GKYAPRN25 • APRNs 2025 (Includes 5 Pharmacology Hours)

Table of Contents

GKYAPRN25 • APRNs 2025 (Includes 5 Pharmacology Hours)

How to Receive Credit

NetCE 1 Hour Course #39060 • Common Concerns for Patients with Dementia

39060 • Common Concerns for Patients with Dementia

1. INTRODUCTION

2. ELDER ABUSE

3. SUICIDE

4. ALCOHOL ABUSE

5. FALLS

6. INTIMACY

7. WANDERING

8. AGGRESSION

9. PARANOIA

10. SPIRITUALITY

11. DRIVING

12. INFORMED CONSENT

13. PRESCRIBED MEDICATIONS

14. SKILLED CARE FACILITIES AND ASSISTED LIVING

15. LONGEVITY CONCERNS

16. CAREGIVER BURNOUT

17. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #94820 • Chronic Cough in Adults

94820 • Chronic Cough in Adults

1. INTRODUCTION

2. BACKGROUND

3. COUGH SEVERITY MEASURES

4. EPIDEMIOLOGY

5. PATIENT IMPACT OF CHRONIC COUGH

6. NATURAL HISTORY AND DISEASE COURSE

7. PATHOPHYSIOLOGY OF CHRONIC COUGH

8. INITIAL EVALUATION OF CHRONIC COUGH

9. IDENTIFICATION AND MANAGEMENT OF UNDERLYING ETIOLOGIES

10. TREATMENT

11. TREATMENT OF REFRACTORY CHRONIC COUGH

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 4 Hour Course #97510 • Intercultural Competence and Patient-Centered Care

97510 • Intercultural Competence and Patient-Centered Care

1. INTRODUCTION

2. DEFINITIONS

3. BIAS: IMPLICIT AND EXPLICIT

4. ROLE OF INTERPROFESSIONAL COLLABORATION AND PRACTICE

5. SOCIAL DETERMINANTS OF HEALTH

6. BARRIERS TO PROVIDING CARE

7. BEST PRACTICES FOR CULTURALLY RESPONSIVE CARE

8. PROMOTING CULTURALLY SENSITIVE COMMUNICATION

9. CULTURALLY SENSITIVE ASSESSMENT GUIDELINES

10. CREATING A WELCOMING AND SAFE ENVIRONMENT

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

GKYAPRN25 • APRNs 2025 (Includes 5 Pharmacology Hours)

Allan G. Hedberg, PhD

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

GKYAPRN25 • APRNs 2025 (Includes 5 Pharmacology Hours)

Expiration Date: 07/31/2026

How to Receive Credit

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

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

39060 • Common Concerns for Patients with Dementia

Allan G. Hedberg, PhD

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

The aging process can become a very challenging time in a person's life. It is often difficult for the aging person to understand and accept the changes that are taking place, to maintain a positive level of functioning for as long as possible, and to compensate for ongoing losses. This course will review the most common risks and problems for patients with dementia, with a focus on strategies to prevent or address them as they arise.

Table of Contents

39060 • Common Concerns for Patients with Dementia

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. ELDER ABUSE

3. SUICIDE

4. ALCOHOL ABUSE

5. FALLS

6. INTIMACY

7. WANDERING

8. AGGRESSION

9. PARANOIA

10. SPIRITUALITY

11. DRIVING

12. INFORMED CONSENT

13. PRESCRIBED MEDICATIONS

14. SKILLED CARE FACILITIES AND ASSISTED LIVING

15. LONGEVITY CONCERNS

16. CAREGIVER BURNOUT

17. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

39060 • Common Concerns for Patients with Dementia

Education Category. Geriatrics

Release Date. 08/01/2024

Expiration Date. 07/31/2027

Course Overview

The aging process can become a very challenging time in a person's life. It is often difficult for the aging person to understand and accept the changes that are taking place, to maintain a positive level of functioning for as long as possible, and to compensate for ongoing losses. This course will review the most common risks and problems for patients with dementia, with a focus on strategies to prevent or address them as they arise.

Audience

This course is designed for nurses in a variety of practice settings who work with older patients.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

NetCE designates this continuing education activity for 1 ANCC contact hour(s). NetCE designates this continuing education activity for 1.2 hours for Alabama nurses. NetCE is authorized by IACET to offer 0.1 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This course meets the Illinois requirement for 1 hour of education on Alzheimer disease and other dementias.

Course Objective

The purpose of this course is to provide nurses with an overview of the physical and psychosocial problems encountered by patients with dementia, so they might intervene to protect their well-being.

Learning Objectives

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

1. Discuss the risks of elder abuse and suicide among patients with dementia.

2. Evaluate the potential risks of alcohol use and misuse among older adults, particularly those with dementia.

3. Describe additional risks that patients with dementia experience and steps nurses can take to monitor and facilitate the safety and welfare of these patients.

Faculty

Allan G. Hedberg, PhD, received his Master's in psychology from Northern Illinois University and his PhD in clinical psychology from Queen's University in Ontario, Canada. He has practiced clinical psychology in mental health centers, hospitals, and rehabilitation units as well as in private practice since 1969. More recently, he has maintained an active consultation service to patients and staff of nursing homes and assisted living facilities in the Central Valley of California. Over this time, Dr. Hedberg has consulted with staff, trained staff, and assisted in the establishment of appropriate programs for elderly patients with special needs, such as Alzheimer's disease.

Faculty Disclosure

Contributing faculty, Allan G. Hedberg, PhD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Mary Franks, MSN, APRN, FNP-C

Division Planner Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Dementia is a progressive and profound disruption in brain function and intellectual capacity. The primary signs include problems with memory, language, spatial-temporal reasoning, judgment, emotionality, thought disorder, and personality. Dementia is a subtle progressive loss of cognitive functioning, with memory loss as its hallmark impairment, particularly loss of short-term memory. The ability to concentrate, make judgments, problem solve, and engage in abstract thought processes is also impaired. Personality and mood changes distinct from previous experiences are likely to develop, such as depression, apathy, elation, and anger. Impulse control becomes a major impairment with associated difficulties in social and physical relationships. Finally, grandiose and persecutory delusions are fairly common, especially in the more advanced stages of dementia [1]. It is possible for a young person to have dementia, but this is usually a result of a neurologic traumatic event or major illness with neurologic corollaries.

Dementia is a physical illness as well. It progressively shuts down the body as the brain is attacked. The first signs of dementia are generally related to reduced physical agility and strength, not just cognitive skills. Dementia can continue for years, but in the advanced stages, life expectancy is similar to that seen with advanced terminal cancer [2]. Patients with various severities of dementia are at risk for a variety of health and mental health conditions. Nurses are in a position to recognize patients at risk for these conditions and to intervene to protect their safety and welfare.

2. ELDER ABUSE

Elder abuse is a real threat for patients with dementia [3]. They are at risk for financial, physical, emotional, and sexual abuse, particularly from caretakers, family members, and even healthcare providers. Any suspicion of abuse should be reported to the adult social services department of the state and county in which the patient is living. Abuse can be intended (e.g., physical abuse) or unintended (e.g., neglect). Perpetrators of elder abuse may be motivated by many different factors, from overwhelm and burnout to sadism [3]. Some perpetrators are financially dependent upon the victim, leading to an imbalance in the relationship and dangerous expectations. Financial abuse is common, for example, by a child or grandchild who has been dependent on the elder for years and is now seeing their "support funds" being terminated and bank accounts closed. Health and mental health providers should be vigilant for any signs of abuse or neglect.

Signs of financial abuse or neglect should be closely monitored. This can be done by monitoring the interaction of family members/carers with patients, particularly behaviors involving finances and/or signing documents such as wills, trusts, or bank accounts. If necessary, an ombudsman or the patient's attorney should be consulted. If the patient is in a care facility, the facility's attorney may be a resource.

3. SUICIDE

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends screening for depression in older adults.

https://jamanetwork.com/journals/jama/fullarticle/2806144

Last Accessed: July 12, 2024

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

Older Americans are at an increased risk for suicide. Individuals older than 65 years of age comprise 16.8% of the population but represent 20.0% of all suicide deaths. The rate of suicides for older adults in 2021 was 17.3 per 100,000, with one suicide in this population every 54.5 minutes [4]. Persons older than 85 years of age, especially white men, have the highest rate. Although older adults attempt suicide less frequently than other age groups, they have a higher completion rate [4]. Common risk factors for suicide in older adults include [4]:

- Recent loss of a loved one

- Physical illness, uncontrollable pain, or fear of prolonged illness

- Perceived poor health

- Social isolation and loneliness

- Major changes in social roles (e.g., retirement)

A dementia diagnosis encompasses several of these risk factors, and these patients should be monitored closely and directed to appropriate professional help. The loss of health, purpose, or meaning must be addressed at all stages of aging, but even more so in the later years of life.

