesis is performed, fluid should be tested by RT-PCR. When an infant is born with microcephaly or intracranial calcifications to a mother with potential ZIKV infection during pregnancy, the infant should be evaluated for congenital ZIKV infection. Interim guidelines for the evaluation and testing of infants with possible congenital ZIKV infection have been published by the CDC, and updated guidance is available at the CDC website [33]. Serum samples for testing may be obtained from umbilical cord blood, but test results can be misleading; the current recommendation is to obtain a sample of blood, and cerebrospinal fluid if available, directly from the infant within two days of birth for RT-PCR and anti-ZIKV IgM testing. Frozen and fixed placenta tissue samples should also be tested by RT-PCR and submitted for ZIKV-specific immunohistochemical analysis at specialized reference laboratories [33]. For infants with any positive or inconclusive test findings for ZIKV infection, healthcare providers should report the case to state, territorial, or local health department and assess the infant for long-term sequelae.

CASE DEFINITION AND NOTIFICATION

As noted, ZIKV disease and congenital ZIKV infection have been added to the list of nationally notifiable diseases. Healthcare providers are encouraged to report probable and confirmed ZIKV disease cases to the local or state health department in order to facilitate diagnosis and mitigate the risk for local transmission in areas where Aedes species mosquitoes are active. The WHO has developed an interim case definition for acute ZIKV disease [45]. A suspected case is defined by the presence of rash and/or fever combined with at least one of the following: arthralgia, arthritis, or nonpurulent conjunctivitis. A probable case is a person with this syndrome and a positive IgM antibody test against ZIKV plus an epidemiologic link (i.e., contact with a confirmed case or residence/travel to an endemic area within the previous two weeks). A confirmed case requires laboratory confirmation of recent ZIKV infection by either molecular diagnostic testing (e.g., presence of ZIKV RNA in serum or other body fluids) or serologic test results specific for ZIKV and exclusive of other flaviviruses (e.g., positive anti-ZIKV IgM ELISA confirmed by PRNT).

The CDC is working with the Council of State and Territorial Epidemiologists (CSTE) to improve surveillance and promote effective prevention and control of ZIKV transmission within the United States. The CSTE has developed an interim position statement intended to standardize case definitions and establish criteria for the classification of ZIKV infection [34]. When evaluating a patient with suspected, probable, or newly confirmed ZIKV infection, healthcare providers should consult this source or contact the local or state health department.

The CDC has established the U.S. Zika Virus Registry to gather information about the timing, absolute risk, and spectrum of outcomes associated with ZIKV infection during pregnancy. It is accessible at http://www.cdc.gov/zika/hc-providers/registry.html. The data collected through this registry will be used to update recommendations for clinical care, to plan for services for pregnant women and families affected by ZIKV, and to improve prevention of ZIKV infection during pregnancy [43]. The CDC also offers consultation services as part of the registry, which may be accessed by calling (770) 488-7100 or emailing ZIKAMCH@cdc.gov.

6. CLINICAL MANAGEMENT ISSUES

GENERAL TREATMENT

There is no effective antiviral therapy for ZIKV infection; treatment is supportive and directed toward relief of symptoms. When the diagnosis is uncertain and dengue, or co-infection with dengue, is a possibility, the patient should be managed expectantly for each. In consideration of dengue, aspirin and nonsteroidal anti-inflammatory drugs should be avoided and the patient should be monitored for signs of progression to hemorrhagic fever or shock [32]. In managing ZIKV disease, patient education and secondary prevention are important, especially in regard to sexual transmission and risk reduction in pregnancy. All pregnant women with molecular or serologic evidence of recent ZIKV infection should be evaluated and managed (monitored) for adverse pregnancy outcomes.

CARE OF THE PREGNANT PATIENT

The CDC has published interim guidance for healthcare providers caring for pregnant women with possible ZIKV exposure and those with confirmed or suspected ZIKV infection [35]. As noted, the CDC maintains a 24-hour consultation service for health officials and healthcare providers caring for pregnant women as a component of the Zika Virus Registry. The general recommendations for women residing in the United States and its territories are [35]:

- All pregnant women should be assessed for possible ZIKV exposure at each prenatal care visit.

- Pregnant women are advised not to travel to an area with active ZIKV transmission.

- Pregnant women who must travel to one of these areas should strictly follow steps to avoid mosquito bites and prevent sexual transmission during the trip.

- Pregnant women with a sex partner who has traveled to or lives in an area with active ZIKV transmission should use condoms or other barrier methods to prevent infection or abstain from sex for the duration of the pregnancy.

Evaluation of the Symptomatic Pregnant Patient

Pregnant women who report symptoms or signs consistent with acute ZIKV disease should be tested for ZIKV infection. Serum and urine RT-PCR tests are recommended for those seeking care less than two weeks after onset of symptoms [35]. A positive RT-PCR result confirms the diagnosis of recent maternal ZIKV infection. Patients with a negative RT-PCR test result should receive ZIKV IgM and dengue virus IgM antibody testing. Symptomatic pregnant women who seek care 2 to 12 weeks after symptom onset should first receive ZIKV and dengue virus antibody testing. If the ZIKV antibody test is positive or equivocal, reflex RT-PCR should be automatically performed on the serum sample to determine whether ZIKV RNA is present.

Evaluation of the Asymptomatic Pregnant Patient

ZIKV testing is recommended for asymptomatic pregnant women who have traveled to areas with active ZIKV transmission or who have had potential sexual exposure (i.e., sexual contact without barrier/condom method with a person who lives in or has traveled to an area with ZIKV). RT-PCR testing of serum and urine is recommended for those presenting more than two weeks from the date of last possible exposure [35]. RT-PCR testing is also indicated for pregnant women who present for care two or more weeks after exposure and have been found to be IgM positive. Serologic screening with the ZIKV IgM ELISA should be offered to asymptomatic pregnant women who, in the previous 2 to 12 weeks, have traveled to an area with ZIKV or have had sexual contact with a man confirmed to have ZIKV infection. In areas with active ZIKV transmission, asymptomatic pregnant women should undergo IgM testing as part of routine obstetric care in the first and second trimester.

Management of the Pregnant Patient with ZIKV Infection

Updated interim guidance provided by the CDC also includes recommendations for prenatal and postnatal management of the pregnant patient with confirmed or possible ZIKV, and for postnatal evaluation of the newborn infant (Table 1) [35].

Table 1: CLINICAL MANAGEMENT OF A PREGNANT WOMAN WITH SUSPECTED ZIKA VIRUS INFECTION

Interpretation of Laboratory Results

Prenatal Management

Postnatal Management

Recent Zika virus infection

Consider serial ultrasounds every three to four weeks to assess fetal anatomy and growth.a Decisions regarding amniocentesis should be individualized for each clinical circumstance.b

Live births: Cord blood and infant serum should be tested for Zika virus by rRT-PCR, and for Zika IgM and dengue virus IgM antibodies. If CSF is obtained for other reasons, it can also be tested. Zika virus rRT-PCR and IHC staining of umbilical cord and placenta are recommended.

Fetal losses: Zika virus rRT-PCR and IHC staining of fetal tissues are recommended.

Recent flavivirus infection, specific virus cannot be identified

Presumptive recent Zika virus or flavivirus infectionc

Consider serial ultrasounds every three to four weeks to assess fetal anatomy and growth.a Amniocentesis might be considered; decisions should be individualized for each clinical circumstance.b

Live births: Cord blood and infant serum should be tested for Zika virus by rRT-PCR, and for Zika virus IgM and dengue virus IgM antibodies. If CSF is obtained for other reasons, it can also be tested. Zika virus rRT- PCR and IHC staining of umbilical cord and placenta should be considered.

Fetal losses: Zika virus rRT-PCR and IHC staining of fetal tissues should be considered.

Recent dengue virus infection

Clinical management in accordance with existing guidelines.

No evidence of Zika virus or dengue virus infection

Prenatal ultrasound to evaluate for fetal abnormalities consistent with congenital Zika virus syndrome.a

Fetal abnormalities present: Repeat Zika virus rRT-PCR and IgM test; base clinical management on corresponding laboratory results.

Fetal abnormalities absent: Base obstetric care on the ongoing risk for Zika virus exposure risk to the pregnant woman.

CSF = cerebrospinal fluid, IgM = immunoglobulin M, IHC = immunohistochemical, PRNT = plaque reduction neutralization test, rRT-PCR = real-time reverse transcription–polymerase chain reaction.

aFetal abnormalities consistent with congenital Zika virus syndrome include microcephaly, intracranial calcifications, and brain and eye abnormalities.

bHealthcare providers should discuss risks and benefits of amniocentesis with their patients. It is not known how sensitive or specific rRT-PCR testing of amniotic fluid is for congenital Zika virus infection, whether a positive result is predictive of a subsequent fetal abnormality, and if it is predictive, what proportion of infants born after infection will have abnormalities.

crRT-PCR or PRNT should be performed for positive or equivocal IgM results as indicated. PRNT results that indicate recent flavivirus infection should be interpreted in the context of the currently circulating flaviviruses. Because of the overlap of symptoms and areas where other viral illnesses are endemic, evaluate for possible dengue or chikungunya virus infection.

Source: [35]

7. PREVENTION

TRAVEL TO ENDEMIC AREAS

Travelers who plan to visit areas of ongoing mosquito-borne transmission of ZIKV, chikungunya virus, and dengue virus should plan carefully and exercise caution. The CDC guidelines recommend limiting mosquito exposure and avoiding bites by taking the following steps [36]:

- Cover exposed skin by wearing long-sleeved shirts and long pants.

- Use insect repellents that are registered with the Environmental Protection Agency (EPA) and contain diethyltoluamide (DEET), picaridin, IR3535, oil of lemon eucalyptus, or para-menthane-diol. Always use as directed. Pregnant and breastfeeding women can use all EPA-registered insect repellents, including DEET, according to the product label. Most repellents, including DEET, can be used on children older than 2 months of age. To apply, adults should spray insect repellent onto hands and then apply to a child's face. If it might be difficult to find recommended repellent at your destination, pack enough to last the entire trip.

- Use permethrin-treated clothing and gear (e.g., boots, pants, socks, tents). These items may be purchased pretreated or treated when necessary. (Please note that permethrin is not effective in Puerto Rico.)

- Stay and sleep in screened-in and air-conditioned rooms whenever possible.

- Sleep under a mosquito bed net if air-conditioned or screened rooms are not available or if sleeping outdoors.

- Mosquito netting can be used to cover infants younger than 2 months of age in carriers, strollers, or cribs to protect them from mosquito bites.

PREVENTION OF SEXUAL TRANSMISSION

The CDC recommends that men who have traveled to or reside in an area with active ZIKV transmission and their pregnant partners should consistently and correctly use condoms during sex (i.e., vaginal intercourse, anal intercourse, and oral sex) or abstain from sex for the duration of the pregnancy [22]. The purpose is to avoid even a minimal risk of sexual transmission, given the potential for adverse fetal effects when ZIKV is contracted during pregnancy. Pregnant women should discuss their male sex partner's history of travel to areas with active ZIKV transmission and any history of illness consistent with ZIKV disease with their healthcare provider.

Men with known (or presumed) ZIKV disease and their non-pregnant sex partners who want to reduce the risk for sexual transmission of ZIKV are advised to use condoms consistently and correctly during sex or to abstain from sex [22]. The recommended duration of consistent condom use or abstinence depends on whether the man had confirmed infection or clinical illness consistent with ZIKV disease and whether he is residing in an area with ongoing transmission. In weighing the level of risk and a couple's concern about sexual transmission of ZIKV, several factors should be considered [22]. The risk for acquiring mosquito-borne ZIKV infection depends on the duration and extent of exposure to infected mosquitoes and the steps taken to prevent mosquito bites. Viral transmission is of particular concern during pregnancy; therefore, a couple's resolve and strategy for prevention of unintended pregnancy should be taken into account, including use of the most effective contraceptive methods.

ZIKV VACCINE

Because of the burden imposed by complications of ZIKV infection, especially in women of childbearing age, development of a ZIKV vaccine seems a compelling strategy for prevention. Vaccines have been developed against other arboviruses, including dengue and West Nile viruses, and a DNA vaccine has been shown to protect against ZIKV in a mouse model studied in Brazil [46]. However, virologists anticipate it would likely take several years to bring a ZIKV vaccine to implementation, in part because the immunology of flavivirus infection poses potential barriers to a safe, predictable strategy, particularly in endemic areas where exposure to multiple flavivirus infections is common. Just as cross-reactivity of antibodies elicited by related flaviviruses confounds diagnosis, so may antibody cross-reactivity impact vaccine efficacy and safety [47]. Among the issues to be considered is the phenomenon of immune enhancement, whereby immunologic memory acquired from earlier flavivirus infection (or vaccination) may, in response a new flavivirus infection, lead to an IgG antibody/Fc receptor/lymphocyte-mediated augmentation of infection with prolonged viremia, possibly increasing severity and risk for complications. As an example, one consideration could be whether a ZIKV immunization campaign in an area endemic for dengue virus infection places the population at greater risk for more serious illness from dengue virus infection (i.e., hemorrhagic fever and shock). While a ZIKV vaccine could hold greater promise for population groups outside endemic areas for other flaviviruses, its implementation (after years of development) would need to take into account the durable effect of mosquito control programs and the lingering scope of ZIKV circulation.

8. VECTOR CONTROL

Strategies employed for prevention of the transmission of ZIKV and other mosquito-borne flaviviruses are directed toward elimination or control of mosquito vectors and interruption of human-mosquito contact. The initial target of these efforts is A. aegypti mosquito, the principle vector. Adult A. aegypti females feed on humans, rarely travel more than 100 yards from where they hatched, and live for about 10 days. They proliferate by making use of standing rain water or any of the many nearby stagnant sources associated with urban habitat, such as blocked gutters, bird baths, flower pots, abandoned food and beverage containers, and construction sites. Control activities are aimed at eliminating immature and adult mosquito habitats in and around homes, out buildings, work places, schools, and other venues where people gather.

Most governmental agencies use, and the CDC recommends, an integrated mosquito management approach that employs a combination of methods based on mosquito biology, life cycle, and behavior [37]. An important feature of this approach is that all stakeholders become involved: health department and mosquito control specialists, government agencies, and community citizens and neighbors. The five key elements of this approach are [37]:

- Conduct mosquito surveillance: Monitor places where eggs are laid and young mosquitoes are found; track populations and the virus they are carrying; and determine which insecticide will be effective.

- Remove places where mosquitoes lay eggs: Target public places, parks, roadside dumps, yards, and neighborhoods, including weekly removal of common sources of standing water.

- Control young mosquitoes: Use EPA-registered larvicides to treat water-holding structures and containers.

- Control adult mosquitoes: Use EPA adulticides available for public use to reduce the number of mosquitoes in an area, delivered by backpack sprayers, trucks, or airplanes.

- Monitor control programs: Conduct additional studies to assess the effectiveness of efforts.

NOVEL APPROACHES TO VECTOR CONTROL

Two novel approaches that have shown considerable promise are the genetic control of A. aegypti mosquitoes and the development of mosquitoes that are resistant to arbovirus infection. The first field-trialed genetic control strategy is known as the Release of Insects carrying Dominant Lethal (RIDL) genes and involves the mass rearing of A. aegypti that have been genetically modified to express a repressible lethal gene [38]. During their rearing in insectaries, the mosquitoes are provided with a dietary supplement not present in nature (tetracycline), and this supplement represses the lethal gene activation [39].

Only male mosquitoes are released, and these compete with wild males to mate with wild females. Offspring do not survive to the adult stage because they do not receive the dietary additive in the wild. Lines of RIDL males have been shown to have minimal fitness costs (i.e., they are competitive with wild males) and a field release in Bahia, Brazil, reportedly achieved a 95% reduction in local mosquito populations [41].

An alternative approach is the use of endosymbiotic bacteria to prevent arboviruses replicating within the mosquito. The Eliminate Dengue project has demonstrated that Wolbachia bacteria from Drosophila fruit flies can prevent dengue virus transmission in A. aegypti mosquitoes without significant fitness costs [40]. Wolbachia has also been shown to inhibit the replication of additional arboviruses, such as chikungunya virus and yellow fever virus, strongly suggesting potential inhibitory effects against ZIKV [41].

Whereas RIDL is a self-limiting approach (i.e., the genetic modification is not perpetuated in wild populations), Wolbachia-based control strategies rely on this endosymbiont successfully invading wild mosquito populations through a reproductive phenotype known as cytoplasmic incompatibility. This phenotype results in the generation of inviable offspring when an uninfected female mates with a Wolbachia-infected male. By contrast, Wolbachia-infected females can produce viable progeny when they mate with both infected and uninfected males, resulting in a reproductive advantage over uninfected females. Wolbachia-infected A. aegypti mosquitoes were released and successfully invaded wild populations in Australia and releases are ongoing in dengue virus-endemic countries such as Indonesia, Vietnam, and Brazil [41].