Suicide among older adult patients with dementia may be subtle or camouflaged, manifesting as refusal to eat and/or drink water and fluids, rejection of prescribed medication, or intentional isolation from any social contact. These more passive suicide attempts are especially common among older persons in nursing homes or other care settings who have no other means.

4. ALCOHOL ABUSE

Alcohol abuse in the older adult population is generally a hidden problem. Many older adults do not disclose alcohol abuse because they are ashamed. This is compounded by healthcare professionals' reluctance to ask older adults about their alcohol use, mostly due to the prevalent images of young people misusing substances [5]. Older adults are more likely to hide their alcohol use and less likely to seek professional help, and their families, particularly adult children, are often in denial or are ashamed of the problem [6]. Additionally, the symptoms of alcohol use disorder can mimic or resemble conditions associated with aging, including dementia, thereby masking an underlying drinking or substance disorder [5,6]. Finally, some older adults may be isolated, with minimal social contacts or networks to intervene in cases in which alcohol or substance use has become a problem.

According to the National Council on Alcoholism and Drug Dependence, older adults exhibiting symptoms of alcoholism comprised 6% to 11% hospital admissions, 20% of admissions to psychiatric services, and 14% of emergency room admissions [7]. The prevalence of alcoholism in the older population is estimated to be 10% to 18%. It is the second most frequent reason for admitting older adults to inpatient psychiatric facilities [8]. Less than 2% of all admissions for alcohol treatment are people older than 55 years of age [7]. Among nursing home residents, it is estimated that as many as one-half have problems related to alcohol [7,8].

Late-onset alcoholism is common in older adults, and several risk factors may contribute to the development of alcohol use disorders in older age. Some may use alcohol to self-medicate physical symptoms, such as difficulty sleeping or chronic pain. Mourning a loved one, loss of social supports, and loneliness can also instigate alcoholism later in life [6].

One study found that theDiagnostic and Statistical Manual of Mental Disorders, Fifth Edition(DSM-5-TR) criteria for alcohol use disorder might be difficult to apply to older adults [9]. For example, age-related physiologic changes may change an individual's response to alcohol, increasing his or her sensitivity and lowering their levels of tolerance. These persons would not meet the DSM-5-TR criteria for alcohol use disorder, as they would require smaller amounts of alcohol to become intoxicated. In addition, the DSM-5-TR criterion of giving up activities or responsibilities as a result of substance use may not be appropriate for older adults because they may engage in fewer regular activities due to diminished vocational or social responsibilities [10].

After a diagnostic assessment, treatment of alcohol use disorder in older adults may include close monitoring, attendance at 12-step programs, group therapy, increased socialization, and/or medication. For patients with dementia, the urge to drink will likely be lost eventually, but it is important to prevent overconsumption, as it may exacerbate symptoms.

5. FALLS

Falls are common among older adults and can cause serious injury and even death. Decreased mobility, medication side effects, and confusion/disorientation can all predispose the patient with dementia to falls. Patients and their families should be counseled regarding the importance of fall prevention strategies. Older persons' medication profiles must be reviewed relative to their potential contribution to falling. The home environment should also be modified to decrease the risk of falls, keeping pathways cleared and well lit, removing unstable furniture, and eliminating throw rugs and extension cords. Referral to physical therapy for balance training and strengthening may be considered. In addition, occupational therapy is appropriate if modifications in the home are necessary.

6. INTIMACY

It is important for older people to feel loved and cared for. Romance, connection, physical touch, and sex remain important to people as they age and should be considered part of an individual's overall health and well-being. Individuals may be encouraged to explore new ways of spending time with other people and showing affection, including hand-holding, hugging, massage, and dancing. Some may benefit from education on positive aspects of interpersonal relationships. In some patients, hypersexuality may develop. This can be a manifestation of dementia (e.g., frontotemporal dementia) or the effect of medications.

7. WANDERING

Wandering behavior is relatively common among persons with dementia, especially at sundown [11]. It can be unintentionally dangerous, and it is important for all persons with dementia to carry some for of identification (e.g., medical bracelet) at all times. It can also be helpful to alert neighbors and local law enforcement of the possibility of wandering. Door should be kept locked whenever possible, with an alarm and/or a two-step lock including a deadbolt recommended.

8. AGGRESSION

Individuals with dementia may become confused, frustrated, and easily agitated as they become unable to perform formerly routine tasks. When agitation is frequent or excessive, pharmacotherapy may be necessary. It is also important to take steps to protect the individual from harming him/herself and others. This may consist of creating a calm environment (e.g., quiet, reduced clutter) and providing continuing care, support, and reassurance.

9. PARANOIA

Paranoia is a form of delusion in which an individual is fearful, jealous and/or suspicious of others. When a person with dementia displays paranoia, it is best not to directly react. Instead, the individual should be reassured that s/he is safe and protected. It can be helpful to redirect the individual to a different task or activity to interrupt paranoid thinking patterns.

10. SPIRITUALITY

All individuals, including those with dementia, have spiritual needs, and spiritual health is part of holistic care. As much as possible, individuals should remain part of their faith community. Spirituality and religion should be incorporated into discussions and daily activities as much as is desired. In some cases, spiritual music may be comforting. Members from the individual's faith community may be encouraged to remain connected.

11. DRIVING

The risk of driving-related accidents is increased among the older population, and impaired mental status due to cognitive impairment and/or the effects of certain medications can increase risk further. Restricting an individual's driving causes a considerable loss of independence and can be a highly sensitive issue, and the decision should be collaborative, if possible. A dementia diagnosis alone is not considered grounds to revoke driving privileges. Other factors must be present, including cognitive decline and comorbidities [12]. Many states require physicians to report impaired drivers, especially if there is a history of a closed head injury. However, laws vary regarding reporting by other service providers. Professionals are encouraged to study their own state's laws. There are driving schools and classes in many communities specifically designed to assist older adults in maintaining their driving skills and license, which may be an option for some individuals.

It is also important to assess if alcohol or drugs are playing a role in an older driver's abilities. Efforts to intercede to stop drinking/substance abuse or to keep an impaired patient from driving may be necessary.

12. INFORMED CONSENT

Informed consent requires awareness of relevant information and the demonstrated competency to understand the nature of an issue under consideration and its implications and consequences. Agreement from patients who lack the capacity to give consent actually results in no consent at all. In such cases, the patient requires a healthcare surrogate to be designated through the process of a conservatorship, a will and an advance directive for health care, and/or the appointment of a power of attorney. These surrogates are sometimes referred to as the responsible party (RP). Failing a provision for consent to be granted by some preauthorized RP, healthcare and/or financial decisions require court intervention.

If a patient has a preapproved healthcare surrogate, as outlined by law or an advance directive, all treating professionals and facilities should have a copy of the document on file. This is an area of frequent abuse and boundary violations, even by well-meaning family members. The provider of service must be careful to assure that informed consent or permission of the RP has been granted before proceeding, even when the intended service seems necessary and/or obviously desired. Consent to proceed with any treatment or financial dealing must be with the consent of the RP, and all communication regarding the patient is with and through the RP.

13. PRESCRIBED MEDICATIONS

Medication management and polypharmacy are major concerns for older adults. An estimated 30% of individuals older than 65 years of age take five or more prescription medications [13]. This number does not take into account over-the-counter medications, vitamins, minerals, and dietary supplements. Taking multiple medications and supplements significantly increases the risk of interaction with foods, other medications, and alcohol.

Common medication problems include incorrect dosage, erratic drug use, misuse of over-the-counter medications, drug interactions, mixing medications and alcohol, use of drugs at the wrong time of the day, using medications prescribed for another person, using two or more medications with synergistic effects, and using several medications with profound side effects or that might be contraindicated due to comorbid conditions.

Aging itself can contribute to unforeseen medication problems. Older individuals tend to absorb, metabolize, and excrete medications at a slower rate. Many older people also have major complicating medical problems, such as Parkinson disease, cardiovascular difficulties, neurologic disorders, infections, and vertigo, that may be impacted by various medications. In general, older persons are at a greater risk for side effects. If present, cognitive deficits may lead to greater confusion regarding timed doses and medication use.

14. SKILLED CARE FACILITIES AND ASSISTED LIVING

The move to a higher level of care is not an easy decision for any impaired person, family members, or healthcare providers. Each patient has different circumstances that must be taken into account. The decision usually involves consideration of a variety of psychologic, medical, financial, practical, and family issues. Often, it is based on the inability of the family to fully provide the needed level of care. If the family has been the sole care provider, burnout and exhaustion may be factors. It may even depend on the ability to adapt the home to accommodate the new needs of the patient. When selecting a facility, the focus should be on location and the competency and personability of the staff.