What effect either RIDL or Wolbachia will have on arboviral transmission and epidemiology in the field remains uncertain. Mathematical models of dengue virus transmission incorporating the dynamics of viral infection in humans and mosquitoes predict that one strain of Wolbachia (wMel) would reduce the basic reproduction number of dengue virus transmission by 70% [44]. Models of dengue virus transmission control with RIDL also project high efficacy in reducing disease burden. These projections suggest that such strategies could have a direct impact on transmission of arboviruses such as ZIKV in countries, such as Brazil, where A. aegypti is the principle vector [41].

An important benefit of these environmentally friendly, species-specific approaches is the reduced dependence they pose for insecticides—an increasingly important feature of future disease vector control. Moreover, suppressing the mosquito population, or rendering it arbovirus-resistant, holds great potential in the simultaneous control of Zika, dengue, chikungunya, and yellow fever viruses. One hundred fifty countries presently have A. aegypti and are vulnerable to future outbreaks. The costs of implementing these novel technologies in Brazil and across the tropics should be considered in the context of the multifaceted benefits they pose in controlling several emerging infectious diseases.

9. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For patients who are not proficient in English, it is important to provide information regarding prevention strategies, testing recommendations, and signs and symptoms of ZIKV disease in their native language, if possible. The CDC provides patient education posters and handouts in a variety of languages, including Spanish, Portuguese, French, and Vietnamese [45]. Copies of these materials may be accessed at http://www.cdc.gov/zika/fs-posters. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered.

10. SUMMARY

In less than two years, an epidemic of mosquito-borne ZIKV disease has swept through the Americas, leaving in its wake thousands of cases of microcephaly and higher rates of post-infectious Guillain-Barré syndrome. New modes of transmission have been identified to which pregnant women are most vulnerable, and maternofetal transmission during pregnancy is known to cause congenital infection and adverse fetal outcomes. The CDC has announced that evidence supports the existence of a causal relationship between prenatal ZIKV infection and microcephaly and other serious neurologic anomalies. Health agencies have established disease surveillance networks and provided guidance for healthcare providers, travelers, and expectant couples on the best means for avoiding mosquito contact and preventing sexual transmission. More information is needed on the absolute risk and spectrum of fetal outcomes following maternal ZIKV infection during pregnancy, the clinical course and prognosis of infants born with congenital ZIKV syndrome, and the most effective means for vector control and prevention of ZIKV infection.

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49. Centers for Disease Control and Prevention. All Countries and Territories with Active Zika Virus Transmission. Available at http://www.cdc.gov/zika/geo/active-countries.html. Last accessed November 7, 2016.

50. Frieden TR, Schuchat A, Petersen LR. Zika virus 6 months later. JAMA. 2016;316(14):1443-1444.

51. Mead PS, Duggal NK, Hook SA, et al. Zika virus shedding in semen of symptomatic infected men. N Engl J Med. 2018;378:1377-1385.

98930 • Irritable Bowel Syndrome

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2016 NetCE, All rights reserved.

Irritable bowel syndrome (IBS) is common in the general population and has a significant medical and socioeconomic impact. IBS has long been viewed as a functional gastrointestinal (GI) disorder, which means the symptom complex of chronic abdominal pain and altered bowel habits cannot be explained by identifiable structural or biochemical abnormalities. Education on the recent breakthroughs in etiology, pathophysiology, and treatment will empower healthcare providers to optimize treatment of their patients with IBS.

Table of Contents

98930 • Irritable Bowel Syndrome

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. EPIDEMIOLOGY

INCIDENCE AND PREVALENCE

COMMON COMORBID CONDITIONS

NATURAL HISTORY

DISEASE BURDEN

3. ETIOLOGY, PATHOGENESIS, AND PATHOPHYSIOLOGY

CONTRIBUTING FACTORS

BRAIN-GUT AXIS AND PROCESSING

ALTERED PAIN PERCEPTION IN PATIENTS WITH IBS

4. CLINICAL PRESENTATION AND DIAGNOSTIC WORKUP

CLINICAL PRESENTATION

CONCEPTUAL AND DIAGNOSTIC ADVANCES

DIAGNOSTIC CRITERIA AND MEASUREMENT SCALES

CLINICAL EVALUATION AND DIAGNOSTIC WORKUP

5. TREATMENT

THE THERAPEUTIC RELATIONSHIP AND TREATMENT ADHERENCE

LIFESTYLE MODIFICATION

PSYCHOLOGIC INTERVENTIONS

ANTIDEPRESSANT MEDICATIONS

DIARRHEA-PREDOMINANT IBS

CONSTIPATION-PREDOMINANT IBS

ABDOMINAL PAIN-PREDOMINANT IBS

SPECIALIST REFERRAL

6. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

7. CONCLUSION

8. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

98930 • Irritable Bowel Syndrome

Education Category. Infection Control / Internal Medicine

Release Date. 12/01/2016

Expiration Date. 11/30/2019

Course Overview

Irritable bowel syndrome (IBS) is common in the general population and has a significant medical and socioeconomic impact. IBS has long been viewed as a functional gastrointestinal (GI) disorder, which means the symptom complex of chronic abdominal pain and altered bowel habits cannot be explained by identifiable structural or biochemical abnormalities. Education on the recent breakthroughs in etiology, pathophysiology, and treatment will empower healthcare providers to optimize treatment of their patients with IBS.

Audience

This course is designed for physicians, physician assistants, nurses, and other healthcare providers who may improve the identification and care of patients with irritable bowel syndrome.

Course Objective

The purpose of this course is to provide clinicians with the information necessary to appropriately diagnose and treat irritable bowel syndrome and improve patients' quality of life.

Learning Objectives

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

1. Describe the incidence and prevalence of irritable bowel syndrome (IBS).

2. Identify conditions that are commonly comorbid with IBS.

3. Outline the natural history and disease burden of IBS.

4. Review the pathogenesis and pathophysiology of IBS.

5. Discuss risk factors for the development of IBS and underlying etiology.

6. Describe the assessment of patients with suspected IBS, including presenting signs and symptoms, testing, and clinical diagnostic criteria.

7. Identify conditions that should be included in the differential diagnosis of IBS.

8. Discuss the role of laboratory studies and alarm features in reaching a diagnosis of IBS.

9. Evaluate the role of nonpharmacologic therapies for the treatment of IBS.

10. Compare and contract available pharmacotherapies for the treatment of the various IBS subtypes.

Faculty

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

Faculty Disclosure

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

Division Planners

John M. Leonard, MD

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

Division Planners Disclosure

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

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

Until recently, irritable bowel syndrome (IBS) was considered a diagnosis of exclusion. The pathophysiology was poorly understood, patient outcomes were usually unsatisfactory, and clinicians considered IBS difficult and frustrating to manage [1]. The conceptual and empirical framework to inform the clinical care of patients with IBS took a large step forward in 2016, when the Rome Foundation published the Rome IV diagnostic criteria for IBS. These criteria incorporate the many scientific and clinical advances made since the release of the previous version (Rome III) in 2006. This was part of a larger project to overhaul and update scientific knowledge advances and clinical guidance to optimize the diagnosis and treatment of functional gastrointestinal (GI) disorders [2]. In addition, 18 review papers that detail the latest understanding of functional GI disorders were published by members of the Rome Foundation in 2016.

IBS is characterized by recurrent abdominal pain associated with disordered bowel habits (constipation, diarrhea, or a mix of constipation and diarrhea); abdominal bloating/distention is typically present. The symptoms must not have an organic, metabolic, or drug-induced basis [3]. IBS and other functional GI disorders are now understood as disorders of the gut-brain axis that arise through complex, bidirectional interactions of biopsychosocial factors.

2. EPIDEMIOLOGY

INCIDENCE AND PREVALENCE

IBS can have an insidious onset and frequently does not lead patients to seek medical care. This creates a discrepancy between the incidence of symptom onset (in the community) and first IBS diagnosis (physician visit) and renders estimates of IBS incidence difficult [4]. However, some prevalence estimates are available.

General Population

The lifetime prevalence of IBS in adult North American and European populations is 10% to 20%, but only 5% to 7% have been diagnosed. IBS shows highest prevalence in South America (21%) and lowest prevalence in Southeast Asia (7%) [5,6].

Clinical Populations

IBS is the most frequently diagnosed GI condition, accounting for 41% of patients with functional GI disorders [5,6,7]. Among clinical populations, IBS accounts for 12% of all patients seen in primary care and 28% in gastroenterology clinics [7]. In the United States, patients with IBS are evenly distributed among three common presenting clinical patterns: IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), and mixed IBS (IBS-M); in Europe, most patients reportedly have either IBS-C or IBS-M [5,6].

Of all persons with IBS symptoms, only a subset seek primary care medical attention, estimated at 10% to 70% in European countries and around 30% in the United States. Patients with IBS-D tend to seek medical attention at higher rates than those with IBS-C or IBS-M. Those seeking medical care report greater levels of pain and anxiety and greater impact on quality of life. In contrast, GI symptom severity does not differ greatly between the two groups [4,8,9,10].

Sex

The global prevalence of IBS is 14% in women and 8.9% in men, meaning the rate is 67% greater in women than men. This difference in reported sex-specific prevalence may be influenced in part by stigma associated with the diagnosis or by differing attitudes and behaviors that influence the decision to seek medical care rather than merely a variation in susceptibility and severity of underlying pathology [4,11]. Alternatively, female sex hormone physiology may alter regulatory mechanisms of the brain-gut axis more easily and thus promote IBS pathophysiology [12].

In the United States, Canada, and Israel, IBS symptoms are 1.5 to 2 times more prevalent in women than men, while the female/male distribution is closer to even in Asia. Abdominal pain and constipation are more common symptom complaints in women, with diarrhea more common in men [5,11].

Age

A meta-analysis of 81 epidemiologic studies found that IBS prevalence decreases with age. The prevalence rate in patients younger than 40 years of age is 11.0%, with decreased rates in each subsequent decade (9.6% for persons in their 40s, 7.8% for persons in their 50s, and 7.3% for persons in their 60s). Patients 50 years of age and older show the lowest IBS prevalence [13,14].

Challenges to Obtaining Accurate IBS Epidemiology Data

Prevalence estimates for IBS are impacted by stigma associated with seeking health care for IBS symptoms or receiving a functional GI disorder diagnosis. Lower reported prevalence is likely in areas where greater stigma is perceived or where symptoms are so common as to be viewed as variations of normal. For example, diarrhea (from all causes) is common in Mexico and may not be viewed as an illness that requires healthcare contact [15]. The reported prevalence of IBS is likely to be higher in communities with higher perceived stress, lower perceived quality of life, greater potential gain from receiving a diagnosis, or fewer barriers to health care access [4,16,17].

The absence of a criterion-standard case definition or standardized diagnostic criteria over time has created difficulty in defining IBS cases for epidemiologic studies. Widely used ancillary data in other disorders are limited in IBS. Relatively few patients are hospitalized for IBS or diagnosed during admission, and IBS is not a cause of death that would show on death certificates [4]. Prescription data are only recently relevant as more medications have received U.S. Food and Drug Administration (FDA) approval for IBS.

COMMON COMORBID CONDITIONS

IBS is associated with numerous comorbidities. Most cluster into functional somatic syndromes (e.g., fibromyalgia, chronic fatigue syndrome, chronic pelvic pain), other GI disorders (e.g., gastroesophageal reflux disease, dyspepsia), and psychiatric disorders (e.g., major depression, anxiety, somatization). These syndromes overlap on multiple dimensions [5,18].

Panic disorder is highly comorbid with IBS, and the prevalence of IBS symptom characteristics in patients with panic disorder is 25% to 44% [12]. A strong association is also found between IBS and generalized anxiety disorder, and patients with comorbid IBS and generalized anxiety disorder had greater functional impairment and depressive symptoms. Post-traumatic stress disorder (PTSD) is also prevalent, and as many as 36% of patients with IBS meet the criteria for lifetime diagnosis for PTSD. Major depressive disorder is the most frequent psychiatric comorbidity in IBS. Patients with major depressive disorder showed a 27% to 47% prevalence of IBS, although patients with major depressive disorder in remission did not differ from healthy controls in terms of IBS symptoms [12].

IBS severity and abdominal pain intensity are positively correlated with anxiety and depression [19]. Significantly greater levels of anxiety have been found in patients with IBS-D than in patients with IBS-C or IBS-M; patients with IBS-D also show significantly greater incidence of depression [18].

A higher percentage of patients with IBS and anxiety or depression had extra-intestinal physical symptoms than patients without anxiety (44.8% versus 16.8%, respectively) or depression (57.0% versus 21.5%, respectively) [20,21].

Patients with IBS are much more likely to have psychiatric conditions than persons without IBS. Many patients with IBS receive anxiolytics and antidepressants, and one study found that 62% of patients received these agents prior to being diagnosed with IBS. A greater percentage of patients with severe IBS have at least one psychiatric disorder compared with patients with mild or moderate IBS (94.4% versus 35.7% and 76.1%, respectively) [21,22,23].

IBS, fibromyalgia, chronic fatigue syndrome, temporomandibular joint (TMJ) disorder, and vulvodynia syndrome are characterized by distressing symptoms of pain and fatigue in the absence of clinically obvious pathology. This group of conditions have been termed "central sensitivity syndromes." Neuroimaging studies using evoked sensory paradigms have revealed a common sensory augmentation to both painful and nonpainful stimulation, a transformative observation for these syndromes historically considered entirely hysterical or feigned in origin. Whether amplified pain is causal to these syndromes, a predisposing factor, an endophenotype, or an epiphenomenon cannot be discerned without additional research [24].

Roughly 50% of all patients with IBS also experience fibromyalgia, chronic fatigue syndrome, chronic back pain, chronic pelvic pain, chronic headache, or TMJ dysfunction. Symptoms of these functional somatic syndromes considerably overlap with IBS and with each other, and functional somatic syndromes occur almost twice as often in patients with IBS than in the general population [25,26]. Fatigue, sleep problems, and back pain have been reported by 69.3%, 47.5%, and 37.3% of patients with IBS, respectively [20,27]. Low back pain was found more common in patients with IBS-C than IBS-D [21].

Patients who have IBS and somatic comorbidities report more severe symptoms than those with IBS alone. More than 50% of patients with IBS report depression or anxiety and experience more severe somatic symptoms than patients without psychiatric conditions [4,28,29]. Many physical symptoms affect the overall well-being of patients with IBS (including psychologic health) and should not be overlooked or marginalized [21].

At the time of IBS diagnosis, the likelihood of an organic lesion being found on colonoscopy in patients lacking alarm symptoms is no higher than in healthy controls, and even most patients with alarm symptoms have no organic pathology [4,30]. In contrast to endoscopy findings at diagnosis, the subsequent risk of developing inflammatory bowel disease was found to be 9 to 16 times greater in patients diagnosed with IBS than the general population, with an average two- to three-year interval between onset of IBS and inflammatory bowel disease diagnosis. These data implicate some overlap in pathogenesis for IBS and inflammatory bowel disease [31].

Colorectal cancer incidence is around 1% in the first year of IBS diagnosis. While initially higher than the general population incidence, colorectal cancer incidence returns to population levels after one year [4,32].

NATURAL HISTORY

Symptom Patterns

For most patients with IBS, the symptoms of IBS are intermittent and over time show consideration fluctuation in frequency and duration. In the first three months after diagnosis, patients experience an average of four distinct symptom episodes per month, with the longest episode averaging five days, and most patients experience symptoms more than 50% of the days. One year after initial diagnosis, 30% to 45% of patients report they now have prolonged symptom-free periods. In the second year of follow-up, some patients experience symptom resolution, while others develop new symptoms and rate of symptomatic IBS episodes remains stable. After 10 years, 50% to 70% of patients report persistent symptoms [33,34,35].

Long-term follow-up data from clinical IBS populations indicate that 2% to 18% of patients worsened, 30% to 50% remained unchanged, and 12% to 38% improved over time. Poor outcomes were associated with previous surgery, longer disease duration, higher somatic scores, and higher baseline levels of anxiety or depression [5,36].

Up to 67% of patients with IBS experience functional dyspepsia. Among patients who report IBS symptom resolution, 45% subsequently develop other functional GI disorders [25,37,38]. Even if all GI symptoms resolve, many patients with IBS develop symptoms of other functional disorders. Patients with lower quality of life and higher levels of anxiety are most susceptible to comorbid functional disorders. Converging evidence suggests IBS is one expression of an underlying predisposition for functional disease [4,25,39,40,41].

Patients may also experience migration between predominant symptoms and IBS subtypes over time. Most commonly, IBS-C or IBS-D switches to IBS-M; switching between IBS-C and IBS-D is less common. A possible confounding factor in natural history studies of IBS is the effect of treatment, which can result in difficulty discerning symptom variation due to medical intervention versus true natural history [5,42].

With the passage of time, overlapping symptoms and adjustments in the prevailing diagnostic subtype within a given patient are very common. In one study of 432 primary care patients with IBS-C or functional constipation followed over 12 months, roughly 33% had a change in dominant diagnosis from functional constipation to IBS-C or from IBS-C to functional constipation [43,44]. In female patients with IBS initially classified as constipation, diarrhea, or mixed subtypes, roughly 25% had the same subtype at 12-month follow-up, while 75% made at least one transition into another subtype [45].

Evidence of lower IBS prevalence in older age groups suggests symptom resolution over time, which is contradicted by natural history studies showing symptom chronicity. One explanation is that the diagnosis changes, rather than resolves. As discussed, patients with IBS are more likely to experience other functional syndromes. In addition, "symptom shifting" occurs in some patients, characterized by resolution of functional bowel symptoms followed by development of extra-intestinal functional symptoms [4].

Mortality

Although patients with IBS have a significantly reduced quality of life, greater risk of depression and suicidal ideation, and higher frequency of invasive procedures and surgery, community-based studies have not associated IBS with increased mortality risk [4,46].

DISEASE BURDEN

Like other chronic functional disorders, the overall burden of IBS is high and medical treatments for IBS have been suboptimal. Patients with IBS exhibit high rates of psychopathology, low quality of life, and increased suicidal ideation. These patients also miss more days of work, are less productive at work, and use many healthcare resources [47].

IBS significantly diminishes emotional, physical, and occupational functioning and health-related quality of life. IBS accounts for 3.1 million ambulatory care visits and 5.9 million prescriptions annually in the United States, with total direct and indirect annual expenditures exceeding $20 billion [5,48].

IBS is usually diagnosed and managed in outpatient settings. In 2010, IBS accounted for 0.03% of U.S. hospital discharges, with a mean inpatient stay of 3.7 days costing a mean $21,153 [49].

The impact of IBS subtypes on quality of life was studied in 542 patients with IBS in the United States using the IBS Quality of Life (IBS-QOL) questionnaire. The overall and subscale scores attained from the IBS-QOL range from 0–100, with higher scores suggesting better quality of life. Overall IBS-QOL scores of patients with IBS-D (61.6) and IBS-M (63.0) were lower than those of patients with IBS-C (74.5). Patients with IBS-D scored lower than those with IBS-C on food avoidance (45.0 vs. 61.1) and interference with activity (59.6 vs. 82.3). Compared with patients with IBS-C, patients with IBS-M had greater interference in activities (61.6 vs. 82.3) and impact on relationships (73.3 vs. 84.7). Patients with IBS-M scored lower than IBS-C on food avoidance (47.2 vs. 61.1) and concern over negative social reaction (66.1 vs. 80.0) [50].

Patients with IBS-D or IBS-M are more likely to avoid culprit foods perceived to be symptom triggers than patients with IBS-C. IBS had a significantly greater negative impact on relationships in patients with IBS-M than in those with IBS-C, and more than 50% reported workplace embarrassment. Interpersonal problems were more pronounced in patients with IBS-D. This study indicates that clinicians should pay special attention to food avoidance and negative effects on relationships, daily activities, and social reaction in patients with IBS-D and IBS-M, as these domains drove down the quality of life [50].

Bloating is perhaps the most bothersome IBS symptom to patients. Bloating often leads to seeking medical care and adversely affects energy level, food intake, and physical functioning [51]. A large population-based study in Japan found abdominal bloating to be the most bothersome symptom in patients with IBS-C. The levels of anxiety and distress in daily life were associated with severity of abdominal pain, discomfort, and bloating, and abdominal bloating was more likely to occur after a meal, at work/school, and during times of stress [52].

A study assessed past-week impairments in work productivity and daily activities in American patients with IBS-C. Among those working, the average rate of past-week absenteeism was 10.6%. In addition, 37.4% reported presenteeism, 39.3% overall work productivity loss, and 45.7% daily activity impairment due to general health problems over the past week. The economic cost from lost productivity due to IBS-C is estimated at about $155 per employed patient/week, suggesting IBS-C-related impairment is a significant burden for patients and employers [53].

Perceived stigma is an important consideration in the patient with IBS. Patients with symptoms of IBS or other functional disorders present for medical care with painful, embarrassing, and life-limiting symptoms that lack objective confirmation on routine diagnostic exam and laboratory workup. Moreover, the common inclusion of IBS and fibromyalgia in psychiatric diagnostic classification systems as somatoform disorders (e.g., psychologic distress manifesting as physical symptoms) adds to the consternation. Lacking a consistent and valid illness concept or suitable term for the disorder, some caregivers may be tempted to label the patient with dismissive terms like "difficult patient," "frequent attender," or "heart-sink patient." This type of labeling may result in patient reluctance to seek medical care [54].

3. ETIOLOGY, PATHOGENESIS, AND PATHOPHYSIOLOGY

GI syndromes/symptoms may be classified into three general diagnostic categories: organic, motility, or functional disorders [2,15]. Organic (or structural) disorders are characterized by macro- or micro-level pathology of organs or structures and include esophagitis and inflammatory bowel disease. Motility disorders are characterized by pathology of organ (motility) function. Examples of motility disorders are gastroparesis and intestinal pseudo-obstruction.

Functional GI disorders are idiopathic disorders of gut-brain interaction and, unlike organic and motility disorders, diagnosis involves identification of symptom clusters. These disorders may be further categorized as functional bowel, functional esophageal, IBS, noncardiac chest pain, functional gastroduodenal, and other disorders.

IBS is a functional bowel disorder, as are functional constipation, functional diarrhea, and functional abdominal bloating/distension. More precisely termed "disorders of gut-brain interaction," functional GI disorders develop from complex, bidirectional interactions of biopsychosocial factors. These environmental, psychologic, and biologic factors interact to drive the genesis, clinical expression, and chronicity of functional GI disorders (Table 1) [2,15].

Table 1: FACTORS AFFECTING THE DEVELOPMENT, EXPRESSION, AND CHRONICITY OF FUNCTIONAL GI DISORDERS

Genetic and environmental factors

Genetic polymorphism

Early life experiences

Parental beliefs and behaviors

Social learning, support, stress

Trauma

Infection

Psychologic factors

Psychopathology (anxiety, depression)

Cognitive-affective processes:

- Health anxiety and somatization

- GI-specific anxiety

- Attentional bias/symptom hypervigilance

- Catastrophizing

CNS structure and function

Structural brain abnormalities

Functional network connectivity

Emotional and cognitive modulation of visceral afferent signals

Fear conditioning

Gut physiology

Gut permeability

Motility

Sensation

Altered bacterial flora

Inflammation and immune dysfunction

Source: [2,15]

Psychosocial factors such as early life events, trauma, social learning, and/or psychiatric and psychologic disorders influence the brain and gut, which interact bidirectionally via the autonomic nervous system and hypothalamic-pituitary-adrenal (HPA) axis through brain-gut mediation. The integrated effects of altered physiology and psychosocial status shape the illness experience and clinical outcome, which in turn influences the severity of the disorder [55].

IBS pathophysiology is complex and multifactorial. Genetic, environmental, and psychosocial factors increase the risk of developing IBS. Factors that trigger IBS onset or exacerbation include gastroenteritis, food intolerances, chronic stress, and surgery. Pathophysiologic mechanisms vary but commonly include altered colonic motility, visceral hyperalgesia, increased intestinal permeability, immune activation, altered microbiota, and disturbances in central nervous system (CNS) function [3].

CONTRIBUTING FACTORS

Familial and Environmental Factors

Childhood Social Learning

Childhood functional GI disorders aggregate in families. Research into genetic factors is ongoing, but what children learn from parents is considered a greater contributor to the risk for developing functional GI disorders. One important contributor is the learning principle of positive reinforcement or reward. Children whose mothers reinforce illness behavior experience more severe stomachaches and more school absences than other children. In children with functional abdominal pain, cognitive-behavioral therapy (CBT) that targets coping strategies and parent and child beliefs about, and responses to, children's pain complaints leads to greater decreases in pain and GI symptoms than an educational intervention. This effect is mediated by changes in parents' cognitions about their child's pain [39,55,56].

A strong association is found between parental psychologic status, especially anxiety, depression, and somatization, and children's abdominal symptoms [57]. This association may occur through modeling, whereby children observe and learn to display the behaviors they observe—in this context, heightened attention to or catastrophizing about somatic sensations. This effect of parental traits on children's symptoms can also occur through reinforcement. Parents with certain traits or beliefs (e.g., excessive worry about pain) might pay more attention to and reward somatic complaints. Parental catastrophizing about their own pain reinforces these types of responses to abdominal pain in their children, which encourages illness behavior and predicts child functional disability [55,58,59].

Childhood and Adult Stressors

Early life trauma is associated with increased risk for IBS and other functional GI disorders, major psychiatric disorders, ischemic heart disease, diabetes, asthma, and other medical disorders in adulthood [60]. Patients with IBS report a high prevalence of adverse life events in general, and childhood physical punishment, emotional abuse, and sexual abuse in particular. This psychosocial history is related to greater functional GI disorder severity and worse clinical outcomes, such as psychologic distress and impaired daily functioning. These effects increase health care seeking and explain the higher prevalence of abuse histories in patients with IBS seen in specialty clinics than in primary care; those with mild IBS symptoms and psychosocial histories may not seek medical care. High frequencies of childhood abuse (approaching 50%) are also found in patients with chronic functional somatic syndromes such as chronic pelvic pain, headaches, and fibromyalgia [61,62,63].

Functional GI disorder onset frequently coincides with experiencing a highly threatening event, such as the breakup of an intimate relationship. Stressful life events are associated with symptom exacerbation and frequent health care-seeking in adults with IBS. Chronic life stress is the greatest predictor of IBS symptom severity one to two years after diagnosis and negatively affects functional GI disorder treatment outcomes. Presence of a single stressor within 6 months of initiating IBS treatment predicts poor outcomes and higher symptom intensity at 16-month follow-up [55,64].

Social Support

Quality of social support is related to many aspects of IBS. Patients have reported that finding social support helps them overcome IBS. Perceived social support adequacy is linked to IBS symptom severity, possibly through reducing stress levels. Negative social relationships with frequent conflict and adverse interactions show a consistently greater effect on poor IBS outcomes than lack of social support. A supportive patient-practitioner relationship improves symptoms and quality of life in patients with IBS, showing the clinically valuable role of social support [55,65,66].

Psychologic Factors and Psychiatric Disorders

Psychologic distress is an important risk factor for developing functional GI disorders. The presence of psychologic comorbidity may perpetuate or exacerbate symptoms and negatively affects the clinician-patient relationship and treatment outcomes. Comorbid anxiety or depression strongly predicts postinfectious IBS and functional dyspepsia and can also result from symptoms and quality of life impairment. The absence of co-occurring psychiatric comorbidity does not exclude contribution to functional GI disorder from dysfunctional cognitive and affective processes.

Mood Disorders

The overlap between major depressive disorder and functional GI disorder is about 30% in primary care and slightly higher in specialist care. Depression can influence the number of functional GI symptoms and diagnoses. Suicidal ideation is present in 15% to 38% of patients with IBS and is linked to hopelessness surrounding symptom severity, interference with life, and inadequate treatment. Comorbid major depressive disorder is linked to poor outcomes, including high health care utilization and cost, functional impairment, poor quality of life, and poor treatment engagement and outcomes [67,68,69].

Anxiety Disorders

With a prevalence of 30% to 50%, anxiety disorders are the most common psychiatric comorbidity in patients with functional GI disorders. Anxiety can initiate or perpetuate functional GI disorder symptoms by amplifying autonomic arousal (in response to stress) or interfering with GI sensitivity and motor function. Common pathways might exist between vulnerability to anxiety disorders and functional GI disorders, especially through anxiety sensitivity, bodily vigilance, and discomfort intolerance [67,70].

Somatization, Somatic Symptom Disorder, and Functional Somatic Syndromes

In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), somatic symptom disorder replaced the abandoned term "somatization," which described patients who responded to psychosocial stress by experiencing, communicating, and seeking medical help for physical symptoms unconfirmed by pathologic findings. The number of symptom complaints was emphasized [55,71].

In the DSM-5, somatic symptoms may or may not be medically unexplained but are distressing, disabling, and associated with excessive and disproportionate thoughts, feelings, or behaviors persisting longer than six months. This approach shifts the experience of medically unexplained symptoms from subconscious manifestations of psychologic distress to the abnormal cognitive-affective processes surrounding the symptoms [55,72,73].

Somatization is associated with GI processes such as gastric sensitivity and emptying, symptom severity, and impaired quality of life. It is linked to higher health care use and predicts poor treatment response and discontinuing medication from side effects. Somatization remains extensively used in the medical literature to describe syndromes, often with prominent pain, that lack apparent physiologic cause following standard diagnostic workups. Assessing somatization through severity of the multiple somatic symptoms remains clinically useful [73,74,75].

Somatization was considered the basis for frequent extra-intestinal symptoms in patients with IBS and the high co-occurrence between functional GI disorder and other functional somatic syndromes. The overlap is extensive; 67% of patients with functional GI disorders also have a positive history for conditions such as interstitial cystitis, chronic pelvic pain, headaches, fibromyalgia, or other functional somatic syndromes, independent of psychiatric comorbidity [55,76,77].

Cognitive-Affective Processes

The psychologic constructs of health anxiety, GI symptom-specific anxiety, attentional bias/symptom hypervigilance, and catastrophizing are linked to functional GI disorders independent of psychiatric comorbidity (Table 2). These are important treatment targets for CBT [55].

Table 2: COGNITIVE-AFFECTIVE PROCESSES INFLUENCING THE SYMPTOM EXPERIENCE IN FUNCTIONAL GI DISORDERS (FGIDs)

Term

Definition

Association with FGID

Outcomes

Management

Illness anxiety

Global tendency to worry about current and future bodily symptoms, formerly referred to as hypochondriasis

Low insight

Extensive research into what is wrong

Not easily reassured

Lack of acceptance

Rick factor for the development of FGID

Chronicity

Social dysfunction

Occupational difficulties

High health costs

Negative physician-patient relationship

Poor treatment response

Responsive to CBT

Symptom-specific anxiety

Worry/hypervigilance around the likelihood/presence of specific symptoms and the contexts in which they occur

Belief that normal gut sensations are harmful or will lead to negative consequences

Promotes GI symptoms

Drives health care use

Negatively impacts treatment response

Aerophagia improved with distraction

May be differentially responsive to interoceptive exposure-based therapy

Hypervigilance/

attentional bias

Altered attention toward, and increased engagement with, symptoms and reminder of symptoms

Patients with IBS: Higher recall of pain words and GI words compared with healthy controls

Patients with NCCP: Hypervigilance toward cardiopulmonary sensations

Dismiss signs of improvement

Ignore information suggesting FGID is not serious

Responsive to CBT

Catastrophizing

Individual magnifies the seriousness of symptoms and consequences while simultaneously viewing him/herself as helpless

Symptom amplification

Increased pain

Inhibits pain inhibition

Negatively affects interpersonal relationships

Leads to increased worry, suffering, disability

High symptom reporting

Reduced quality of life

Can impact patient self-report

Burdens provider

Improves with CBT

Mediates outcome

CBT = cognitive-behavioral therapy, NCCP = noncardiac chest pain.

Source: Reprinted from Van Oudenhove L, Levy RL, Crowell MD, et al. Biopsychosocial aspects of functional GI disorders: how central and environmental processes contribute to the development and expression of functional GI disorders. Gastroenterology. 2016;150(6):1355-1367, with permission from Elsevier.

GI symptom-specific anxiety is an important perpetuating factor that describes threatening interpretation and out-of-proportion behavioral response to GI sensations. This anxiety is characterized by worry and hypervigilance around GI sensations from normal bodily functions (e.g., hunger, satiety, gas) to symptoms of an existing GI condition (e.g., abdominal pain, diarrhea, urgency). Worry and hypervigilance generalizes into fear that sensations/symptoms will occur and contexts where this could happen. Avoidance or behaviors disproportional to symptoms follows [55,78].

As an example, a person has not eaten all day and becomes aware her stomach is rumbling. Interpreted to mean the need to defecate may be imminent, anxiety is triggered. In public with friends, the anxiety increases when no restroom is visible, and the person leaves her friends, feeling they would not understand [55].

Other Factors

Genetic Predisposition

Variations in the gene that encodes serotonin reuptake transport system have been found in patients with IBS. It is believed that polymorphism of the 5-HT2A receptor gene may be associated with the development of IBS [79].

Acute Infectious Gastroenteritis

The prevalence of IBS is increased six- to seven-fold in persons who have experienced a prior infectious gastroenteritis or enterocolitis, and postinfectious IBS accounts for 5% to 25% of all cases of IBS [80]. IBS develops in 3% to 30% of patients following acute gastroenteritis, illustrating an acute pathogen and host interaction that predisposes to development of chronic IBS [5,81]. Factors with the greatest risk for postinfectious IBS are elongating toxin and longer duration of the initial illness [82,83]. Other predisposing factors include:

- Female sex

- Younger age

- Toxicity/severity of infecting strain

- Cigarette smoking

- Mucosal inflammation

- Immune function

- Microbiome

- Concurrent depression or anxiety

- GI infection severity

- Antibiotic treatment

Psychopathology increases the risk of developing postinfectious IBS by enhancing susceptibility to infectious gastroenteritis [5,84]. Mucosal inflammation and abnormal gut-host microbial interactions also promote postinfectious IBS. Mucosal immune activation and immune cell proliferation may amplify peripheral sensory signaling to result in visceral hypersensitivity, a primary IBS pain mechanism [5,84].