Generally, a patient will need to be hospitalized for three days to qualify for referral to a skilled nursing facility under the Medicare guidelines. Admission to an assisted living program, on the other hand, is not covered by Medicare or most health insurance plans. Long-term care insurance may be a financial help to offset medical costs and the costs of alternative nursing care, including home care.

Selecting a skilled nursing or assisted living facility is difficult for many families. The following may be offered to families to assist in making the best possible decision:

- Is the facility within a reasonable distance to supportive family members?

- Is the facility able to provide the appropriate level of care and needed services anticipated?

- Is the facility stable, with a low staff turnover rate? Has the facility changed ownership several times?

- Is the facility nonprofit for for-profit?

- Does the facility have a positive record with the state (e.g., facility infractions, wrongful staff actions)?

- Is the food reasonably prepared and served in a manner consistent with the patient's culture and eating history?

15. LONGEVITY CONCERNS

The number of individuals 85 years of age and older is growing steadily in the United States. In 2020, there were 6.7 million individuals in this age-group; this number is expected to grow to 19 million by 2060 [14]. Many people who live past 85 years of age fear they will outlive their resources. Providing education about healthcare savings programs throughout life may be helpful, even into the aging years. Preparation for long-term assisted living is essential, such as having long-term healthcare insurance, having a healthcare reserve fund, and being compliant with healthcare treatment plans (if possible). Regular exercise, rest, social support, and a good attitude are among the essential factors needed for healthy longevity [15].

16. CAREGIVER BURNOUT

Care providers tend to experience burnout within a few years of constant care of a loved one. In general, male caregivers experience burnout sooner than women. Care providers should try to take respite breaks at least one day per week. Taking mini-vacations can be helpful. Respite care coverage for even a few hours a day can also be helpful. The underlying lesson is for caretakers to take care of themselves physically and mentally, so they are able to continue to provide care for the loved one.

17. CONCLUSION

The aging process can become a very challenging time in a person's life. It is often difficult for the aging person to understand and accept the changes that are taking place, to maintain a positive level of functioning for as long as possible, and to compensate for ongoing losses. It is vital for nurses to support these patients to best protect their health, safety, and well-being.

Works Cited

1. Mayo Clinic. Dementia. Available at https://www.mayoclinic.org/diseases-conditions/dementia/symptoms-causes/syc-20352013. Last accessed July 12, 2024.

2. Mitchell SL, Teno JM, Kiely DK, et al. The clinical course of advanced dementia. N Engl J Med. 2009;361(16):1529-1538.

3. Ramsey-Klawsnik H. Elder-abuse offenders. Generations. 2000;24(2):17-22.

4. Suicide Awareness Voices of Education. USA Suicide: 2021 Final Data. Available at https://save.org/wp-content/uploads/2023/01/2021datapgsv1.pdf. Last accessed July 12, 2024.

5. Deblinger L. Alcohol problems in the elderly. Patient Care. 2000;3(10):68.

6. National Council on Alcoholism and Drug Dependence, Inc. Seniors and Alcohol. Available https://www.ncadd.org/about-addiction/seniors. Last accessed July 12, 2024.

7. National Council on Alcoholism and Drug Dependence, Inc. An Invisible Epidemic: Alcoholism and Drug Dependence Among Older Adults. Available at https://www.naadac.org/assets/2416/effective_treatment_of_addiction_and_trauma_for_older_adults_webinar_slides.pdf. Last accessed July 12, 2024.

8. Aging.com. Alcohol Abuse Amongst the Elderly: A Complete Guide. Available at https://aging.com/alcohol-abuse-amongst-the-elderly-a-complete-guide. Last accessed July 12, 2024.

9. Mejldal A, Andersen K, Bilberg R, et al. The Alcohol Dependence Scale and DSM-5 alcohol use disorder: severity ratings correspond insufficiently in older patients. Int J Methods Psychiatr Res. 2020;29:e1811.

10. National Institute on Alcohol Abuse and Alcoholism. Understanding Alcohol Use Disorder. Available at https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/understanding-alcohol-use-disorder. Last accessed July 12, 2024.

11. National Institute on Aging. Caring for a Person with Alzheimer's Disease. Available at https://order.nia.nih.gov/sites/default/files/2019-03/Caring_for_a_person_with_AD_508_0.pdf. Last accessed July 12, 2024.

12. Alzheimer's Association. Driving and Dementia. Available at https://www.alz.org/help-support/caregiving/safety/dementia-driving. Last accessed July 12, 2024.

13. Quinn KJ, Shah NH. A dataset quantifying polypharmacy in the United States.Sci Data. 2017;4:170167.

14. Population Reference Bureau. The U.S. Population Is Growing Older, and the Gender Gap in Life Expectancy Is Narrowing. Available at https://www.prb.org/resources/u-s-population-is-growing-older/. Last accessed July 12, 2024.

15. Murphey C. Aging is an Attitude: Positive Ways to Look at Getting Older. Chattanooga, TN: Living Ink Publishers; 2005.

Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Screening for depression and suicide risk in adults: U.S. Preventive Services Task Force recommendation statement. JAMA. 2023;329(23):2057-2067. Available at https://jamanetwork.com/journals/jama/fullarticle/2806144. Last accessed July 12, 2024.

94820 • Chronic Cough in Adults

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

Chronic cough is common, debilitating, often treatment-refractory, and can persist for years or decades as patients cycle through repetitive clinical workups without effective treatment. Hypersensitivity of vagal afferent neurons in the airways and their central projections underlies chronic cough, regardless of inciting etiology or comorbid disease. Thorough assessment to identify and treat potential causes is required. Coughing that persists is considered refractory chronic cough; for these patients, the therapeutic focus shifts to downregulating the hypersensitive cough pathway. Chronic cough is now considered a distinct pathologic entity and not merely a symptom of another disease. This distinction is important for clinicians to make.

Table of Contents

94820 • Chronic Cough in Adults

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. BACKGROUND

3. COUGH SEVERITY MEASURES

4. EPIDEMIOLOGY

PREVALENCE

REFRACTORY AND UNEXPLAINED CHRONIC COUGH

DISEASE BURDEN AND HEALTHCARE UTILIZATION

RISK FACTORS

5. PATIENT IMPACT OF CHRONIC COUGH

PHYSICAL IMPACT

PSYCHOSOCIAL AND QUALITY OF LIFE IMPACT

6. NATURAL HISTORY AND DISEASE COURSE

7. PATHOPHYSIOLOGY OF CHRONIC COUGH

NORMAL PHYSIOLOGY

PATHOPHYSIOLOGY OF CHRONIC COUGH AND COUGH REFLEX HYPERSENSITIVITY

SUMMARY

8. INITIAL EVALUATION OF CHRONIC COUGH

DEFINITIONS OF COUGH

PATIENT HISTORY

PHYSICAL EXAMINATION

MANDATORY INITIAL TESTS

"RED FLAG" ASSESSMENT OF SERIOUS UNDERLYING CAUSES OF COUGH

RECORDS REVIEW

THE ANATOMIC DIAGNOSTIC PROTOCOL (ADP)

DIAGNOSTIC TESTS

9. IDENTIFICATION AND MANAGEMENT OF UNDERLYING ETIOLOGIES

THE "TREATABLE TRAITS" APPROACH IN CHRONIC AIRWAY DISEASES

ENDOTYPES OF COUGH-RELATED CHRONIC INFLAMMATORY DISEASES

10. TREATMENT

CHRONIC AIRWAY INFLAMMATION

EMPIRIC TREATMENT APPROACH

BEHAVIORAL TREATABLE TRAITS

LOWER AIRWAY ETIOLOGIES OF CHRONIC COUGH AND MANAGEMENT

UPPER AIRWAY ETIOLOGIES OF CHRONIC COUGH AND THEIR MANAGEMENT

REFLUX DISORDER ETIOLOGIES OF CHRONIC COUGH AND THEIR MANAGEMENT

TREATABLE TRAITS AND THOROUGHNESS

11. TREATMENT OF REFRACTORY CHRONIC COUGH

PHARMACOTHERAPY

INVESTIGATIONAL PHARMACOTHERAPIES

NONPHARMACOLOGIC THERAPY

12. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

94820 • Chronic Cough in Adults

Education Category. Infection Control / Internal Medicine

Release Date. 08/01/2024

Expiration Date. 07/31/2027

Course Overview

Chronic cough is common, debilitating, often treatment-refractory, and can persist for years or decades as patients cycle through repetitive clinical workups without effective treatment. Hypersensitivity of vagal afferent neurons in the airways and their central projections underlies chronic cough, regardless of inciting etiology or comorbid disease. Thorough assessment to identify and treat potential causes is required. Coughing that persists is considered refractory chronic cough; for these patients, the therapeutic focus shifts to downregulating the hypersensitive cough pathway. Chronic cough is now considered a distinct pathologic entity and not merely a symptom of another disease. This distinction is important for clinicians to make.