Patients with postinfectious IBS are important to identify because roughly 50% will experience spontaneous remission within six to eight years of the initial infection. This disease course differs from the chronic relapsing nature of typical IBS [5,85].

Acute gastroenteritis is now known to cause marked disruptions in the gut microbiota by pathogen overgrowth and substantial reduction in the diversity of normal flora. In the past, gut equilibrium was assumed to normalize after the infection cleared. However, research indicates individuals recovering from Campylobacter jejuni enteritis (a common cause of food poisoning) are as likely to show continued alteration in microflora (with potential progression to IBS-D) as they are full recovery of gut equilibrium [86,87].

Alterations in the Intestinal Microbiome

Gut dysbiosis is defined as an imbalanced or maladapted, but stable, gut ecosystem that has reduced capacity for protection and is associated with disease [88]. Gut dysbiosis has potentially significant consequences in psychiatric disorders, cognitive disorders, and chronic visceral pain (due to brain-gut mediation). The intestinal flora of patients with IBS differs from healthy persons, and intestinal flora profiles also differ among IBS subtypes [89]. Deficiency in Bifidobacterium has been associated with greater abdominal pain and bloating in patients with IBS. As such, treatment with probiotics has shown some promise in alleviating symptoms in IBS. In one study, probiotic administration was found to alter central processing of emotional stimuli and resting brain connectivity in sensory and affective brain circuits. The hypothesis of a microbiome gut-brain axis is emerging, and there is a possibility that gut microbiota will represent a therapeutic target in the treatment of IBS [55,90,91].

Bile Acids and Bowel Dysfunction

Secretory diarrhea results from colonic perfusion of bile acids due to inadequate ileal reabsorption (less than 95%). Excess bile acids entering the colon increase gut permeability, activate adenylate cyclase, stimulate colonic secretion, and increase stool water and colonic motility. Decreased circulating fibroblast growth factor 19 (FGF19) leads to excessive bile acid production and can be primary or secondary to ileal resection or ileitis. Around 10% of patients with IBS-D have severe bile acids malabsorption—defined as less than 5% retention at seven days. In the United Kingdom, bile acid diarrhea accounts for nearly 25% of patients with IBS referred to specialist care for diarrhea [87,92].

Bile salt overproduction can be identified by reduced seven-day retention of the synthetic radiolabeled bile acid selenium-75 homocholic acid taurine (SeHCAT), but access to SeHCAT is limited. Another approach measures fasting FGF19 using an enzyme-linked immunosorbent assay (ELISA). FGF19 <145 pg/mL predicts reduced SeHCAT retention [87].

The cause of low FGF19 levels is not fully known, but bile acid malabsorption can begin acutely after an ileitis episode, common with Salmonella spp. or C. jejuni gastroenteritis. Sudden onset and high-volume nocturnal diarrhea are characteristic features [87].

The prevalence and role of ileal malabsorption of bile acids in diarrhea-like symptoms has historically been underestimated in IBS-D. Identification can lead to specific treatment with bile acid sequestrants [15,93].

Diet

Many patients identify food as an IBS symptom trigger. The contribution of true food allergies to IBS is small, but food intolerances are common in patients with IBS. Gluten (present in wheat products) is increasingly recognized as an important symptom trigger in patients with IBS and inducer of IBS-like symptoms in persons without IBS diagnosis. Non-celiac gluten sensitivity is an emerging syndrome provoked by gluten ingestion in patients in whom celiac disease and wheat allergy are ruled out. Other triggers of non-celiac gluten sensitivity pathogenesis include wheat proteins (i.e., amylase and trypsin inhibitors) and FODMAPs (fermentable oligo-, di-, monosaccharides, and polyols) [94,95]. Emerging evidence supports gluten-free and low-FODMAPs diets for patients with IBS. FODMAPs are poorly absorbed carbohydrates that can induce osmotic effects, result in increased fermentation in the small bowel or colon, and trigger symptom exacerbation in patients with IBS with abnormal gut function or sensitivity [5,94].

Dietary constituents also influence the impact of intraluminal factors on gut function. Among these are microflora alterations in short-chain fatty acids; the effects of enteroendocrine cell products (i.e., granins) on nervous, endocrine, and immune cells; and the ratio of secondary to primary bile acids that impact gut transit rates [15,96].

A six-week placebo-controlled, double-blinded trial in patients with IBS with gluten sensitivity histories found poorly controlled IBS symptoms in 68% randomized to diets with gluten versus 40% receiving a gluten-free diet. In patients receiving a gluten-free diet, double-blinded gluten re-challenge worsened pain, bloating, stool consistency, and fatigue [97]. A study of patients with IBS-D reported that gluten administration led to altered gut permeability and increased stool frequency and immune activation [98].

While these data suggest that symptom exacerbation after ingesting wheat is primarily caused by gluten, wheat also contains fructans and other proteins that may trigger symptoms in patients with IBS [5]. A clinical trial of 920 patients with IBS found that 33% of subjects experienced worsened symptoms of increased abdominal pain and distension after receiving wheat (not limited to gluten), but not after placebo [99].

BRAIN-GUT AXIS AND PROCESSING

Bidirectional interactions involving multiple components of the (peripheral) GI system (microbiome, altered mucosal inflammation, visceral hypersensitivity) and the CNS (emotional arousal, sensorimotor function, salience and executive function, central autonomic function) contribute to the development of IBS. Neurophysiologic mechanisms in the brain-gut axis link psychologic processes, psychiatric comorbidity, and IBS symptoms [2,100].

In the brain-gut axis, homeostatic information about visceral physiologic status is continuously signaled to the brain through afferent neural and humoral "gut-brain" pathways. Most gut-brain signals are not consciously perceived under normal conditions. Visceral pain results from the perception of strong gut-brain signaling, triggered by noxious stimuli to warn of potential threat to homeostasis that requires a response [55,100].

Visceral afferent signals are relayed to the brain and then processed, modulated, and integrated through the afferent network, emotional arousal, and cortical modulatory neurocircuits [55]. Emotional arousal and cortical modulation circuits project "top-down" to brainstem areas, which send descending projection neurons to dorsal horns of the spinal cord, where pain transmission is modulated. This circuitry is termed the descending pain modulation system (DPMS) [55].

ALTERED PAIN PERCEPTION IN PATIENTS WITH IBS

The hallmark symptom of IBS in the Rome IV criteria is chronic visceral pain and/or discomfort, and patient perception of visceral pain in IBS is disproportionate to the intensity of visceral afferent inputs, which is the result of complex psychobiologic processes [55].

Visceral hypersensitivity (also referred to as sensitization) describes lowered thresholds for visceral pain and occurs in the majority of patients with IBS. In these patients, lower pain thresholds are reflected by an exaggerated pain response to normally modest GI discomfort and/or painful response to stimuli that are not normally pain- or discomfort-inducing (e.g., normal bowel function). Visceral sensitivity is amplified in patients with IBS [15].

Psychologic processes and psychosocial factors substantially influence visceral hypersensitivity. In patients with IBS, hypervigilance (defined as a heightened psychologic tendency to focus on and report pain) is considered a greater contributor to lowered pain thresholds than actual increased neurosensory sensitivity. Anxiety and depression levels are directly related to pain severity in patients with IBS [101,102,103,104].

As discussed, extra-intestinal chronic pain conditions are highly prevalent in IBS, and widespread hypersensitivity and extra-intestinal pain syndromes suggest CNS involvement and central sensitization. Descending neural modulatory circuits from the brain can inhibit or facilitate ascending nociceptive transmission, influenced by cognitive processes and mood. Changes in DPMS function are thought to influence pain perception [105]. Dysregulated cortical modulation of descending pain regulatory pathways can amplify sensitivity to noxious and innocuous stimuli [106].

Neural pathways play a major role in modulating visceral pain experience and other IBS symptoms. Spinothalamic tracts localize and differentiate visceral stimuli, while spinoreticular pathways influence the reflexive, affective, and motivational aspects of sensation and pain [81]. Pain modulatory system dysfunction promotes visceral hypersensitivity, and studies of IBS have shown abnormalities in pain signal processing and modulation that include functional and structural abnormalities in sensory, emotional arousal, and prefrontal cortical modulatory regions [55,106].

Altered Brain Network Function

Colorectal distension in patients with IBS activates brain stress response areas but deactivates brain areas that modulate stress response [80,107,108]. This pattern reflects up-regulated connectivity in emotional arousal circuitry; the increased sympathetic arousal, anxiety, and vigilance often observed in patients with IBS; and the association between IBS symptoms and functional alteration in multiple brain networks [55].

When anticipating experimentally induced visceral pain, anticipatory response in the locus coeruleus predicts subjective perception and brain response to the actual painful stimulus. Sensory filtering is degraded by anxiety-related dysfunction of the descending pain modulation system [107,109].

Altered Brain Structure

Alterations in brain structure have been demonstrated in patients with IBS. The role of structural brain changes in IBS and other functional pain disorders is not clear, because these changes may represent pre-existing vulnerability factors or consequences of long-term exposure to the pain [106].

Female patients with IBS have shown increased cortical thickness in the somatosensory cortex and decreased cortical thickness in pain processing regions, including the insula and anterior cingulate cortex. IBS symptom severity is negatively correlated with cingulate thickness, suggesting a role for loss of neural density in symptom generation [106,110,111].

Patients with IBS have also shown decreased gray matter volumes in widespread regions, with early life trauma contributing to these decreases [106]. Decreased gray matter density in prefrontal and posterior parietal cortex areas is consistent with the close relationship between IBS and mood disorders. Pain catastrophizing negatively correlates with the degree of cortical thickness in the prefrontal cortex [112,113,114].

Abnormal structure of brain white matter tracts have been found in multiple areas in patients with IBS. These white matter changes are associated with symptom severity, trait anxiety, and catastrophizing [115,116,117].

4. CLINICAL PRESENTATION AND DIAGNOSTIC WORKUP

CLINICAL PRESENTATION

Altered Bowel Habits

Patients with prominent constipation may describe painful or infrequent defecation, non-response to laxatives, and hard, narrow stools. If present, diarrhea is usually described as small volumes of loose stool preceded by urgency or frequent defecation. Postprandial urgency is common, as is alternation between constipation and diarrhea predominance [118]. Stools may also be white or clear (mucosa).

Abdominal Pain

Descriptions of pain associated with IBS often change, but the pain is typically diffuse without radiation. The most common site of pain is the lower abdomen, specifically the left lower quadrant. Acute episodes of sharp pain are often superimposed on a more constant dull ache. Meals can precipitate pain, and defecation may or may not improve pain. Pain from what feels like gas pockets in the splenic flexure can mimic anterior chest pain or left upper quadrant abdominal pain. Termed splenic flexure syndrome, balloon inflation in the splenic flexure will provoke this pain and should be considered to differentiate from chest or left upper quadrant abdominal pain [118].

Abdominal Distention

Patients with IBS frequently report increased amounts of bloating and intestinal gas, but confirmation by quantitative measurements is elusive. People with IBS can experience expanding, and measurable, abdominal circumference throughout the day. Intolerance of otherwise normal amounts of abdominal distention is common [118].

Other Common Symptoms and Complaints

Dyspepsia, heartburn, nausea, vomiting, sexual dysfunction (including dyspareunia and poor libido), and urinary frequency and urgency frequently occur in patients presenting with IBS complaints. Fibromyalgia commonly co-occurs. Careful questioning can reveal stressor-related symptoms; if disclosed, ask further about avoidance of stressors [118].

Perimenstrual Symptom Exacerbation

Many women of reproductive age experience cyclical changes in GI symptoms (including alteration in bowel habits) during their menstrual cycle. Female patients with IBS often experience worsened GI symptoms of abdominal pain, bloating, or diarrhea during menses, possibly due to elevated prostaglandin levels during menses that enhance perception of viscera-somatic stimuli and increases nausea, abdominal distension, and pain [119].

Fatigue

Despite receiving little attention in the medical literature, fatigue is a frequent symptom in patients with IBS and is associated with poor quality of life. A study of 160 patients with IBS found a multidimensional and negative impact from fatigue on daily life [120]. Fatigue may interfere with patients' ability to perform physical activities, work, domestic work, and interact socially. Poor stamina is the most prominent feature, and strategies to limit the bodily consequences of tiredness are common. Severe fatigue is associated with more severe IBS symptoms, anxiety, and depression. Fatigue is a distressing symptom in a sizeable proportion of patients with IBS and should be assessed and, if confirmed, targeted for intervention [120].

CONCEPTUAL AND DIAGNOSTIC ADVANCES

Over time, the definitions of IBS and functional GI disorders have been shaped by societal perspectives of illness and disease, available scientific evidence, and clinician training and bias. Even today, some consider functional GI disorders to be "less legitimate" than pathologically based disorders, and patients with functional GI disorders may be stigmatized for having functional symptoms. This is a carry-over from the influence of dualistic principles that dichotomized organic disorders from functional disorders, which were often considered psychiatric or undefined. However, the definition has changed from the absence of organic disease, to a stress-related or psychiatric disorder, a motility disorder, a disorder of GI functioning, and finally to a disorder of gut-brain interaction [2].

The Rome Foundation was founded in the 1980s to promote global recognition of functional GI disorders, advance scientific understanding of functional GI disorder pathophysiology, optimize clinical management for patients with functional GI disorders, and develop educational resources to achieve these goals. The Foundation is comprised of scientists and clinicians from around the world with expertise in diverse areas relevant to functional GI disorders [121].

The Rome III criteria incorporated scientific data
on IBS diagnosis and treatment. Rome III defined IBS as recurrent abdominal pain or discomfort three or more days per month in the preceding three months, associated with two or more of the following: symptom improvement with defecation, symptom onset coupled
with altered stool frequency, or symptom onset
coupled with altered stool form [122,123].

Over the past decade, the need to revise Rome III became increasingly apparent. Knowledge of IBS pathophysiology continued evolving, and many clinicians found Rome III criteria unhelpful and lacking in real-world clinical applicability. For example, Rome III did not recommend basic laboratory testing and ignored the fact that, for many patients, abdominal pain worsened rather than improved with defecation. Some Rome III criteria were seen as vague or incorrect [122].

In 2016, the Rome IV guidelines were published to address these criticisms and improve guidance to healthcare providers based on latest scientific and clinical evidence. Important changes in Rome IV IBS diagnostic criteria include [2,3]:

- The term "abdominal discomfort" was removed because it was determined to be imprecise and difficult to translate.

- The required frequency and presence of abdominal pain was increased to reflect research that identified pain as a cardinal symptom of IBS.

- Rome IV recognizes that IBS is often associated with irregular bowel habits of constipation, diarrhea, a mix of both, or their alternation and that common symptoms include bloating and distension.

- As IBS is a chronic condition, Rome IV requires symptom persistence for six or more months for diagnosis.

- Rome IV now acknowledges the role of diagnostic tests to exclude other common conditions with similar symptoms to IBS, such as celiac disease, lactose intolerance, and inflammatory bowel disease.

- Replacing the term "functional" was found impractical due to its pervasive use in healthcare nosology, so this term was limited to the extent possible.

By clarifying language, updating the definition, and including the option of laboratory testing, the new criteria should make IBS easier to diagnose. The emphasis on abdominal pain validates clinician reports of this symptom as the essential element of IBS. Rome IV should also help differentiate IBS from intermittent abdominal spasms or cramps and chronic constipation or diarrhea [3,122]. The revised Rome IV IBS criteria are part of a larger project by the Rome Foundation to overhaul and update scientific data, educational information, and clinical guidance to optimize the diagnosis and treatment of functional GI disorders.

Functional bowel disorders, a functional GI disorder subgroup, describe a spectrum of chronic GI disorders characterized by predominant signs or symptoms of abdominal pain, bloating, distention, and/or bowel habit abnormalities (i.e., constipation, diarrhea, or mixed constipation and diarrhea) [3]. These disorders are distinguished from other GI disorders based on chronicity (more than six months of symptoms at the time of presentation), current activity (symptoms present within the last three months), frequency (symptoms present, on average, one or more days per week), and absence of obvious anatomic or physiologic abnormalities identified by routine diagnostic workup. Functional bowel disorders include IBS, functional constipation, functional diarrhea, functional abdominal bloating/distention, unspecified functional bowel disorder, and opioid-induced constipation, a new entry that differs from other functional bowel disorders by etiology but resembles functional constipation in clinical presentation [3].

Importantly, these disorders significantly overlap and should be viewed as a continuum instead of discrete diagnostic entities. Given the extent of overlap, differentiation of functional bowel disorders may not always be possible [3].

DIAGNOSTIC CRITERIA AND MEASUREMENT SCALES

Evidence Based Practice Recommendation

The National Collaborating Centre for Nursing and Supportive Care recommends that healthcare professionals should consider assessment for IBS if the person reports having had any of the following symptoms for at least six months: abdominal pain or discomfort, bloating, and/or change in bowel habit.

https://www.nice.org.uk/guidance/cg61

Last Accessed: December 11, 2018

Level of Evidence: Consensus Statement/Expert Opinion

As noted, IBS is a functional bowel disorder with recurrent abdominal pain associated with defecation or a change in bowel habits. Disordered bowel habits and symptoms of abdominal bloating/distention are typically present. Symptom onset occurs at least six months before diagnosis, and symptoms should be present during the last three months [3].

For all IBS subtypes, the key requirement is that symptoms must not have an organic, metabolic, or drug-induced origin. A symptom-focused patient history and careful physical examination are mandatory to rule out intestinal or extra-intestinal diseases, symptom-inducing medications, and alarm symptoms that prompt further diagnostic exploration [44].

The Rome IV IBS diagnostic criteria are [3]:

- Recurrent abdominal pain occurring, on average, one or more days per week

- The abdominal pain is associated with two or more of the following criteria:

- Related to defecation

- Associated with a change in frequency of stool

- Associated with a change in form (appearance) of stool

Diagnosis is made with criteria fulfilled the last three months and symptom duration at least six months.

Bristol Stool Form Scale

The Bristol Stool Form Scale (BSFS) illustrates and describes the appearance of seven different stool types that correspond to intestinal transit time ranging from severe constipation (Types 1 and 2) to diarrhea (Type 7). Patients can use the BSFS to record frequency and subtype of their stools [124]:

- Type 1: Separate hard lumps, like nuts (hard to pass)

- Type 2: Sausage-shaped but lumpy

- Type 3: Like a sausage with cracks in the surface

- Type 4: Like a sausage or snake, smooth and soft

- Type 5: Soft blobs with clear-cut edges

- Type 6: Fluffy pieces with ragged edges, a mushy stool

- Type 7: Entirely liquid, no solid pieces

Diagnostic Criteria for IBS Subtypes

IBS is subtyped by predominant bowel habit change, but only after all medications to treat bowel habit abnormalities are discontinued. The BSFS can be used to categorize IBS into subtypes based on stool characteristics (Table 3). Predominant bowel habits are based on stool form on days with at least one abnormal bowel movement [3,44].

Table 3: DIAGNOSTIC CRITERIA FOR IBS SUBTYPES

Subtype

BSFS Criteria

Alternative

IBS with predominant constipation (IBS-C)

>25% of bowel movements with BSFS types 1 or 2 AND <25% of bowel movements with BSFS types 6 or 7

Patient reports that abnormal bowel movements are usually constipation (BSFS type 1 or 2).

IBS with predominant diarrhea (IBS-D)

>25% of bowel movements with BSFS types 6 or 7 AND <25% of bowel movements with BSFS types 1 or 2

Patient reports that abnormal bowel movements are usually diarrhea (BSFS type 6 or 7).

Mixed-type IBS (IBS-M), in which constipation and diarrhea alternate

>25% of bowel movements with BSFS types 1 or 2 AND >25% of bowel movements with BSFS types 6 or 7

Patient reports that abnormal bowel movements are usually both constipation and diarrhea.

IBS unclassified (IBS-U)

—

Patients who meet diagnostic criteria for IBS but whose bowel habits cannot be accurately categorized into one of the other three groups.

BSFS = Bristol Stool Form Scale.

Source: [3,44]

Diagnostic Criteria for Related Functional Bowel Disorders

Functional bowel disorders are diagnosed when criteria are fulfilled for the last three months, with symptom onset more than six months before diagnosis [3].

Functional Constipation

In order for a diagnosis of functional constipation to be made, two or more of the following must be present [3]:

- Straining during >25% of defecations

- Lumpy or hard stools (BSFS 1 or 2) in >25% of defecations

- Sensation of incomplete evacuation in >25% of defecations

- Sensation of anorectal obstruction/ blockage in >25% of defecations

- Manual maneuvers to facilitate >25% of defecations (e.g., digital evacuation, support of the pelvic floor)

- Fewer than three spontaneous bowel movements per week

In patients with functional constipation, loose stools are rarely present without laxative use. Although symptoms may be similar, these patients do not meet the full criteria for IBS-C.

Functional Diarrhea

Functional diarrhea is characterized by loose or watery stools (>25% of stools) without predominant abdominal pain or bothersome bloating. These patients do not meet the criteria for IBS-D.

Functional Abdominal Bloating/Distension

Functional abdominal bloating (FAB) or distention (FAD) represent two different sets of signs and symptoms but are combined by Rome IV into the diagnostic entity of FAB/FAD. In patients with FAB/FAD, mild abdominal pain related to bloating and/or minor bowel movement abnormalities may be present. Symptoms of recurrent abdominal fullness, pressure, a sensation of trapped gas, and/or measurable increase in abdominal girth must be present. Abdominal bloating and/or distention predominates over other symptoms, occurring, on average, at least one day per week. These patients do not meet the diagnostic criteria for IBS, functional constipation, functional diarrhea, or postprandial distress syndrome.

CLINICAL EVALUATION AND DIAGNOSTIC WORKUP

IBS is diagnosed by a thorough patient history, physical examination, and limited laboratory testing. While not necessary for diagnosis, a brief psychosocial assessment should be performed in all patients. In most patients who fulfill Rome IV diagnostic criteria and for whom alarm features are absent, the need for diagnostic testing should be minimal; performing a battery of tests in all patients suspected of IBS is not warranted. However, focused diagnostic testing may be required to differentiate IBS from several conditions with mimicking symptoms when ambiguity is present. IBS mimics include inflammatory bowel disease, celiac disease, lactose and fructose intolerance, and microscopic colitis [3].

Clinical History

Abdominal pain is a hallmark of IBS; the absence of abdominal pain precludes the diagnosis of IBS. Pain can be present anywhere throughout the abdomen, although it is more common in the lower abdomen [3].

A history of disordered bowel habits (i.e., constipation, diarrhea, or both) should be identified, along with their temporal association with episodes of abdominal pain. Unpredictable bowel pattern (i.e., three or more different stool form types/week) reinforces the diagnosis of IBS-D. An increasing number of consecutive days without a bowel movement suggests a diagnosis of IBS-C.

Ask patients for specific information regarding bowel habits and stool characteristics, as this informs subtyping of their IBS. A diagnosis of unclassified IBS (IBS-U) is reserved for patients meeting IBS diagnostic criteria whose bowel habits cannot be accurately grouped into one of the three main subtypes; this group is uncommon. Difficulty in accurate subtyping can result from frequent changes in diet or medications or an inability to stop medications that affect GI transit. Subtyping should be based on the patient's reported predominant bowel habit on days with abnormal bowel movements. As noted, the BSFS should be used to record stool consistency [124].

Diagnosing patients with IBS-D or IBS-C is usually straightforward, but IBS-M can be more complex. A detailed history helps determine whether mixed bowel patterns originate from the underlying disease state or are a consequence of medical intervention. All prescription and over-the-counter medications and supplements with known influence on IBS symptoms should be considered. A stool diary helps identify patterns in the erratic bowel habits of many patients with IBS. Patients with IBS-M often report protracted periods when bowel movement is absent or appears with small, hard stools; this is followed by periods of multiple stools of variable consistency interpreted by patients as diarrhea. In most cases, this reflects IBS-C, and radiographic demonstration of fecal loading helps confirm clinical suspicion [5].

Non-Specific Symptoms

Common non-specific symptoms in IBS include abnormal stool frequency, abnormal stool form (BSFS types 1/2 or 6/7), excessive straining during defecation, urgency to defecate, feelings of incomplete evacuation, and mucus with bowel movements. Abdominal bloating is present in most patients with IBS and abdominal distention may be reported, but neither is required for an IBS diagnosis [3].

Patients with IBS frequently report that symptoms are induced or worsened by meals, although these symptoms are not specific to IBS. Many other functional GI (e.g., dyspepsia) and non-GI (e.g., migraine headaches, fibromyalgia, interstitial cystitis, dyspareunia) disorder symptoms are reported in patients with IBS; their presence supports an IBS diagnosis [3].

Physical Examination

A physical examination should be performed for every patient evaluated for IBS. This reassures the patient and helps exclude organic etiology. Physical examination frequently reveals tenderness in the left lower quadrant over a palpable sigmoid colon. A rectal examination is warranted to rule out rectal disease and abnormal function of the anorectal sphincter (e.g., paradoxical pelvic-floor contraction during a defecation attempt), which may contribute to symptoms of constipation [125]. The presence of ascites, hepatosplenomegaly, or abdominal mass warrants further evaluation. An anorectal examination is mandatory to identify anorectal causes of bleeding, evaluate anorectal tone and squeeze pressure, and identify dyssynergic defecation [3].

Differential Diagnosis

Several diseases should be considered in patients with IBS symptoms, including celiac disease, inflammatory bowel disease, and dyssynergic defecation. When detailed history taking, physical examination, and/or routine laboratory testing results make it crucial to rule out a disease that requires diagnostic tests or functional studies not available in primary care, referral to a specialist is indicated.

Celiac Disease

Patients with IBS symptoms have a fourfold increased risk of biopsy-proven celiac disease [5]. However, the prevalence of celiac disease in patients with IBS symptoms varies by region, with European studies, but not American studies, demonstrating a higher prevalence of the disease. Routine celiac disease screening in patients with IBS becomes cost-effective with prevalence ≥1%. Given the potential long-term consequences of a missed celiac disease diagnosis, clinicians caring for patients with IBS should have a low threshold of suspicion, especially in patients with IBS-D [5,126].

Serologic tests for celiac disease should be performed in patients with IBS-D or IBS-M who fail empiric therapy. Upper GI endoscopy with duodenal biopsies should be performed if serologic tests for celiac disease are positive or clinical suspicion is high; duodenal biopsies can also identify tropical sprue, another mimic of IBS.

Microscopic Colitis

A small subgroup of patients with suspected IBS-D have microscopic colitis. Risk factors for microscopic colitis include age older than 50 years, nocturnal stools, weight loss, shorter duration of diarrhea, recent introduction of new medications, and comorbid autoimmune disease. When colonoscopy is performed in patients with suspected IBS-D, random colon biopsies should be obtained to rule out microscopic colitis [5,126].

Inflammatory Bowel Disease

Chronic inflammatory bowel diseases, like Crohn disease, can mimic IBS symptoms during acute inflammatory flares. Nerve and muscle changes can persist following acute inflammation, even in remission. The underlying mechanisms may include altered gut permeability and persistent low-level immune activation, shown by cecal biopsies from patients with inflammatory bowel disease in apparent remission with ongoing IBS symptoms. Other mechanisms may include persisting alterations in enteric nerves and serotonin signaling. This information can help identify patients with inflammatory bowel disease and persistent IBS symptoms who may respond better to dietary restriction and other IBS treatments than to escalated immunosuppression [87,127,128].

Because even low-grade chronic inflammation can alter gut permeability, sensitize visceral afferent neurons, and lead to aberrant motility and visceral sensitization, inflammatory bowel disease should be considered in all patients with IBS symptoms. IBS criteria are met by more than 33% of patients with inflammatory bowel disease, but the proportion of patients with inflammatory bowel disease and overlapping IBS symptoms with alarm features is unclear [5].

The pragmatic question is how often inflammatory bowel disease is ultimately identified in patients with typical IBS symptoms who lack alarm features. A prospective U.S. study of more than 900 non-constipated patients with IBS and healthy controls receiving colonoscopy found inflammatory bowel disease in less than 1% of patients with IBS and none in the controls. This argues against routine colonoscopy in patients with typical IBS symptoms who lack concerning features. Noninvasive biomarkers may be more cost-effective than colonoscopy for inflammatory bowel disease screening [5,129].

Fecal calprotectin, a biochemical assay for intestinal inflammation, is a cost-effective choice in inflammatory bowel disease screening, although 33% of patients with inflammatory bowel disease and IBS-like symptoms show negative results. C-reactive protein levels of <0.5 mg/dL or fecal calprotectin levels of <40 mcg/g confer a ≥1% risk of inflammatory bowel disease in patients with typical IBS symptoms [5,130]. However, inflammatory bowel disease was found to develop two to three years after initial IBS diagnosis at rates far exceeding population norms, despite negative colonoscopy findings [31].

If inflammatory markers are mildly elevated but the probability of inflammatory bowel disease is low, testing should be repeated before performing colonoscopy (unless other indications for colonoscopy are present). Inflammatory markers are not useful in patients with constipation-predominant symptoms.

Bile Acids Diarrhea

As noted, perfusion of bile acids into the colon stimulates water and electrolyte secretion and accelerates transit. Evidence of bile acid malabsorption may be present in up to 33% of patients with IBS-D symptoms. Clinicians can empirically assess for bile acid malabsorption by initiating a bile acid sequestrant trial. Several tests can identify such malabsorption but are not widely available in the United States [5,92].

Dyssynergic Defecation

Dyssynergic defecation is an under-recognized, constipation-associated condition characterized by an inability to coordinate abdominal wall, anal sphincter, and pelvic floor muscles for normal defecation. Symptoms are non-specific and include abdominal pain, discomfort, and bloating. Intervention with biofeedback can improve bowel and abdominal symptoms. Thus, patients with medically refractory IBS-C symptoms should be referred to a specialist for evaluation of dyssynergia by digital rectal examination, anorectal manometry, balloon expulsion testing, or anorectal imaging [131,132,133].

Laboratory Studies

A complete blood count is useful to rule out anemia or infection in patients with IBS symptoms. In the absence of alarm symptoms or suspicion of abnormalities that other laboratory testing can confirm, no other testing is needed for diagnosis. However, the presence of alarm criteria requires further testing specific to the index alarm finding—colonoscopy in most cases [3,44].

Thyroid tests are not routinely indicated in all patients but can be ordered if clinically warranted. Stool analysis (for bacteria, parasites, and ova) may be useful if diarrhea is the main symptom, especially in patients recently living in developing countries where infectious diarrhea is prevalent.

Colonoscopy is indicated in the presence of alarm symptoms, family history of colorectal cancer, or persistent diarrhea that has failed empiric therapy. Biopsies of different segments of the colon may be required in patients with chronic diarrhea to rule out microscopic colitis. Colorectal cancer screening colonoscopy is indicated in patients 50 years of age or older (or 45 years of age or older in African Americans) in the absence of warning signs based on national recommendations.

With failure of empiric therapy, other diagnostic options in limited use include [3]:

- Scintigraphic evaluation (75SeHCAT test)

- Postprandial serum C4 (7a-hydroxy-4-cholesten-3-one)

- FGF19

Breath tests to rule out carbohydrate malabsorption may be useful in some patients with IBS symptoms and persistent diarrhea.

Alarm Features

Concerning features that may suggest organic disease require assessment. Although the presence of these features may identify patients with organic disease, most will have negative evaluation findings, and concerning features are valuable for their negative (not positive) predictive value. IBS can be confidently diagnosed in patients who meet symptom-based criteria and lack concerning features, because extensive diagnostic testing is infrequently positive. However, the perspective of IBS as a diagnosis of exclusion remains widespread, and many healthcare professionals are uncomfortable relying solely on symptom-based criteria for its diagnosis [5,134].

Alarm criteria requiring further testing to rule out organicity include [3,44]:

- Personal or family history of colorectal cancer, intestinal polyposis, inflammatory bowel disease, or celiac disease

- Symptom onset after 50 years of age

- Recent changes in bowel movement habit

Additional signs and symptoms that may suggest organicity are:

- Nocturnal symptoms

- Fever

- Anemia

- Unintended weight loss not explained by other causes

- Fecal blood in the absence of documented bleeding hemorrhoids or anal fissures

- Severe abdominal pain

- Palpable abdominal mass, visceromegalias, or abnormal digital rectal examination on physical exam

Psychosocial Assessment

As discussed, psychosocial factors influence physiologic functioning of the GI tract (including motility, sensitivity, and barrier function), mediate pain experience and symptom behavior of the patient, and impact treatment selection and clinical outcome [15]. This makes psychosocial assessment a vital part of the evaluation of patients with IBS symptoms.

Primary care clinicians and gastroenterologists can use psychosocial screening to identify patients at risk for refractory symptoms, poor treatment response, or low quality of life. When overt psychopathology or moderate-to-severe symptoms are absent, visceral-specific anxiety, catastrophizing, somatization, and quality of life can be assessed to determine if comprehensive evaluation by a health psychologist or psychiatrist is indicated [55].

Clinicians can include a brief psychosocial assessment for each patient with functional GI disorder, with the precondition that a satisfactory patient-clinician relationship is established earlier in the evaluation. A few specific questions on key psychosocial processes can be woven into routine history taking. If a patient asks about the relevance of this inquiry, a truthful response is, "I always ask my patients these questions as part of my initial assessment—it helps me determine the best way to help. The items may or may not apply to you." This psychosocial assessment will only be satisfactory if the patient is able to speak freely, which requires privacy, a lack of judgment or stigma, and sufficient time. Sensitive areas of discussion include abuse history, depressed mood, possible suicidal thoughts, and the nature of intimate relationships. These may require a second appointment for a full assessment.