Audience

This course is designed for physicians, physician assistants/associates, and nurses involved in the care of patients with chronic cough.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 10 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 10 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 10 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacology hour(s) for physician assistants. NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. This activity has been designated for 10 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 1 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

Chronic cough is difficult to effectively assess and treat, leading to extended periods before diagnosis and significant negative impact on patients' quality of life. The purpose of this course is to provide clinicians with the knowledge and skills necessary to identify and treat patients with chronic cough, regardless of underlying etiology, in accordance with clinical guidelines.

Learning Objectives

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

1. Describe the background and terminology related to chronic cough.

2. Compare and contrast available cough severity measures.

3. Outline the epidemiology of chronic cough and underlying etiologies.

4. Evaluate the impact of chronic cough on various dimensions of patients' lives.

5. Discuss the natural history and course of chronic cough.

6. Describe the pathophysiology of chronic cough.

7. Outline components of the initial evaluation of patients with chronic cough.

8. Identify potential underlying etiologies of chronic cough as well as appropriate management approaches for these conditions.

9. Analyze available treatment modalities for chronic cough of various underlying causes, including upper respiratory, lower respiratory, and reflux-associated cough.

10. Identify appropriate modalities for the treatment of refractory chronic cough, including pharmacotherapy, nonpharmacologic approaches, and investigational agents.

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

Mary Franks, MSN, APRN, FNP-C

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Chronic cough, or cough lasting longer than eight weeks, is a debilitating disease that can result in patients coughing hundreds to thousands of times every day. This physically exhausting and socially isolating condition can persist for years or decades, degrade the quality of life in nearly every domain, result in numerous medical and psychosocial consequences, yet its adverse impact on patients is often overlooked or underappreciated by clinicians. While acute cough is typically transient and self-limited, chronic cough often poses a diagnostic and therapeutic challenge; both non-treatment and over-treatment with ineffective medication are common [1,2]. Cough that persists despite investigation and treatment is especially vexing for patients and clinicians [3].

2. BACKGROUND

The anatomic, diagnostic protocol (ADP) established in the late 1970s that chronic cough in patients with negative chest x-ray findings is a symptom of asthma, postnasal drip, or acid reflux. Later refined to asthma, nonasthmatic eosinophilic bronchitis, upper airway cough syndrome, and GERD, it was believed that treating these underlying etiologies led to a favorable outcome in 90% of patients with chronic cough [4,5,6].

However, a large proportion of patients with these conditions do not have chronic cough [7]. Moreover, in many patients, cough persists despite treatment of its presumed cause (referred to as refractory chronic cough) or an underlying cause cannot be identified (referred to as unexplained chronic cough) [8]. This suggested that additional pathophysiological processes were involved [7].

In 2014, the European Respiratory Society (ERS) introduced cough hypersensitivity syndrome, defining chronic cough as a distinct clinical entity [9]. The 2020 ERS clinical practice guideline for chronic cough was pivotal in establishing cough hypersensitivity syndrome, influencing subsequent national and international chronic cough guidelines [10,11,12,13].

In 2016, the "treatable traits approach" was introduced to improve the outcomes of pulmonary patients with complex clinical syndromes (e.g., asthma and COPD) and variable treatment responses by moving beyond practice guidelines directed at diagnostic categories as a single disease entity, to identify and treat relevant phenotypic and endotypic "traits" instead [14,15,16]. The treatable traits approach gained rapid acceptance in pulmonary medicine and endorsement in chronic cough guidelines [5,17,18].

Cough performs an essential physiological function, mediated by cough reflex pathways in the airways and brain. In some individuals, irritation or inflammation of vagal afferent nerves in the airway leads to cough reflex hypersensitivity, the cardinal feature of cough hypersensitivity syndrome, peripheral and central sensitization, and clinical manifestations of allotussia, hypertussia, and/or laryngeal paresthesia (Table 1) [3,19,20]. The demographic, pathophysiological, and clinical similarities between cough hypersensitivity syndrome and chronic neuropathic pain are numerous. Chronic pain research has substantially informed how chronic cough and cough hypersensitivity syndrome are understood; both are disorders of sensory processing [4,21,22].

Table 1: CHRONIC COUGH TERMINOLOGY

Term

Definition

Acute cough

Cough lasting less than 3 weeks

Subacute cough

Cough lasting 3 to 8 weeks

Chronic cough

Cough lasting more than 8 weeks

Refractory chronic cough

Cough that persists despite guideline-based treatment of the presumed underlying cause(s)

Unexplained chronic cough

No diagnosable cause of cough is found despite extensive investigation for common and uncommon causes

Allotussia

Cough triggered by innocuous stimuli (e.g., laughing, talking, changes in ambient temperature)

Hypertussia

Exaggerated coughing triggered by mildly tussive stimuli (e.g., strong odors, second-hand cigarette smoke)

Urge to cough (laryngeal paresthesia)

A distinct, often debilitating sensation of irritation or "itch" in the throat or chest that precede cough and is not satiated by coughing

Cough reflex hypersensitivity

The cardinal feature of cough hypersensitivity syndrome

Cough hypersensitivity syndrome

Disorder characterized by cough triggered by mildly tussive or innocuous stimuli, with features of allotussia, hypertussia, and/or laryngeal paresthesia

Source: [5,9,26]

Sensitization of cough pathways may persist long after resolution of the inciting acute or subacute event. These chronic coughs will remain unexplained by diagnostic workups that do not consider cough hypersensitivity. Cough hypersensitivity syndrome may improve with the targeted intervention of other treatable traits. If chronic cough persists, the patient has refractory chronic cough [5].

Refractory and unexplained chronic cough are diagnoses of exclusion. A thorough, systematic clinical workup is required so that non-obvious and obvious causes of chronic coughing can be identified. The treatable traits approach may significantly expand clinically important intervention targets. After a diagnosis of refractory/unexplained chronic cough is made, therapeutic attention shifts to downregulating the hypersensitive cough reflex [5].

Maturation in research and practice has led to novel and emerging therapeutic options for patients with refractory chronic cough. Randomized controlled trials of existing centrally acting agents have identified the efficacy of low-dose morphine and gabapentin [10,23,24]. The development of P2X3 receptor antagonists, a novel peripherally acting drug class, has led to the approval of gefapixant for the treatment of refractory chronic cough in the European Union, Japan, and Switzerland, with U.S. Food and Drug Administration (FDA) advisory committee review believed imminent as of 2024 [25]. In a given patient, refractory/unexplained chronic cough may primarily involve peripheral mechanisms, central mechanisms, or both, and no tool is available for predicting therapeutic response to peripherally or centrally acting antitussive agents.

As of 2024, there are no FDA-approved treatments for chronic cough or for refractory chronic cough. When chronic cough persists after potential underlying causes are identified and treated according to current practice guidelines (e.g., for chronic cough related to nonasthmatic eosinophilic bronchitis or GERD), all therapeutic options for refractory chronic cough are prescribed off-label.

Important knowledge advances in this rapidly evolving field are not reaching healthcare professionals in the United States because chronic cough guidelines published for domestic consumption have become outdated. From this course, clinicians will gain current information on chronic cough and refractory/unexplained chronic cough, including the pathophysiology, differential diagnosis, and clinical management, essential for healthcare professionals in primary care, respiratory medicine, and ear/nose/throat (ENT) settings.

3. COUGH SEVERITY MEASURES

Patients with chronic cough experience cough-related physical, psychological, and social burdens, which can result from different aspects of cough severity, including cough frequency, cough intensity, disruption of daily activities due to cough, and cough-specific health-related quality of life. The severity and impact of chronic cough on physical, psychological, and social domains can be quantified through several validated objective and subjective measures [27].

Patient-reported outcome measures obtain a comprehensive understanding of the impact across these domains [27]. Patient-reported outcomes capture many issues that cannot be assessed effectively by objective measures and are also inexpensive, readily available, convenient, and easy to use for the patient [28]. A minimal clinically importance difference, the smallest change in an outcome that patients would perceive as important, is established for both objective and patient-reported outcome tools [29]. Cough measures mentioned throughout this course are summarized inTable 2. Cough frequencies of greater than 700 over an hour have been recorded [28].

Table 2: COUGH MEASURES

Name

Domains/Items, Rating and Minimal Clinically Importance Difference (MCID)

Comments

Health-related quality of life patient-reported outcome tools

Leicester Cough Questionnaire (LCQ)

Seven-point Likert scale (1=all of the time; 7=none of the time); 19 items in 3 domains: physical, psychological, and social. Total score range: 3 (maximal impairment) to 21 (no quality-of-life impairment).

MCID: 1.5 to 2.5 increase

The most widely used tool for assessing quality of life impact of chronic cough

Cough Quality of Life Questionnaire (CQLQ)

Four-point Likert scale (1=strongly disagree; 4=strongly agree); 28 items over 6 domains: physical and extreme physical complaints, psychosocial issues, emotional well-being, safety fears, and functional abilities. Total score range: 28 (no adverse effect of cough) to 112 (worst possible impact).

MCID: 10.6 to 21.9

Contains more items on physical impact of chronic cough (e.g., fractured ribs, headaches, immune deficiency, tuberculosis)

Hull Airway Reflux Questionnaire (HARQ)

Six-point scale (0=no symptoms; 5=most severe) of 14 items that measure airway hypersensitivity in chronic cough. Total score range: 0 to 70

Normal is <14

MCID: 16

Also used as a diagnostic tool for airway reflux, and to assess unexplained respiratory symptoms

Cough Severity Diary (CSD)

11-point scale (0=never; 10=constantly) of 7 items on frequency; intensity; disruptiveness

MCID ≥1.3 total score, −1.4 to −1.1 domain scores

Captures the severity and impact of chronic cough. Developed in response to patient feedback.

Objective assessment tools

VitaloJAK Cough Monitor

Electronic cough recording monitors worn by patients to measure cough frequency, typically as coughs per hour over 24 hours

MCID: ≥20% to 30% decrease

Does not capture the episodic nature of chronic cough, a primary factor in patients' disease burden

Leicester Cough Monitor (LCM)

Subjective tools

Visual Analogue Scale (VAS)

Score range 0 (no cough) to 100 mm (worst cough ever)

MCID: 30-mm reduction on the 100-mm cough severity VAS

—

Numerical Rating Scale (NRS)

Score range 0 (no cough) to 10 (worst cough ever)

Source: [28,29,30]

4. EPIDEMIOLOGY

PREVALENCE

Cough is a frequent reason for seeking outpatient medical attention in the United States, accounting for as many as 30 million clinical visits per year, up to 40% of which result in specialist referral [31].

Chronic cough has a prevalence among U.S. adults of roughly 10%, of whom 92% visited healthcare clinicians in the past six months [32]. Chronic cough is estimated to cost $6.8 billion annually in the United States, and an estimated $3.6 billion is spent annually on over-the-counter therapies [33]. The economic implications of chronic cough include the cost of outpatient visits, plus diagnostic workups, prescription medications to treat cough, and lost work and lost school productivity [1]. While inconsistent definitions prohibit direct comparisons of chronic cough prevalence between different countries or ethnicities, chronic cough appears to be more common in Europe, North America, and Australia than in Asian countries [32,34].

In KNHANES, a nationally representative study of the Korean adult population, the point prevalence of acute (<3 weeks), subacute (3 to 8 weeks), and chronic (>8 weeks) cough was 2.5%, 0.8% and 2.6%, respectively. The modal durations of current cough were less than one week (31.1%), and more than one year (27.7%); this bimodal distribution reflects the different pathophysiology of acute and chronic cough [35].

REFRACTORY AND UNEXPLAINED CHRONIC COUGH

Refractory chronic cough is seen in 20% to 59% of patients presenting to specialist cough clinics [36]. At Kaiser Permanente Southern California, 11,290 patients with specialist-diagnosed chronic cough were treated and followed for one year; 40.6% continued coughing despite etiological treatment by specialists (i.e., refractory chronic cough) [37].

Roughly 10% of patients with chronic cough lack an identifiable cause despite thorough evaluation (i.e., unexplained chronic cough), including 17% of patients with chronic cough in the Kaiser Permanente cohort [1,37]. Of 43,453 patients receiving primary care for chronic cough in the UK, 31% had ongoing chronic cough in the absence of associated comorbidities (i.e., no causal explanation or unexplained chronic cough) [4].

DISEASE BURDEN AND HEALTHCARE UTILIZATION

The Kaiser Permanente study examined the disease burden of chronic cough in comorbidities, medication use, and exacerbations [37]. Diagnoses included GERD (44%), hypertension (42%), allergic rhinitis (33%), chronic rhinitis (31.5%), asthma (31%), chronic sinusitis (24.4%), obesity (24%), upper airway cough syndrome (20.4%), depression (20%), and cough complications (19%). Nearly 40% of patients with unexplained chronic cough consulted at least two different specialist departments. In the previous three years, about half of the patients with emergency department visits (28.5%) or hospitalizations (10%) were for respiratory events [37]. Medications were respiratory: nasal corticosteroids (55%), short-acting b2-agonists (50.5%), inhaled corticosteroids/long-acting b2-agonist (27%), inhaled corticosteroid monotherapy (24%), and leukotriene modifiers (18.6%); non-respiratory: antitussive codeine (59%), proton pump inhibitors (PPIs) (45%), antidepressants (26%), anxiolytics (15.5%), and gabapentinoids (14%); and other: systemic antibiotics (72.4%) and oral corticosteroids (47%).

Over one year, patients with emergency department visits (26%) and hospitalizations (12%) remained high; more than 50% were respiratory-related. Antitussive and psychotherapeutic drugs were dispensed at a frequency similar to the baseline year. The clinical and economic burden was especially high in patients with both respiratory disease and GERD, but chronic cough persistence (40.6%) was similar between subgroups [37].

A subsequent Kaiser Permanente study of patient-level burden used patient-related outcomes (average chronic cough 8 years) [38]. Mean scores were 11 on LCQ (maximum: 21), 33 on HARQ (normal: ≤13), and 57 on CQLQ (maximum: 112). Correlations were high between LCQ and HARQ (–0.65), LCQ and CQLQ (–0.80), and HARQ and CQLQ (0.69). Patients with chronic cough-related respiratory and gastrointestinal disorders were generally similar. Treatment responses were suboptimal. Women (compared with men) and non-White individuals (compared with White individuals) reported significantly worse cough severity and poorer LCQ, HARQ, and CQLQ scores.

The patient-reported burden of chronic cough was substantial, with long duration, high severity, poor health status, high degree of cough hypersensitivity, low quality of life, multiple cough triggers, and frequent laboratory testing, specialist care, and medications. The study provides strong evidence that patients with chronic cough exhibit frequent poor responses to medications and overall control [38].

The objective and patient-reported burden of chronic cough is substantial, particularly in women and non-White minorities, which markedly affects daily living with inadequate response to treatments.

RISK FACTORS

Risk factors of chronic cough include smoking, female sex, older age, obesity, asthma, allergic rhinitis, rhinosinusitis, and angiotensin-converting enzyme (ACE) inhibitor use for hypertension treatment [34,39].

In the United States, 18% of adults who smoke cigarettes have chronic coughs [39]. Cigarette smokers are three times more likely to report chronic cough than never-smokers and ex-smokers, and the cough is usually due to chronic bronchitis. However, most patients in cough specialist clinics are nonsmokers [19]. Among 1,000 patients evaluated at a cough center in the Bronx, 2.7% were active smokers and 27% former smokers [40]. Of 11,290 Kaiser Permanente patients with chronic cough, 65% were never-smokers and 2.3% were current smokers [37].

Age and sex underlie the burden and prevalence of chronic cough; more than 67% of patients presenting with chronic cough to specialist clinics are female, likely due to gender differences in cough reflex sensitivity [1,19]. Cough reflex sensitivity was assessed in individuals from China, India, and northwest Europe. No differences between ethnic groups were found, suggesting that racial variation in chronic cough prevalence may not reflect differences in cough reflex sensitivity and may be influenced by asthma, allergy, or environmental factors [34,39,41]. Women in all three ethnic groups demonstrated lower cough thresholds [41].

While chronic cough can occur at any age, the rate rises substantially in women who are 40 years of age or older and is highest in the 60 to 69 age group. The highest rates in men occur between 50 and 69 years of age [1]. In KNHANES, chronic cough increased significantly with age. The odds ratio of 2.20 suggests a substantial increase in chronic cough likelihood for individuals 65 years of age or older (compared with those 18 to 39 years of age). The associations with older age were independent of current smoking and comorbidities [35].

In separate longitudinal European population studies, chronic cough was associated with low educational level and lower socioeconomic status [34]. A systematic review found a significant association between low education level and risk of chronic cough [42].