The clinician should provide feedback about results of the overall evaluation and discuss treatment options, which can include medical and psychosocial approaches [55]. Consider referring patients with severe symptoms, previous treatment failure, poor treatment adherence, or marked disability to a clinician with special training in psychosocial assessment [55].

Changes in Symptom Severity, Frequency, or Treatment Response

When a plausible explanation for a change in symptoms or treatment response in patients with an established IBS diagnosis is lacking, it is important to assess for an underlying causal condition. Following a new physical examination, time since the last diagnostic workup should be considered. Changes in epidemiologic characteristics of the family should be assessed and recorded. IBS can include phases where symptom severity changes, and patients may perceive they have an inadequately explored organic disease. With these considerations, additional diagnostic testing should generally be limited to the presence of alarm symptoms or signs [44].

5. TREATMENT

Treatment of IBS should be directed at the dominant symptom type and severity [3]. In this section, interventions for all IBS subtypes (e.g., lifestyle, psychologic interventions, dietary, antidepressants) are discussed first, followed by therapeutic options specific to dominant symptom type (i.e., constipation, diarrhea, abdominal pain).

THE THERAPEUTIC RELATIONSHIP AND TREATMENT ADHERENCE

IBS treatment begins by explaining the condition, providing reassurance of the benign natural history, and educating the patient about the benefits and safety of diagnostic tests and treatment options [3]. Clinical experience suggests that providing the patient with a plausible disease model (e.g., "brain-gut disorder") and accepting patient symptoms and distress as real instead of dismissing them as "psychosomatic" helps to establish a positive therapeutic relationship. An approach that acknowledges the disease, educates the patient about the disease, and reassures the patient may improve treatment outcomes [125].

Steps to Enhance the Therapeutic Relationship

Healthcare professionals who repeatedly perform unnecessary diagnostic studies to rule out pathologic disease, dismiss patient concerns, or do not collaborate effectively in patient care can promote a vicious cycle of symptom anxiety and health care seeking [2]. Effective provider-patient relationships can improve patient satisfaction, treatment adherence, symptom reduction, and other health outcomes. General guidelines can help optimize this relationship with patients with IBS [2]. Patient satisfaction is based on a perception of healthcare providers' humaneness, technical competence, interest in psychosocial factors, and provision of relevant health information; over-emphasis on biomedical issues can have a negative effect. In addition to verbal communication, engagement involves nonverbal communication such as good eye contact, affirmative nods, a gentle tone of voice, close interpersonal distance, and creation of a partner-like interaction.

It is important to conduct the patient history using a nondirective, nonjudgmental, patient-centered approach. This involves active listening and asking questions based on the patient's thoughts, feelings, and experiences, instead of a preset agenda of questions. A good first step is to inquire regarding the reason for the appointment. Immediate reasons for a patient's visit may include [135]:

- New or exacerbating factors (e.g., dietary change, concurrent medical disorder, side effects of new medication)

- Personal concern about a serious disease (e.g., recent family death)

- Personal or family stressors (e.g., recent or anniversary of death or other major loss, abuse event, or history)

- Worsening or development of psychiatric comorbidity (e.g., depression, anxiety)

- Impairment in daily function (e.g., recent inability to work or socialize)

- A hidden agenda (e.g., opioid or laxative abuse, pending litigation, disability claims)

The next step is a careful physical examination and investigation. Although this obviously assists in diagnosis and assessment of new complaints, a well-conducted physical examination itself has therapeutic value [136].

Determine patient concerns and understanding of their illness and provide an explanation of the disorder that takes into consideration patient beliefs. When possible, provide a link between stressors and symptoms consistent with patient beliefs. Many patients are unable or unwilling to associate stressors with illness, but most understand the impact of illness-related stress on their emotional state.

Patients should be given options and be involved in treatment decision-making. When possible, treatment recommendations should be consistent with patient interests. Identifying and responding realistically to the patient's expectations for improvement can strengthen rapport. However, it is also important to set consistent limits, especially as related to pain management and opioid use.

Finally, patients should be reassured that care will continue and that they should expect an ongoing relationship. It can help to let patients know that many treatment options can be explored to help control IBS.

Steps to Enhance Therapy Adherence

Adherence is essential for the effectiveness of prescribed therapy, including dietary measures, lifestyle changes, and pharmacotherapy. A therapy regimen alone is often insufficient unless the patient understands and accepts the approach and agrees to follow it. This highlights the importance of a trust-based therapeutic relationship that promotes cooperation and empowers patient participation in decision-making and responsibility for self-care [44].

In addition to consideration of best-available therapeutic options, the following measures can facilitate patient engagement and adherence [44]:

- Prescribing therapeutic regimens with the least number of effective daily doses

- Providing simple, easy-to-understand written information and reminders

- Providing adherence "diaries" to the patient

- Including information on the pathophysiology of the condition (according to education level) in patient education

- Including family members and caregivers who can positively reinforce patient behavior

The importance of regularity should be stressed for constipation management. Some patients only use medication intermittently for exacerbations, which is less effective. Other patients avoid laxatives altogether due to false beliefs that laxatives induce dependence or may be ultimately dangerous.

LIFESTYLE MODIFICATION

Limited data suggest that IBS symptoms may be improved by lifestyle modifications that include exercise, stress reduction, and good sleep habits [3]. Greater evidence supports dietary interventions.

Increased physical activity in patients with IBS has been found to improve GI symptoms and help protect against symptom deterioration [137]. In one study, exercise for 12 weeks significantly improved symptoms and extra-intestinal manifestations of IBS in 102 patients, while another 12-week exercise trial significantly improved constipation but not other IBS symptoms [137,138]. In adolescent patients with IBS, one hour of yoga daily for four weeks significantly improved symptoms [139].

Evidence Based Practice Recommendation

The National Collaborating Centre for Nursing and Supportive Care recommends drinking at least eight cups of fluid per day, especially water or other non-caffeinated drinks, for example herbal teas. Tea and coffee should be limited to three cups per day.

https://www.nice.org.uk/guidance/cg61

Last Accessed: December 11, 2018

Level of Evidence: Consensus Statement/Expert Opinion

Other recommendations that may improve IBS symptoms include [118]:

- Judicious water intake (particularly for patients with IBS-C)

- Caffeine avoidance

- Legume avoidance

Poor sleep quality is relatively common in patients with IBS, and studies have shown that sleep difficulties predict next day exacerbations, fatigue, and depressed mood [140]. Researchers have suggested autonomic nervous system dysregulation may be a common factor underlying both IBS symptoms and sleep disturbances. As such, patients should try to get enough sleep (at least seven to eight hours per night) and should keep good sleep hygiene (e.g., avoidance of electronics in the bedroom, going to sleep and rising at the same time every day).

Perceived high stress levels can also increase the risk for IBS exacerbations and increased symptoms [141]. Avoidance of high-stress situations, when possible, is recommended. However, psychologic interventions may also help provide effective stress-coping strategies.

Dietary Interventions

Dietary and Supplemental Fiber

Dietary fiber supplementation has long been the foundation of treatment in all patients with IBS, and IBS guidelines have consistently recommended dietary fiber by increasing fiber-rich foods or adding soluble fiber (usually Psyllium seed, but polycarbophil compounds may produce less flatulence) [44,118].

While evidence indicates soluble fiber has modest benefits in reducing global IBS symptoms in patients with IBS-C with mild constipation, it can worsen abdominal pain and distension and has little benefit in patients with IBS-D. Eating a fiber-rich diet can worsen symptoms of abdominal pain and distension in all patients with IBS; wheat bran, in particular, can exacerbate problems of abdominal distention, abdominal pain, and flatulence and should be avoided [3,5,44]. If fiber is indicated, initiate soluble fiber at a very low dose and gradually increase to total daily intake of 20–30 g [5].

Gluten Restriction

Dietary restriction of gluten may improve symptoms in some patients with IBS. Two small prospective studies in patients with IBS, in which celiac disease was carefully excluded, demonstrated global symptom improvement [97,98].

Dietary FODMAP Restriction

Numerous short-chain carbohydrates, including lactose, fructose, and polyols, can provoke IBS symptoms [84,143,144]. These short-chain fermentable carbohydrates are collectively termed FODMAPs, and there is direct evidence (using magnetic resonance imaging) that some FODMAPs may induce IBS symptoms via increased small bowel water content or increased colonic gas production [84,143,144].

FODMAPs promote poor absorption in the small bowel and rapid fermentation in the colon. FODMAP is an acronym for [87]:

- Fermentable

- Oligosaccharides (e.g., fructo-oligosaccharides, galacto-oligosaccharides, fructans, raffinose, inulin)

- Disaccharides (e.g., lactose, sucrose)

- Monosaccharides (e.g., fructose)

- AND

- Polyhydric alcohols (e.g., sorbitol, mannitol, xylitol, maltitol)

The most common sources of FODMAPs in the western diet are wheat, onions, fruit in which fructose exceeds glucose (e.g., apples, pears), and processed food. Dairy products are important in those with lactose malabsorption.

True lactose intolerance may induce IBS-like symptoms, but only with relatively high lactose loads (20 g) that are easily avoidable. Psychologic factors have a major influence on symptomatic responses to lactose intake [145,146].

Fructose is a monosaccharide abundantly present in many processed foods. The small bowel has a relatively limited absorptive capacity that particularly affects free fructose—the fraction in excess of the glucose that facilitates fructose absorption. High fructose loading can induce symptoms even in healthy individuals.

Polyols such as sorbitol, mannitol, and xylitol are naturally present in many fruits and vegetables and are added as artificial sweeteners to processed food products and pharmaceuticals. Polyols tend to induce bowel discharges from their stimulant effect on intestinal motility.

Dietary FODMAP restriction is associated with reduced fermentation and significant symptom improvement in some patients with IBS. In a randomized, controlled, single-blind cross-over trial, patients with IBS who had not previously tried dietary manipulation reported significant reduction in overall GI symptom scores compared with those on a standard Australian diet [87]. The complexity of the FODMAP diet makes implementation difficult, but this may be overcome by excluding only the major sources of FODMAPs (e.g., wheat, onions, dairy), avoiding processed food, and not focusing on items with small specific contribution [87]. Adding a gluten-free diet to patients with IBS already on a low FODMAP diet does not appear to offer additional benefit [147,148,149].

Probiotics

Manipulation of intestinal microbiota has promise as a potential therapy for gut dysbiosis to ameliorate symptoms of IBS and restore health. The concept of probiotics is more than 100 years old, and modern research methods are establishing empiric support for the perceived benefits of probiotic bacteria, which mainly include Lactobacillus and Bifidobacterium species [150].

Probiotics are live bacteria, selected on the basis of ability to survive in the GI tract, adhere to intestinal epithelium, and modulate intestinal flora. Probiotics promote gut health, prevent infection from intestinal pathogens, and prevent bacterial translocation by inhibiting potentially pathogenic bacteria, modulating or stimulating immune response, promoting immune cell proliferation, enhancing phagocyte activity, and increasing production of immunoglobulin A [44,151].

The therapeutic effects for patients with IBS may occur through multiple mechanisms. Bifidobacterium infantis 35624 led to significant improvements in abdominal pain/discomfort, bloating/distention, and/or bowel movement difficulty (vs. placebo) in two randomized controlled trials of patients with IBS [152,153]. A 2016 meta-analysis that included 43 clinical trials using different products found probiotics to offer benefits for global IBS symptoms, pain, bloating, and flatulence. However, the overall usefulness of these findings has been limited by use of different IBS diagnostic criteria and symptom measurement methods in published randomized controlled trials [154].

Prebiotics/Symbiotics

Prebiotics are food products that promote proliferation of bifidobacteria and other species potentially associated with anti-inflammatory effects (e.g., oligofructose, inulin, galacto-oligosaccharides, lactulose, breast milk oligosaccharides). Prebiotics do not seem particularly effective in IBS, possibly due to fermentation products that may themselves stimulate IBS symptoms. Trials for prebiotics are few in number, and no definite conclusions can be drawn [84].

Symbiotics aim to simultaneously produce synergic pro- and prebiotic effects, but evidence has not substantiated their theoretical benefits in IBS. Further evidence is required to establish the role of prebiotics or synbiotics in IBS [84].

PSYCHOLOGIC INTERVENTIONS

As discussed, psychologic factors can amplify pain perception and experience, and strong empirical evidence confirms that pain experience is powerfully influenced by pain catastrophizing, fear avoidance behavior, self-efficacy, lack of perceived control, and passive pain coping. Other psychosocial research has found that depression and anxiety mediate the effect of pain on impaired function and that trauma history can negatively influence pain experience, pain and stress coping, and the clinician-patient relationship. This all supports the utility of psychologic interventions in IBS management [62,155,156].

Psychologic interventions address the cognitive-affective and psychosocial variables that interact with, reinforce, and perpetuate the physiologic factors that are involved in symptom expression, symptom severity, and impact of the disease on other health outcomes (e.g., quality of life, health care use) [55].

Cognitive-Behavioral Therapy

CBT refers to a family of psychologic treatments rather than a specific technique. CBT is derived from behavior theories that focus on learning processes and cognitive theories that emphasize faulty cognitions or thinking processes. These same learning processes are used to help patients gain control and reduce symptoms of IBS. Cognitive theory views external events, cognitions, and behavior as interactive and bidirectional, with primary emphasis on how patients process information about their environment, self, and the future. Cognitive factors, especially the way people interpret or think about stressful events, can intensify the impact of events on patient response. Emotional, physiologic, and behavioral responses to life events will be problematic to the extent that thought processes are faulty. Clinically modifying patient thinking can change behavior and emotional and physical well-being. Cognitive changes can occur by teaching patients to systematically identify cognitive errors generated by automatic thinking, or by providing experiential learning that systematically exposes patients to the situations that cause discomfort [55,157].

Unlike traditional, insight-oriented "talk therapy," which identifies the root causes of a problem, CBT focuses on teaching people how to control their current problems by identifying the thoughts and behaviors that are maintaining them. CBT requires active patient participation during and between sessions and patient responsibility for learning symptom self-management skills. With IBS, CBT can include a combination of techniques such as self-monitoring, cognitive restructuring, problem solving, exposure, and relaxation methods [55].

Self-Monitoring

Self-monitoring is the ongoing, real-time recording of problem behaviors. In IBS, the focus of self-monitoring is internal and external triggers and the thoughts, somatic sensations, and feelings that usually accompany flare-ups. Self-monitoring provides clinically relevant information with which to structure treatment and serves as a useful therapeutic strategy by increasing patient awareness of triggers and contributing factors [55].

Cognitive Strategies

Cognitive strategies are designed to modify thinking errors that bias information processing (e.g., tendencies to overestimate risk and magnitude of threat or underestimate one's ability to cope with adversity). These self-defeating beliefs are clinically important because they are believed to moderate excessive stress experiences. Negative beliefs are identified, and the patient works with the healthcare provider to challenge and dispute them. This involves examining the accuracy of beliefs in light of available evidence and replacing biased beliefs with more logical and constructive cognitions [55].

Problem Solving

Problem solving refers to an ability to define problems, identify solutions, and verify their effectiveness once implemented. The intervention is rooted in the problem-solving model of stress, which acknowledges that a causal relationship exists between health and stressors. Using this model, the health or mental health professional teaches patients how to effectively apply the steps of problem solving to actively cope with stress [55,158].

Relaxation Procedures

Various relaxation techniques are effective in managing IBS symptoms, and relaxation procedures have long been a staple of psychologic treatments for functional GI disorders. These techniques, including progressive muscle relaxation, breath work, and meditation, are designed to directly modify autonomic arousal believed to aggravate GI symptoms [159].

Progressive muscle relaxation training involves systematically tensing and relaxing selected muscle groups throughout the body, from forehead to feet. This exercise helps patients dampen physiologic arousal and achieve a sense of mastery of physiologic self-control over previously uncontrollable and unpredictable symptoms [55,160].

In breathing retraining, the patient is taught to take slow, deep breaths and focus on bodily sensations during exhalation. This technique is based on the idea that patients with stress-related physical ailments develop inefficient respiratory patterns (e.g., shallow chest breathing), which, if chronic, can intensify physiologic arousal and increase somatic complaints [55,161].

Meditation is a self-directed practice that can emphasize focused breathing and mindfulness. Mindfulness is defined as purposefully paying attention in the moment without judgement. This nonjudgmental acceptance of thought processes allows the practitioner to achieve a state of calmness, physical relaxation, and psychologic balance. In mindfulness meditation for IBS, the patient disengages him/herself from the ruminative thoughts considered core aspects of pain and suffering by developing a nonreactive, objective, present-focused approach to internal experiences and external events as they occur [55,162]. Small studies have indicated that engagement in a mindfulness-based stress reduction program can ameliorate IBS symptoms, reduce stress, and improve patients' quality of life, with continued improvements evident after six months [163].