In South Korea and China, higher male prevalence of chronic cough was attributed to differences in smoking habits and air pollution exposures, respectively [28]. Occupational irritants, such as fumes, gases, cleaning products or dust, may cause cough by triggering cough reflex or by inducing oxidative stress and eosinophilic inflammation, but the effect of such factors on chronic cough remains elusive. Air pollution is an important risk factor for chronic cough. Levels of fine particulate matter ≤2.5 mcm in diameter (or PM2.5) are higher in East Asian than in European or North American countries but the prevalence of chronic cough is lower, suggesting potential host-environment interactions in developing chronic cough [19].

Persistent cough is a class-wide adverse effect of ACE inhibitors, and the 5% to 35% prevalence is much higher in East Asian than in other populations. In genotype studies, the genetic polymorphisms ACE I/D and SLCO1B1 were related to ACE inhibitor-induced cough and were more common in East Asian populations, which may account for the ethnic differences and possibly predict risk of ACE inhibitor-induced cough [43].

5. PATIENT IMPACT OF CHRONIC COUGH

Patients report numerous cough-related physical and psychosocial effects, most commonly fatigue, sleep disturbance, exhaustion, breathlessness, headache, dizziness, musculoskeletal pain, wheezing, impairment of speech, vomiting, excessive perspiration, self-consciousness, and interference with daily activities [28,44]. These effects have a significant impact on patients' quality of life.

PHYSICAL IMPACT

During vigorous coughing, intrathoracic pressures may reach 300 mm Hg and expiratory velocities approach 500 miles per hour (mph) (85% of the speed of sound). These physical forces cause many of the cardiovascular, gastrointestinal, genitourinary, quality of life, musculoskeletal, neurologic, ophthalmologic, psychosocial, and respiratory complications of chronic cough, ranging from the relatively minor to life-threatening or even fatal. Comorbid illnesses or older age can magnify these effects [44,45].

Surgical Complications and Hernia

Surgical complications from uncontrolled coughing include extrusion (i.e., expulsion) of ocular contents during eye surgery, and wound dehiscence (i.e., splitting or bursting open) following cardiac or abdominal surgery. Similarly, severe coughing can cause inguinal, femoral, umbilical, lumbar, or abdominal wall hernia [45].

Fracture

Cough-induced rib fractures, another painful and potentially serious complication of chronic cough, often involve multiple ribs, particularly ribs 5 through 7. The number of ribs fractured is associated with higher mortality rates, particularly in older patients who often have decreased bone density due to osteoporosis (also an adverse effect of long-term corticosteroid treatment). However, rib fractures can also occur in patients with normal bone density [44,46].

Stress Urinary Incontinence

Stress urinary incontinence, defined as the unintentional loss of urine during or following a bout of coughing or other physical activity, significantly contributes to quality-of-life disruption caused by chronic cough in women. Of 210 consecutive adult women evaluated at a cough center for chronic cough, 63.3% reported stress urinary incontinence induced by cough episodes; stress urinary incontinence developed after the onset of chronic cough and solely occurred during or after coughing in 92.5% and at least daily in 47.3%. For context, 3.5% of similarly aged women in the community experience stress urinary incontinence, while only 5% of men with chronic cough report stress urinary incontinence as an issue significantly impacting their quality of life [28,47].

Surveys have reported lower rates of urinary incontinence in women with chronic cough, but most women will not volunteer a history of cough-induced stress urinary incontinence unless specifically asked. This may explain the higher prevalence in this study, because the establishment of trust between patient and physician may have encouraged sharing such information. After discussion ensues, patients are often relieved to learn this is a common problem faced by women with chronic cough [47].

Cough Syncope

Cough-evoked syncope is a serious and potentially fatal consequence of coughing. Numerous reports of motor vehicle accidents resulting from cough syncope include the deaths of drivers and pedestrians. While the exact mechanism of remains debated, the required generation of very high intrathoracic pressures likely explains the nearly uniform profile of patients with cough syncope as large male subjects with obstructive airway disease [48]. Cough syncope is considered relatively uncommon, although 10% of subjects with chronic cough in a community sample reported experiencing cough syncope [5,49]. The mandatory loss of driver's license in some countries (e.g., the UK) has a major impact on employment prospects for these patients [28].

PSYCHOSOCIAL AND QUALITY OF LIFE IMPACT

Chronic cough can interfere with all aspects of patients' lives, including daily living activities, social interactions, home management, recreational activities, and employment. Importantly, when triggers of coughing bouts are very difficult to avoid, the psychosocial impact can be substantial. Chronic cough has a negative impact on relationships, with spouses not being able to tolerate the cough as a key reason for patients' health-related dysfunction [28]. In a multinational European survey of 1,120 persons with chronic cough, most reported that coughing affected their quality of life (96%), disturbed their family and friends (94%), and affected activities they enjoyed (81%) [51].

The psychological effects associated with chronic cough are highly prevalent, with an impact on mental health comparable to that of stroke or Parkinson disease. Studies of patients with chronic cough have reported high rates of anxiety (33% to 52%) and depression (16% to 91%) [28].

Patients may avoid or be uncomfortable in social situations due to the embarrassment of coughing, its effects (e.g., stress urinary incontinence, retching), and/or the perception by others that they have a contagious condition or are a heavy smoker [28]. The COVID-19 pandemic increased the social stigma of persistent coughing due to its association with contagious respiratory diseases [50].

6. NATURAL HISTORY AND DISEASE COURSE

Little is known about the natural history of cough hypersensitivity, but the available evidence suggests that patients often suffer from it for many years [4]. In a longitudinal study of patients with unexplained chronic cough, cough severity worsened (36%) or was unchanged (23%) over 7 to 10 years. Predictors of cough persistence or improvement could not be identified. Unexpectedly, longitudinal spirometry data showed declines in forced expiratory volumes over one second (FEV1) that were well above population norms for similarly aged nonsmokers. The striking magnitude of decline argued against a chance finding. Around 10% of patients developed spirometric features of COPD [52].

The abnormally rapid decline in FEV1 and a significant minority of patients developing COPD raise the possibility that unexplained chronic cough is associated with a persistent damaging airway process and could be a risk factor for COPD [52]. A 2023 study confirmed that chronic cough is highly associated with FEV1 decline, regardless of COPD presence, while chronic cough in patients suffering from COPD is associated with lower FEV1, more dyspnea, worse health status, and is an independent risk factor for exacerbations of COPD possibly linked to altered transient receptor potential (TRP) channel function [53].

Cough is often the most bothersome and intractable symptom reported by patients with asthma, and the significant disease burden of chronic cough was described in a prospective cohort of 323 consecutive adult participants with asthma who received optimized asthma therapy. After 12-month, those with chronic cough had more airflow obstruction; worse asthma control and quality of life; increased airway inflammation; upper respiratory tract infection as a trigger; more psychological, rhinitis, and COPD comorbidities; greater work productivity loss and daily activity impairment; and increased exacerbations. These findings call for more attention to chronic cough in asthma [54].

In summary, chronic cough is related to an accelerated FEV1 decline over time, regardless of smoking history or COPD diagnosis, but the relationship between chronic cough and worse clinical outcomes lacks a clear pathophysiological explanation [55].

7. PATHOPHYSIOLOGY OF CHRONIC COUGH

NORMAL PHYSIOLOGY

The Cough Reflex

Cough is an innate reflex that protects the airways from foreign objects, clears excess secretions, and preserves airway patency. The cough reflex consists of peripheral airway receptors of afferent nerves, cough control centers in the central nervous system (CNS), and efferent nerves.

Cough occurs in three phases [31,56]. The first is inspiratory, during which the glottis opens widely followed by rapid inhalation sufficient for generating enough air movement to be productive. The second phase is compression. This phase is characterized by the rapid closure of the glottic apparatus and contraction of abdominal and other respiratory muscles compresses the alveoli and bronchiole, increasing intrathoracic pressure to greater than 300 mm Hg. The final phase is expiration, or the sudden opening of the epiglottis and vocal cords results in rapid, high-volume expiratory airflow that may exceed 500 mph in velocity. The force of this process loosens and expels mucous secretions from the airway wall, while the rapid airflow vibrates the larynx and pharynx, inducing the characteristic sounds of cough.

Vagal Afferents

The cough reflex is activated by vagal afferent A-δ and C fibers, sensory neurons originating from brainstem vagal ganglia that innervate the larynx and proximal airways. A-δ fibers are mechanoreceptors, activated by airway mucus, inhaled foreign bodies, and low pH (i.e., acidity). C-fibers are nociceptive chemoreceptors, activated by signaling molecules and mediators of inflammation or tissue damage within the airway [19,25,57,58].

Neurobiological Processes

Complex neurobiological processes in the peripheral nervous system, brainstem, and higher cerebral cortex mediate coughing [59]. Receptors (e.g., P2X3 purinergic receptors, voltage-gated sodium channels [NaV], bradykinin receptors, and transient receptor potential [TRP] ion channels) and neuropeptides (e.g., substance P, calcitonin gene-related peptide [CGRP]) play important roles [60].

Noxious mechanochemical stimuli in the airways activate ligand-gated ion channels and G protein-coupled receptors on vagal nerve endings; NaV channels depolarize, propagating the signal up the vagus nerve to first-order synapses in brainstem nuclei. From there, the signal is relayed by second-order neurons to brainstem and spinal motor neurons to reflexively modify breathing; to third-order neurons of the primary somatosensory cortex where the unpleasant urge-to-cough sensation is mediated; and to higher-order cortical neurons that mediate conscious perception of cough [23,60].

These ascending third-order pathways enable perception of airway irritation, and regulatory control of descending motor pathways that terminate in the brainstem and in spinal respiratory circuits [22,61]. Under physiologic conditions, higher inhibitory brain processes permit the modification of coughing behavior, and the urge to cough may be suppressed [21].

Extrapulmonary airways (i.e., larynx, trachea, and mainstem bronchi) are also reflexogenic sites essential for preventing aspiration, inhalation of noxious chemicals, and accumulation of excessive mucus; all can induce reflex coughing with irritation of vagal afferent nerves [21].

Coughing is a reflex and a voluntary behavior with or without the sensation of an urge to cough. Reflex cough, behavioral cough, and the urge to cough (which precedes the motor act of coughing) are three separate entities, each dependent on their own neural processes [21,22]. The relevance of these neurophysiological processes is apparent when considering the development of cough hypersensitivity syndrome [21].

PATHOPHYSIOLOGY OF CHRONIC COUGH AND COUGH REFLEX HYPERSENSITIVITY

Chronic cough, unlike protective cough, is a pathologic state that no longer serves a physiologic role [60]. Excessive coughing is a consequence of increased activation of neuronal cough-mediating pathways due to [62,63]:

- Excessive activation of airway vagal afferent terminals by chemical or mechanical irritants

- Neuroplastic changes in vagal afferent fibers

- Neuroplastic changes in the CNS

Nervous system plasticity, or malleability, dictates that excessive stimulation of peripheral nerve fibers can reshape their excitability through changes in receptor expression; synaptic transmission in the CNS is subsequently altered, further increasing the gain within the system [62].

Chronic cough is most associated with and traditionally considered a symptomatic byproduct of asthma, nonasthmatic eosinophilic bronchitis, upper airway cough syndrome, and/or GERD, but most patients with these chronic inflammatory diseases do not have chronic cough. Further, cough severity correlates poorly with cough-associated disease severity, and chronic cough can occur in the absence of these conditions as unexplained chronic cough or unexplained chronic cough [19,20,64]. This implies individual differences in cough reflex sensitivity and that hypersensitivity of airway sensory nerves may underlie chronic cough [65].

Cough hypersensitivity, defined as repeated episodes of coughing often in response to minimal or no discernible triggers, is common to all persons with chronic cough [66]. Extracellular adenosine triphosphate (ATP) may play a prominent role in cough hypersensitivity. During cellular injury or inflammation, cells release ATP to alert neighboring cells to damage. In respiratory conditions associated with chronic cough and airway inflammation, such as COPD and asthma, extracellular ATP may be elevated and sensitivity to ATP is heightened [33]. The NK-1 receptor and its ligand, substance P, may also be involved in inducing and maintaining cough hypersensitivity, both peripherally and centrally, either indirectly through inflammatory mediators or directly by stimulating sensory nerve fibers [33].

Cough Hypersensitivity Syndrome

Cough hypersensitivity syndrome frames chronic cough as a hypersensitivity disorder, akin to chronic pain. Sensitization of vagal afferents by upper or lower airway inflammation leads to increased cough sensitivity to normally anodyne stimuli, the cardinal feature of cough hypersensitivity syndrome [22,58].

In chronic cough, as in chronic pain, peripheral sensitization is necessary but probably insufficient without central sensitization, which alters the efficacy of neurotransmission in the brainstem and regulation of cough reflex-mediating brain pathways [21]. Patients with cough hypersensitivity or chronic pain have shown abnormal activity in the same midbrain areas that amplify incoming cough (or pain) signals [58,67,68].

Chronic pain research substantially informs the conceptual transformation in how chronic cough and refractory chronic cough are understood. Both disorders involve abnormal sensory processing. Taking inspiration from chronic pain, hypertussia describes abnormal excessive coughing in response to airway irritation. Allotussia describes coughing in response to innocuous stimuli. Laryngeal paresthesia describes noxious sensations in the throat or chest associated with an "urge to cough." Peripheral and central sensitization describe processes that alter cough pathway function [62,63].

Peripheral Sensitization

Dysregulation of airway innervation contributes to chronic coughing and is considered the main driver of cough in refractory chronic cough [63].

In airway inflammation, vagal neuron sensitization and plasticity is shown by increased production of neuropeptides, upregulation of glutamate receptors and nociceptive ion channels (e.g., TRPV1), and lower thresholds for activating sensory-evoked cough responses. Neuropeptide upregulation occurs in airway sensory neurons where they are not normally expressed. These effects underlie hypertussia by expanding the cough-evoking stimuli field [21].

For example, bronchoscopic biopsies of patients with chronic cough demonstrated increases in airway epithelial nerve length and branching. The remodeling of these vagal C fibers may contribute to airway hypersensitivity through increased density of fiber terminals and enlargement of their receptive fields. The shearing forces of chronically coughing and/or the resultant release of inflammatory mediators (e.g., ATP) may explain the increased density of epithelial innervation [69].

Whether the primary stimulus for peripheral sensitization is cellular damage, mechanical stress, or nociceptor stimulation is unclear, as all three can trigger ATP release, activating P2X3 receptors [59].

Central Mechanisms

While peripheral nervous system dysfunction is the most-described component of cough hypersensitivity, central dysfunction plays a fundamental role [70]. Patients with cough hypersensitivity attempting to voluntarily suppress coughing show reduced activity in dorsomedial prefrontal and anterior mid-cingulate cortices, suggesting diminished ability to inhibit cough reflex activation [66,67,71].

Patients with refractory chronic cough demonstrate structural and functional alterations in the left frontal brain regions, including lower gray matter volume and enhanced frontoparietal functional connectivity, which may underlie the higher cough scores, greater psychosocial impact, longer disease duration, and impaired cough inhibition in these patients [72].

Studies of chronic cough in asthma and nonasthmatic eosinophilic bronchitis identified increased neuronal sensitivity and subsequent central sensitization via mechanisms of inflammatory-mediated nociceptor sensitization and altered afferent nerve terminal excitability, phenotypic changes in vagal afferent neurons, and central neuroplasticity resulting from increased synaptic signaling from peripheral afferents [73].

The contribution of CNS mechanisms accounts for the efficacy of centrally acting medications (e.g., gabapentin and low-dose morphine) in patients with refractory chronic cough [58].

Laryngeal Hypersensitivity

A study of refractory/unexplained chronic cough patients with cough hypersensitivity referred to a cough clinic suggests highly prevalent laryngeal dysfunction. The 12-month cohort of all referred patients showed high rates of cough hypersensitivity (100%), multiple cough triggers (75%), laryngeal paresthesias (95%), voice abnormalities (50%), upper airway dyspnea (25%), and laryngeal functional abnormalities on nasoendoscopy (73%). Given the frequent constellation of symptoms typifying laryngeal dysfunction and cough hypersensitivity, the authors suggest designating laryngeal hypersensitivity as a specific cough phenotype [74].

Many refractory chronic cough cases have a sensory neuropathic etiology in the hypopharynx and larynx, with laryngeal hypersensitivity a key mechanism [75]. Pharyngeal/laryngeal sensations (e.g., irritation, tickle, throat-clearing), frequently associated with upper airway cough syndrome and reflux cough, may represent sensory neuron dysfunction of vagal afferents in the upper airways and a phenotype of cough hypersensitivity syndrome. Dysphonia, dysphagia, dyspnea, and abnormalities of vocal fold motion on laryngoscopy may present with chronic cough as part of the pharyngeal/laryngeal nerve dysfunction seen in cough hypersensitivity syndrome [76].