Hypnosis

In hypnosis, a therapist typically induces a trance-like state of deep relaxation and/or concentration using strategically worded verbal cues suggestive of changes in sensations, perceptions, thoughts, or behavior. Most hypnotic suggestions are designed to elicit feelings of improved relaxation, calmness, and well-being. Hypnotic suggestions in IBS are "gut directed," meaning suggestions are conveyed that are incompatible with aversive visceral sensation. Hypnosis might include a suggestion to feel a sense of warmth and comfort spreading throughout the abdominal area [55,164]. Hypnosis has shown some benefit in decreasing IBS symptoms in adults [165].

Exposure Therapy

Exposure therapy is designed to reduce catastrophic beliefs about IBS symptoms, hypervigilance for IBS symptoms, fear of IBS symptoms, and/or excessive avoidance of unpleasant visceral sensations or situations by helping patients confront maladaptive thoughts and beliefs in a systematic manner. Exposure can include interoceptive cue exposure (i.e., the patient repeatedly provokes unpleasant sensations) or situational/in vivo exposure (i.e., feared situations or activities are confronted). Through exposure treatments, patients learn the stimuli that led to fear and avoidance are neither dangerous nor intolerable and that fear will subside without resorting to avoidance, a behavior that reinforces fear and hypervigilance in the long-term [166,167]. In an experimental study of 13 patients with IBS, 70% improved on measures of GI symptoms, pain catastrophizing, and quality of life following 12 sessions of exposure therapy [168].

Efficacy of Psychologic Treatments

Two meta-analyses have concluded that psychologic therapies, as a class of treatments, are at least moderately effective for relieving symptoms of IBS when compared with a pooled group of control conditions. The Internet has been used as a treatment delivery platform to give a larger proportion of patients with functional GI disorder access to, and engagement in, therapy than would have been feasible through clinic-based treatment [169,170,171].

Another meta-analysis investigated the duration of psychologic therapy effects in reducing GI symptoms in patients with IBS. Forty-one trials recording data from 2,290 subjects (1,183 assigned to therapy, 1,107 assigned to a control condition) were analyzed. Compared with a mixed group of control conditions, psychologic therapies had a medium effect size on reducing GI symptom severity immediately after treatment. On average, subjects receiving psychotherapy had greater post-therapy reduction in GI symptoms than individuals assigned to a control condition. After short-term follow-up (1 to 6 months after treatment) and long-term follow-up (6 to 12 months after treatment), this effect remained significant and medium in magnitude [172].

ANTIDEPRESSANT MEDICATIONS

Although antidepressants are used extensively in the treatment of IBS and other functional GI disorders, the accumulated clinical experience, lack of other effective treatment options, and evidence from other functional somatic syndromes such as fibromyalgia make these agents viable options for treating pain and improving quality of life in patients with IBS. In general, antidepressant medications should be reserved for patients with moderate-to-severe symptoms with significant impairment of quality of life for which other first-line treatments have not been sufficiently effective [173,174].

Choice of Agent

The choice of antidepressant agent is determined by the patient's predominant symptoms, disease severity, presence of comorbid anxiety or depression, prior experience with medications in the same class, and patient and prescriber preference. The three broad antidepressant classes most often used in IBS are tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-noradrenalin reuptake inhibitors (SNRIs) [55].

Tricyclic Antidepressants

TCAs such as amitriptyline, imipramine, desipramine, doxepin, and trimipramine are the most widely used psychotropic agents for treating neuropathic (e.g., postherpetic neuralgia, diabetic neuropathy) and functional (e.g., fibromyalgia) pain syndromes. Their analgesic effect is thought to be independent of antidepressant mechanisms and effects because TCAs can benefit patients with diverse pain syndromes in whom psychopathology is modest or absent and because they are often effective for pain at low (sub-psychiatric) doses [106,175,176].

In general, TCAs are the first antidepressant choice for pain in non-constipated patients with IBS due to their dual mechanism of action (serotonin and norepinephrine reuptake inhibition). Nortriptyline or desipramine is better tolerated than amitriptyline or imipramine due to fewer anti-histaminergic and anti-cholinergic effects. The usual starting dose is 25–50 mg at night and can be titrated up as needed up to about 150 mg/day, while carefully monitoring side effects and/or blood levels. Typically, lower doses than the full antidepressant dose are effective for visceral pain if no psychiatric comorbidity is present [55].

In one study, amitriptyline 10 mg/day in patients with IBS-D significantly improved overall IBS symptoms, reduced frequency of loose stool and feelings of incomplete defecation, and led to complete response (remission) in some [165,177].

SSRIs

Evidence Based Practice Recommendation

The American Gastroenterological Association (AGA) suggests against using selective serotonin reuptake inhibitors for patients with IBS.

https://www.gastrojournal.org/article/S0016-5085(14)01089-0/pdf

Last Accessed: December 11, 2018

Strength of Recommendation/Level of Evidence: Conditional recommendation/low-quality evidence

SSRIs are less effective for pain and are less commonly prescribed as monotherapy for IBS. Review papers have arrived at different conclusions concerning SSRI utility in IBS treatment, with some authors concluding no convincing evidence has been reported for functional GI disorders and others reporting beneficial effects for overall IBS symptoms [3,93,165].

However, SSRIs are considered useful in patients with high levels of anxiety that contribute directly to IBS exacerbations and symptom severity. SSRIs and SNRIs have a more narrow therapeutic range, and therefore, the doses used for the treatment of pain are closer to the doses used for mood and anxiety disorders. Starting doses are usually within the lower range of the psychiatric dose (e.g., citalopram 20 mg or duloxetine 30 mg) and titrated up as needed [173,174,178].

A systematic review of SSRIs found benefits over placebo for overall IBS symptoms. Several clinical characteristics, including the predominant stool complaint, presence of insomnia, or comorbid anxiety, can influence antidepressant selection for individual patients with IBS [165].

SNRIs and Other Psychotropics

For SNRIs, especially venlafaxine, higher doses (≥225 mg) are usually required to attain effective analgesia because the noradrenergic mechanism of action is only evident at these doses. If nausea and weight loss are concerns, the addition of a low dose (15–30 mg) of mirtazapine can be helpful.

Atypical antipsychotics, such as quetiapine, are only recommended for patients with severe, refractory IBS, especially if severe anxiety and sleep disturbances are also present and the patient has failed to respond to other centrally acting agents. A low starting dose of 25–50 mg is recommended and can be titrated up as required [173,174].

Augmentation of Therapy

Augmentation, or the use of a combination of drugs from different classes in submaximal doses instead of one drug at a maximal dose, is common in psychiatry and is increasingly used in the treatment of functional GI disorders. Examples of augmentation include adding buspirone to an SSRI, TCA, or SNRI to enhance therapeutic effect, or adding a low-dose antipsychotic (e.g., quetiapine) to a TCA or SNRI to reduce pain and anxiety and improve sleep. If there is a component of abdominal wall pain associated with the GI pain, pregabalin or gabapentin can be added to a TCA or SNRI [173,174].

Combination Antidepressant and Psychologic Treatment

Combining antidepressants with psychologic therapy can be an effective augmentation strategy. Antidepressants can improve pain and vegetative depression symptoms, and psychologic therapy improves higher cortical functioning, including coping, reappraising maladaptive cognitions, and adapting to previous losses and trauma. Psychotherapy can optimize medication adherence, while antidepressants can sufficiently increase physical and psychic energy to improve the level of engagement in therapy. The difference in effect size with combined treatment can exceed 50% compared to either treatment alone [106,179,180,181].

Although drugs work faster and are readily available, psychologic treatments have several advantages. They are safe and effective, their effects persist beyond the duration of the treatment, and they may be more cost-effective. Potential barriers to the use of psychologic approaches in the treatment of IBS are a longer treatment duration, the need for patient motivation, and limited availability and access to a mental health professionals trained in IBS treatment [55,182].

Adherence

Careful patient selection, initiation at a low dose with gradual escalation, monitoring for side effects, and a good patient-clinician relationship are important for medication adherence and, by extension, therapeutic response. In particular, eliciting and addressing any potential concerns/barriers to taking psychotropic medications for IBS, discussing potential side effects, setting realistic expectations, and involving the patient in decision making result in improved adherence [55,174].

DIARRHEA-PREDOMINANT IBS

Chronic diarrhea in IBS is usually associated with a non-infectious cause, and symptomatic drug therapy is indicated when definitive treatment is unavailable. Pharmacologic agents for IBS-D are diverse in mechanism of action, and prescribing these agents requires proper diagnosis and differential diagnosis in order to ensure effectiveness [183].

Mu Opioid Receptor Agonists

Loperamide is a synthetic, peripheral-acting mu opioid receptor agonist with limited ability to penetrate the blood-brain barrier (and therefore limited abuse potential). It decreases peristaltic activity, inhibits secretion, increases water and ion absorption, reduces colonic transit, and increases resting anal sphincter tone. This results in reduced fluid and electrolyte loss and improved stool consistency [93,183]. Loperamide is available over the counter.

Diphenoxylate is another mu opioid receptor agonist, but unlike loperamide, it can cross the blood-brain barrier and is therefore combined with atropine to reduce abuse potential. Both of these agents are effective in reducing diarrhea in general, but research for the treatment of IBS-D is not well developed [93].

Several small randomized controlled trials of loperamide in IBS-D have shown reduced bowel frequency and improvements in stool consistency, urgency, and subjective overall response. Pain outcomes were mixed, with reduced pain intensity or increased nightly abdominal pain both reported in separate trials [3,183]. However, loperamide may improve quality of life by allowing the planning of trips and socializing, which anxious patients with IBS-D often avoid for fear of fecal urgency or even incontinence [87].

Adverse effects with loperamide or diphenoxylate are rare, but include bladder dysfunction, glaucoma, and tachycardia. These may be more likely with diphenoxylate due to the atropine constituent [93].

Bile Acid Binders (Sequestrants)

As discussed, the underlying pathophysiology in some patients with IBS-D is bile acid perfusion into the colon, and bile acid sequestrants are used as treatment for these patients. Cholestyramine is the agent generally considered first-line treatment for IBS-D with bile acid diarrhea [3,183]. Other options include colesevelam and colestipol. Cholestyramine granules are often poorly tolerated due to poor taste and adherence to the teeth [93].

Nonabsorbable Antibiotics

Antibiotics have traditionally been used as adjunctive IBS treatment. However, they are associated with systemic side effects, and there are concerns of promoting antibiotic-resistant microbes [184].

Rifaximin is a synthetic antibiotic derived from rifamycin and has anti-microbial activity against Gram-positive, Gram-negative, aerobic, and anaerobic bacteria. It is not absorbed by the intestinal mucosa, allowing intraluminal activity without systemic circulation and effects [185]. Rifaximin targets the GI tract to reduce gas-producing bacteria and alter the predominant bacterial species; it may also reduce mucosal inflammation and visceral hypersensitivity [93].

Evidence Based Practice Recommendation

The AGA suggests using rifaximin (over no drug treatment) in patients with IBS-D.

https://www.gastrojournal.org/article/S0016-5085(14)01089-0/pdf

Last Accessed: December 11, 2018

Strength of Recommendation/Level of Evidence: Conditional recommendation/moderate-quality evidence

In 2015, rifaximin was approved by the FDA for the treatment of IBS-D in adults [93]. Clinical trials have demonstrated that rifaximin improved IBS-associated symptoms of bloating, flatulence, stool consistency, and abdominal pain. The drug showed a side-effect profile similar to placebo. Some patients experience relief of IBS symptoms after a course of rifaximin, while others require retreatment at the same dosage [184,186]. Improvement in symptoms relative to placebo showed a gradual reduction over time, but significant improvement persisted for 10 weeks after the treatment course [3]. The usual dosage is 550 mg three times per day for 14 days [93].

Clinical experience suggests that many rifaximin responders eventually develop recurrent IBS symptoms. Data from re-treatment patients suggest that second and third courses produce efficacy similar to the initial course. The role of other antibiotics in IBS treatment remains unknown, but antimicrobial resistance with repeated courses of systemically absorbed antibiotics is a concern [5]. Overall, rifaximin appears to be safe and beneficial as a management option for IBS-D, although optimal dosing and treatment duration and potential resistance require further study [184,186].

5-HT3 Receptor Antagonists

Serotonin (5-HT) plays an important physiologic and pathophysiologic role in regulating GI function [187]. As such, 5-HT3 receptor antagonists (5-HT3RAs) can be effective treatment for IBS-D by slowing transit, reducing bowel frequency, normalizing stool consistency, and reducing urgency—a key symptom that impairs quality of life in patients with IBS-D [87].

Randomized controlled trials have found the potent, selective 5-HT3RAs alosetron and cilansetron may be effective in the treatment of IBS-D. However, alosetron was voluntarily withdrawn due to postmarketing reports of ischemic colitis (a potentially serious class-wide adverse event) and complications of constipation, while cilansetron was never marketed [187]. Alosetron was subsequently reintroduced to market and is currently available for women with severe IBS-D refractory to conventional therapy under an FDA Risk Evaluation and Mitigation Strategy program [188]. Alosetron is effective at relieving pain and reducing stool frequency and rectal urgency in women with IBS-D [3].

The 5-HT3RA ramosetron has also been studied as IBS-D therapy but has not received FDA approval. Ramosetron reduces defecation induced by corticotropin-releasing hormone and inhibited colonic nociception in preclinical studies. In randomized controlled trials of patients with IBS-D, ramosetron increased patient rates of global IBS symptom relief. In trials limited to male patients with IBS-D, ramosetron was as effective as mebeverine (an agent approved outside the United States) in improving stool consistency, relieving abdominal pain/discomfort, and improving health-related quality of life. Ramosetron shows a lower incidence of constipation versus other 5-HT3RAs and has not been associated with ischemic colitis [187]. In data stratified by sex, women reported significant relief of IBS symptoms only after two months, while men reported significant relief of IBS symptoms at all time points. Reasons for these differences are unknown [21].

The much less potent 5-HT3RA ondansetron (4 mg/day, range 2–6 mg/day) has also been found highly effective at improving stool consistency, reducing stool frequency, and reducing urgency. In one study, 70% with ondansetron (versus 16% with placebo) reported adequate IBS-D symptom relief. Worth noting is that ondansetron has been used for more than two decades without reports of ischemic colitis and has an excellent safety record; these features are important for IBS therapy selection [87].

Eluxadoline

Eluxadoline was approved in 2015 for IBS-D treatment in adults. This drug has therapeutic activity as a mixed mu-opioid receptor agonist and delta-opioid receptor antagonist, a novel mechanism of action developed to control GI function and decrease GI pain while mitigating the constipating effects of unopposed mu receptor agonist activity [21,87].

FDA approval of eluxadoline was based on two multi-center, multi-national randomized controlled trials with 2,426 patients with IBS-D receiving twice-daily eluxadoline (75 mg or 100 mg) or placebo for 26 weeks. Therapeutic response was defined as concurrent improvement in diarrhea (using the BSFS) and abdominal pain. In both trials, the proportion of patients with reduced abdominal pain and improved stool consistency was significantly higher with eluxadoline than placebo, at both doses. Eluxadoline reduced IBS-D symptoms in men and women, and efficacy was sustained over six months with the 100-mg, twice daily dose. The most common adverse events were nausea (8%), constipation (8%), and abdominal pain (5.0%) [189,190].

A small but definite risk (0.3%) of acute pancreatitis resulted from sphincter of Oddi spasm; all patients who developed this adverse effect had a history of cholecystectomy or significant ethanol consumption. Eluxadoline should be used at the lower dose with careful monitoring in these patients, who should also receive education of the risk [3,87].

Mast Cell Stabilizers

In patients with IBS-D, jejunal mucosal biopsies have shown mast cell activation and hyperplasia, providing the theoretical basis for possible benefits with mast cell stabilizers [191]. Disodium cromoglycate and ketotifen act primarily by stabilizing the plasma membrane of mast cells and have been evaluated in the treatment of IBS-D [93].

In a six-month trial of disodium cromoglycate for IBS-D, jejunal biopsies showed reduced release of tryptase and reduced expression of toll-like receptor 2 and 4, and patients showed clinical improvement of bowel function [192]. In an earlier trial of patients with IBS-D with food intolerance, disodium cromoglycate (250 mg, four times per day) plus exclusion diet was associated with prolonged symptomatic benefit compared with exclusion diet alone [193,194].

Ketotifen is a mast cell stabilizer with antihistamine properties that showed substantial improvement in patients with IBS despite no effect on mast cell parameters [195]. Further research suggests the effects mediated by histamine-blocking properties, and ketotifen may also be used in the treatment of abdominal pain-predominant IBS.

Muscarinic Type 3 Receptor Antagonists

Muscarinic type 3 (M3) receptor antagonists have beneficial effects in chronic diarrhea that include delayed small bowel and colonic transit, reduced rectal sensitivity, and reduced enterocyte secretion [93]. Preliminary evidence suggests greatest benefit with otilonium in IBS-D, with benefits shown in increased sensory thresholds to colonic volume and pressure, and reduction in abdominal pain [93,196]. Otilonium is investigational in the United States.

Glutamine

Patients with IBS-D have increased gut permeability, and symptomatic patients with IBS have decreased intestinal glutamine synthetase levels. In a preliminary report of a placebo-controlled trial of 10 g glutamine three times per day in 61 patients, the glutamine arm was associated with improved abdominal pain, bloating, and diarrhea and restored intestinal permeability [93,197].

Summary

During clinical development, rifaximin and eluxadoline demonstrated significant improvement in IBS-D endpoints versus placebo. In the absence of comparative randomized controlled trials, direct comparisons of alosetron, rifaximin, and eluxadoline efficacy cannot be made, but general efficacy estimates suggest similar and responses using outcome measures of adequate relief and combined improvements in abdominal pain/stool form. Clinical use of these agents is suggested to follow a sequential scheme that considers patient symptoms and severity, prior medical history, mode of action, cost, availability, managed care coverage, and adverse event profiles [198].

CONSTIPATION-PREDOMINANT IBS

Constipation is one of the most common functional bowel disorder symptoms encountered in primary care and specialty practices. IBS-C and other disorders of chronic constipation are associated with significant medical costs and a negative impact on quality of life [199].

Laxatives

Osmotic laxatives contain nonabsorbable ions or molecules that retain water in the bowel lumen. Polyethylene glycol (PEG), lactulose, and magnesium salts are most commonly used. Osmotic laxatives are generally useful to treat constipation but can promote or worsen abdominal pain and distension in IBS and are not recommended [44].

Stimulant laxatives promote water and electrolyte secretion in the colon or induce colonic peristalsis. They include diphenylmethanes (phenolphthalein, bisacodyl, sodium picosulfate) and anthraquinones (Senna, bearberry, Aloe vera). While useful for constipation, they can worsen abdominal pain and distension in patients with IBS [44]. In patients with IBS-C, a randomized controlled trial of PEG vs. placebo found stool frequency, stool consistency, and straining were improved, but abdominal pain and bloating were unimproved during the four-week study [142].

Secretagogues

Secretagogues act through different pharmacologic mechanisms to stimulate chloride release into the intestinal lumen, which stimulates intestinal fluid secretion to counteract constipation symptoms in IBS-C [200]. The most commonly used agents are lubiprostone and linaclotide.

Lubiprostone

Lubiprostone is a prostaglandin-derived fatty acid that activates intraluminal chloride channels and chloride ion secretion. This leads to a passive influx of water and sodium, which increases intestinal peristalsis and colonic laxation and decreases intestinal stool transit time. Lubiprostone does not affect pain thresholds during rectal distension [5,87].

In patients with IBS-C, lubiprostone has proven effective in reducing constipation symptoms, but reduction of abdominal pain is much more modest (7% greater than placebo) and generally develops after one month of therapy. Side effects mostly involve mild-to-moderate nausea and diarrhea, and lubiprostone should be taken with food to limit dose-dependent nausea [3,5].

Lubiprostone is approved for the treatment of chronic constipation and opioid-induced constipation for men and women at 24 mcg twice daily, and for IBS-C in women at 8 mcg twice daily. No dosage adjustment is required in patients with impaired renal function [44]. Additional research may expand its clinical use [87,199].

Linaclotide

Linaclotide binds and activates guanylate cyclase C (GC-C) receptors expressed locally on the luminal surface of intestinal epithelium. GC-C receptor activation increases cyclic guanosine monophosphate concentrations, which activates the cystic fibrosis transmembrane conductance regulator to stimulate secretion of chloride and bicarbonate into the intestinal lumen. This leads to increased intestinal fluid and accelerated stool transit [87,189].

Evidence Based Practice Recommendation

The AGA recommends using linaclotide (over no drug treatment) in patients with IBS-C.

https://www.gastrojournal.org/article/S0016-5085(14)01089-0/pdf

Last Accessed: December 11, 2018

Strength of Recommendation/Level of Evidence: Strong recommendation/high-quality evidence

In patients with IBS-C, randomized controlled trials have shown highly similar results across studies. Improvements in constipation, abdominal pain, discomfort or bloating, and stool consistency were 15% to 30% greater compared with placebo. These benefits persisted for 26 weeks. Diarrhea, the most commonly reported adverse event, occurred in 19.7% of participants and led to drug discontinuation in 4.5%. Efficacy and safety were similar in elderly and middle-aged adults [44,87,186]. Patients should take linaclotide (290 mcg) 30 to 60 minutes before breakfast to minimize the chance of diarrhea [5].

While lubiprostone and linaclotide led to improvements in stool frequency, constipation severity, and abdominal pain/discomfort in IBS-C, the relatively low response rates, higher costs, and adverse effects generally limit these agents to second-line therapy in IBS-C [201].

5-HT4 Receptor Agonists

5-HT4 receptors are expressed on enteric neurons and in cardiac tissue. 5-HT4 receptor agonists (5-HT4RAs) facilitate fast excitatory cholinergic synaptic transmission between enteric neurons, which stimulates GI motility and secretion [93]. Prucalopride, mosapride, and three other 5-HT4RAs (velusetrag, naronapride, and YKP10811) are in development for IBS-C treatment. These drugs have greater cardiovascular safety compared with older 5-HT4RAs due to higher specificity at intestinal 5-HT4 receptors and low intrinsic activity in cardiac muscle. These agents are expected to show efficacy in IBS-C, but this awaits confirmation by large randomized controlled trials [93].

ABDOMINAL PAIN-PREDOMINANT IBS

Antispasmodics (Spasmolytics)

Abnormal contraction of smooth muscle within the colon and the GI tract underlies pain and other IBS symptoms in some patients, providing the rationale for using agents that relax smooth muscle [21]. Spasmolytics fall into three groups based on mechanism of action [44,202]:

- Calcium channel blockers (e.g., alverine, otilonium, pinaverium bromide)

- Direct smooth muscle relaxants (e.g., mebeverine)

- Antimuscarinic/anticholinergic agents (e.g., hyoscine, cimetropium bromide, dicyclomine hydrochloride)

A review of 23 randomized controlled trials using various antispasmodics found that these agents improved IBS symptoms to a greater extent than placebo, but efficacy of individual antispasmodics varied. Only otilonium (investigational), hyoscine bromide, cimetropium bromide, pinaverium bromide, and dicyclomine showed significant improvements beyond placebo [196,203].

Antispasmodic drugs with anticholinergic or calcium-channel blocking mechanisms are used for relieving diarrheal symptoms, abdominal pain and distension, and spasms in all IBS subtypes. However, anticholinergic agents may be better tolerated in patients with IBS-D [5,183]. Otilonium and hyoscine have the best evidence of efficacy, and otilonium bromide is the most effective agent in preventing IBS symptom recurrence. Some patients with IBS have an exaggerated gastrocolic reflex that is in part cholinergic-mediated, and spasmolytics may be best suited for postprandial abdominal cramping and loose stools in these patients [5].

The most commonly reported adverse effects associated with spasmolytics include dry mouth, dizziness, and blurred vision; serious adverse events are rare. Spasmolytics with greater anticholinergic activity are more likely to induce blurred vision, urinary retention, constipation, and dry mouth. Anticholinergics should be avoided in the elderly and in patients with a history of acute myocardial infarction or hypertension. Use during pregnancy and breastfeeding is not recommended [5,44].

Peppermint Oil

Peppermint oil possesses a calcium-channel blocking mechanism and is classified as an antispasmodic [5]. The spasmolytic properties of peppermint oil may modulate pain by attenuating visceral hypersensitivity [44]. Two systematic reviews found peppermint oil superior to placebo in the management of IBS pain [203,204]. A 2014 review evaluated five trials enrolling a total of 482 patients and showed a statistically significant positive effect of peppermint oil over placebo [203].

Although peppermint oil is typically well tolerated, with no significant side effects reported with standard doses (250–750 mg two to three times/day), some patients may experience reflux symptoms, and allergic reactions, heartburn, and headache have been described [5]. Peppermint oil is available over the counter, and enteric-coated capsules are preferred [44].

Linaclotide

Linaclotide (290 mcg daily) demonstrated improvement in abdominal pain in two large, phase 3 studies in IBS-C, with one trial extending treatment out to 26 weeks [93].

Antidepressants

As discussed, antidepressants are commonly used to treat pain symptoms associated with chronic functional GI disorders, including IBS. In a Cochrane review, the TCAs desipramine (25–100 mg at bedtime) and amitriptyline (10–50 mg at bedtime) demonstrated some global improvements of abdominal pain [93].

Pregabalin

Pregabalin, an a2d ligand that inhibits release of a number of excitatory neurotransmitters, may alleviate visceral pain in patients with IBS [106,205]. Pregabalin increases distension sensory thresholds to normal levels in patients with IBS with rectal hypersensitivity. Studies are in progress to evaluate efficacy in centrally mediated abdominal pain syndrome (formerly termed functional abdominal pain syndrome) [93].

Histamine H1 Receptor Antagonists

Ketotifen

Ketotifen is a mast cell stabilizer with antihistamine properties. An eight-week randomized controlled trial showed evidence of improved pain, bloating, flatulence, diarrhea, quality of life, sleep, and sexual functioning in patients with IBS-D, despite lack of reduction in mast cell mediators [195]. The underlying mechanism of action was identified as histamine H1 receptor antagonism, which helped prompt further study of H1 receptor antagonists in patients with IBS [206].

Ebastine

Evidence suggests disordered GI motility, psychosocial distress, and visceral hypersensitivity converge on common pathways, including transient receptor potential cation channel subfamily V (TRPV). TRPV expressed on sensory neurons throughout the gut produces pain when activated by inflammatory mediators [207].

Researchers examined colorectal biopsies of patients with IBS and found greater TRPV-4 metabolite levels, which correlated with abdominal pain and bloating severity, and significantly greater nervous tissue and nerve growth mediators [207]. From these discoveries and results of ketotifen in the treatment of IBS, the histamine H1 receptor antagonist ebastine was studied for possible effects on visceral pain and hypersensitivity in 56 patients with IBS, randomized to ebastine (20 mg/day) or placebo. Over 12 weeks, a significant reduction of abdominal pain was found with ebastine compared to placebo and to baseline. Significantly more patients treated with ebastine (vs. placebo) had at least considerable relief of symptoms (46% vs. 12%) and lower mean abdominal pain scores (0–100 scale: ebastine 38, placebo 62). Quality of life was significantly improved on all IBS-QOL subscales in the ebastine group compared with baseline and placebo [206,207].

Hypersensitive and normosensitive subgroups did not differ in ebastine response. Visceral pain response, as measured by rectal distension, had no association with clinical response, showing barostat findings as an invalid outcome measure. Most importantly, this study suggests H1-receptor blockade may represent an effective treatment for IBS abdominal pain regardless of subtype. This is encouraging given the lack of targeted treatments for visceral hypersensitivity and abdominal pain in IBS [206,207].

Fecal Microbial Transplantation

Fecal microbiota transplants have been used in the last decade for severe cases of Clostridium difficile infection, with success rates greater than 90%. Fecal microbiota transplants may be a therapeutic option for severe refractory IBS or inflammatory bowel disease, but current FDA regulations limit use to the treatment of severe C. difficile infection [208].

Concerns over introducing pathologic organisms must be addressed before fecal microbiota transplant is approved in clinical management of inflammatory bowel disease. An example is the case of a female patient with C. difficile infection who received fecal microbiota transplant from an obese person and subsequently became obese herself [208].

SPECIALIST REFERRAL

Specialist referral from primary care should be considered for patients with IBS who do not respond or are intolerant to management with dietary and lifestyle changes, common laxatives, spasmolytics, or antidepressants [44]. Referral is also indicated if defecation dysfunction is suspected, there is unexplained worsening in clinical status, or there is an unambiguous need for a second expert opinion.

6. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient education is such an important aspect of the care of patients with IBS, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient or caregiver understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. (In many cases, the terms "interpreting" and "translating" are used interchangeably, but interpreting is specifically associated with oral communication while translating refers to written text.) Frequently, this may be easier said than done, as there may be institutional and/or patient barriers.

Depending upon the patient's language, an interpreter may be difficult to locate. Or, an organization may not have the funds to bring in an interpreter. Also, bringing in an interpreter creates a triangular relationship with a host of communication dynamics that must be negotiated. Many view interpreters merely as neutral individuals who communicate information back and forth. However, another perspective is that the interpreter is an active agent, negotiating between two cultures and assisting in promoting culturally competent communication and practice. In this more active role, the interpreter's behavior is also influenced by a host of cultural variables such as gender, class, religion, educational differences, and power/authority perceptions of the patient. Consequently, an intricate, triangular relationship develops between all three parties. Another factor affecting the communication process is the fact that many interpreters are not adequately trained in the art of interpretation in mental health and general health settings, as there are many technical and unfamiliar terms. An ideal interpreter goes beyond being merely proficient in the needed language/dialect. Interpreters who are professionally trained have covered aspects of ethics, impartiality, accuracy, and completeness. They are also well-versed in interpreting both the overt and latent content of information without changing any meanings and without interjecting their own biases and opinions. Furthermore, knowledge about cross-cultural communication and all the subtle nuances of the dynamics of communicating in a mental health or general health setting is vital.

On the patients' side, they may be wary about utilizing interpreters for a host of reasons. They may find it difficult to express themselves through an interpreter. If an interpreter is from the same community as the patient, the patient may have concerns about sharing private information with an individual who is known in the community and the extent to which the information disclosed would remain confidential. In some cases, raising the issue of obtaining an interpreter causes the patient to feel insulted that their language proficiency has been questioned. Finally, if an interpreter is from a conflicting ethnic group, the patient may refuse having interpreter services. The ideal situation is to have a well-trained interpreter who is familiar with health and mental health concepts.

If an interpreter is required, the practitioner must acknowledge that an interpreter is more than a body serving as a vehicle to transmit information verbatim from one party to another. Instead, the interpreter should be regarded as part of a collaborative team, bringing to the table a specific set of skills and expertise. Several important guidelines should be adhered to in order to foster a beneficial working relationship and a positive atmosphere.

A briefing time between the practitioner and interpreter held prior to the meeting with the patient is crucial. The interpreter should understand the goal of the session, issues that will be discussed, specific terminology that may be used to allow for advance preparation, preferred translation formats, and sensitive topics that might arise. It is important for the patient, interpreter, and practitioner to be seated in such a way that the practitioner can see both the interpreter and patient. Some experts recommend that the interpreter sit next to the patient, both parties facing the practitioner.

The practitioner should always address the patient directly. For example, the practitioner should query the patient, "How do you feel?" versus asking the interpreter, "How does she feel?" The practitioner should also always refer to the patient as "Mr./Mrs. D" rather than "he" or "she." This avoids objectifying the patient.

At the start of the session, the practitioner should clearly identify his/her role and the interpreter's role. This will prevent the patient from developing a primary relationship or alliance with the interpreter, turning to the interpreter as the one who sets the intervention. The practitioner should also be attuned to the age, gender, class, and/or ethnic differences between the patient and the interpreter. For example, if the patient is an older Asian male immigrant and the interpreter is a young Asian woman, the practitioner should be sensitive to whether the patient is uncomfortable given the fact he may be more accustomed to patriarchal authority structures. At the conclusion of the session, it is advisable to have a debriefing time between the practitioner and the interpreter to review the session.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. In any case in which information regarding diagnostic procedures, treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered.

7. CONCLUSION

IBS is common in the general population and has a significant medical and socioeconomic impact. Standard management of IBS has involved psychologic support, dietary measures, and pharmacotherapy directed at symptoms. IBS has long been considered a notoriously difficult condition to manage, because the pathophysiology has been poorly understood. Advances in the understanding of the disease's etiology and pathophysiology are informing the use of novel treatment approaches. This course has striven to provide clinicians with the information necessary to appropriately diagnose and treat IBS and improve patients' quality of life.

8. RESOURCES

American College of Gastroenterology

http://gi.org

American Gastroenterological Association

https://www.gastro.org

International Foundation for Functional Gastrointestinal Disorders

http://www.iffgd.org

http://www.aboutibs.org

National Institute of Diabetes and Digestive and Kidney Diseases

https://www.niddk.nih.gov/health-information/health-topics/digestive-diseases/irritable-bowel-syndrome

North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition

http://www.naspghan.org

The Rome Foundation

http://theromefoundation.org

Society of Gastroenterology Nurses and Associates

http://www.sgna.org

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Evidence-Based Practice Recommendations Citations

1. National Collaborating Centre for Nursing and Supportive Care. Irritable Bowel Syndrome in Adults: Diagnosis and Management of Irritable Bowel Syndrome in Primary Care. London: National Institute for Health and Care Excellence; 2015. Available at https://www.nice.org.uk/guidance/cg61. Last accessed December 11, 2018.

2. Weinberg DS, Smalley W, Heidelbaugh JJ, Sultan S, American Gastroenterological Association. American Gastroenterological Association Institute guideline on the pharmacological management of irritable bowel syndrome. Gastroenterology. 2014;147(5):1146-1148. Available at https://www.gastrojournal.org/article/S0016-5085(14)01089-0/pdf. Last accessed December 11, 2018.