Autonomic Dysregulation

There is also evidence of broader autonomic nervous system dysregulation. Compared with healthy controls, patients with chronic cough report more frequent and severe autonomic symptoms in gastrointestinal, orthostatic intolerance, bladder, and pupillomotor domains, primarily in parasympathetically mediated systems, suggesting this population may suffer from dysautonomia. Whether this results from coughing, or if both the cough and dysfunction are part of wider vagal pathology, is unclear [70].

SUMMARY

Functional changes in TRPV1, TRPA1, and P2X3 nerve channels and the development of peripheral and central sensitization are thought to turn cough from a defensive reflex into a cough hypersensitivity syndrome [77]. Hypersensitivity of the cough reflex and deterioration in central inhibition of the cough explain cough persistence [78].

Evidence Based Practice Recommendation

According to the European Respiratory Society, cough hypersensitivity through cell damage and inflammation underlies much of the increased cough seen in other pathologies. The different pathological processes in individual conditions contribute to the disease-specific heterogeneous etiology of cough in other lung disease.

https://erj.ersjournals.com/content/55/1/1901136

Last Accessed: August 12, 2024

Level of Evidence: Expert Opinion/Consensus Statement

Cough hypersensitivity syndrome is identified by symptoms of allotussia, hypertussia, and/or laryngeal paresthesia and may improve with the treatment of other treatable traits. If the chronic cough persists, the patient has refractory chronic cough [5].

Owing to nervous system plasticity, sensitization of cough pathways may persist long after resolution of the inciting event, such as acute viral airway infection. These chronic coughs will remain unexplained by diagnostic workups that do not consider cough hypersensitivity [5].

Currently, there are no available methods to identify susceptibility to nervous system plasticity and sensitization, objectively diagnose cough hypersensitivity syndrome, or predict treatable versus refractory chronic cough.

8. INITIAL EVALUATION OF CHRONIC COUGH

When initially encountering a patient with chronic cough, the primary task is to perform a thorough evaluation that seeks potential underlying treatable causes of chronic cough and to treat the cause(s) according to current clinical practice guidelines [99]. These patients typically undergo extensive medical workup and treatment across multiple subspecialties without improvements in their symptoms, and clinicians should try to break the often-repetitive cycle of investigations, empirical treatment, and worry experienced by these patients [75]. The degree to which patients have been investigated varies, so basic tests may be required. Further investigations depend on the individual's presentation [5]. After a diagnosis of refractory chronic cough is made, the therapeutic focus shifts from identification and treatment of underlying causes to suppression of the hypersensitive cough reflex [99].

The initial evaluation (detailed history and physical examination) accomplishes the key tasks of identifying or ruling out a wide range of diseases underlying the chronic cough and identifying any danger signs that may indicate a diagnosis that needs urgent attention. Any positive findings should guide the initial management [8,44].

DEFINITIONS OF COUGH

To eliminate confusion on how to define cough, the ACCP and the ERS have standardized the definition of cough according to its duration [10,100]. Consistently applying these guideline-established definitions is crucial [2].

Thus, the first step in evaluating cough is to determine its duration. This also helps to narrow the differential diagnosis based on the most common underlying causes [10,100]:

- Acute (<3 weeks) cough:

- Infectious etiologies, especially with viral causes

- Exacerbations of chronic diseases (e.g., asthma, COPD)

- Pneumonia

- Environmental exposures

- Subacute (3 to 8 weeks) cough:

- Postinfectious cough

- Exacerbations of chronic diseases (e.g., asthma, COPD)

- Upper airway cough syndrome

- Chronic (>8 weeks) cough:

- Upper airway cough syndrome

- Asthma

- Nonasthmatic eosinophilic bronchitis

- GERD

In chronic cough, allergies are considered secondary to upper airway cough syndrome or asthma.

When cough has lasted three or more weeks and is not postinfectious, some experts recommend not waiting for eight weeks to begin a chronic cough workup [6].

PATIENT HISTORY

A detailed evaluation is performed and should include the following [2,5,6,8,10,100]:

- Presenting symptoms or cough characteristics:

- Duration

- Productive or nonproductive

- Associated symptoms (e.g., rhinorrhea, nasal congestion, sneeze, fever, sputum production, hemoptysis, dyspnea, weight loss, dysphonia, dysphagia, peripheral edema)

- Prior episodes

- Preceding illnesses (e.g., recent viral infection)

- Clarify whether the patient is coughing, throat-clearing, or both.

- Medical history, including pulmonary and extrapulmonary (e.g., GERD, hypertension, allergic, immune) conditions

- Surgical history, especially involving cardiac, pulmonary, gastrointestinal, and otolaryngological organ systems

- Family history of atopic disease

- Exposure history

- Tobacco and cannabis smoking or vaping (e.g., electronic cigarettes)

- Occupational and environmental exposures

- Recent travel

- Country of origin

- Potential sick contacts

- Review current medications for potential iatrogenic cause. Ask about current use of both prescribed and over-the-counter NSAIDs and aspirin.

It is important to always rule out culprit medications by assessing whether the patient is taking an ACE inhibitor antihypertensive, NSAID, sitagliptin, or any medication that may be suspected of inducing the cough. A dry persistent cough from ACE inhibitor use is caused by bradykinin, substance P, and prostaglandins that accumulate in the upper respiratory tract or lung when ACE is inhibited, enhancing the cough reflex. Stopping the drug typically resolves coughing within four weeks or improves it sufficiently for a diagnosis of iatrogenic cough. Switching to angiotensin II receptor blockers (ARBs) provides antihypertensive control without provoking coughing [6,101].

PHYSICAL EXAMINATION

The physical examination of a patient presenting with chronic should assess for nasal congestion, pharyngeal erythema, tonsillar swelling, hoarseness, stridor, wheeze (particularly focal wheeze), crackles, and other adventitious sounds.

MANDATORY INITIAL TESTS

Evidence Based Practice Recommendation

The European Respiratory Society suggests that clinicians do not routinely perform a chest CT scan in patients with chronic cough who have normal chest radiograph and physical examination.

https://erj.ersjournals.com/content/55/1/1901136

Last Accessed: August 12, 2024

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

Initial diagnostic testing should include chest radiography (usually x-ray). Spirometry testing of pulmonary function is recommended pre- and post-bronchodilator to evaluate possible asthma or COPD.

"RED FLAG" ASSESSMENT OF SERIOUS UNDERLYING CAUSES OF COUGH

In cough of any duration, the initial evaluation should identify any danger signs that may indicate a diagnosis requiring urgent attention. Important danger signs that will need further evaluation with chest x-ray and possibly laboratory testing and computed tomography (CT) include [44,100]:

- Systemic symptoms (raises suspicion for chronic infection or rheumatic disease):

- Fever

- Night sweats

- Weight loss

- Peripheral edema with weight gain

- Hemoptysis, an indicator of infection (e.g., bronchiectasis, lung abscess, tuberculosis), cancer (e.g., lung, bronchus, or larynx), rheumatologic diseases, heart failure, or foreign body inhalation

- Prominent dyspnea, especially at rest or at night, a possible clue to airway obstruction or lung parenchymal disease

- Possible foreign-body inhalation (requires urgent bronchoscopy)

- Smoker older than 45 years of age with a new cough, change in cough, or co-occurring voice disturbance

- Hoarseness

- Trouble swallowing when eating or drinking

- Vomiting

- Recurrent pneumonia

- Abnormal respiratory exam and/or abnormal chest radiograph coinciding with duration of cough

RECORDS REVIEW

If patients have undergone prior evaluations for upper airway cough syndrome, asthma, GERD, or nonasthmatic eosinophilic bronchitis, obtain and review these medical records, including laboratory values, diagnostic reports, and treatments prescribed, to determine if these etiologies have been accurately assessed, diagnosed, and treated. Patients may not have been completely evaluated for these conditions yet diagnosed based on their response (or lack thereof) to empiric trials, which is important to ascertain [2].

THE ANATOMIC DIAGNOSTIC PROTOCOL (ADP)

Even in current international guidelines that emphasize treatable traits, the anatomic diagnostic protocol (ADP) remains useful in the clinical workup of patients with chronic cough for identifying possible treatable conditions, while recognizing that treatment of the presumed cause(s) does not always improve the cough [19]. Consistent with the ADP, this section organizes chronic cough etiologies and management by their lower airway, upper airway, and gastroesophageal origin.

In nonsmoking, immunocompetent patients not taking an ACE inhibitor and with unremarkable chest radiography, cough lasting longer than eight weeks is considered a symptom of asthma, nonasthmatic eosinophilic bronchitis, upper airway cough syndrome, GERD, or any combination [6]. These four common causes to consider should be evaluated (Table 3).

Table 3: EVALUATION OF COMMON CAUSES OF CHRONIC COUGH

Evaluation

Common Causes

Asthma

NAEB

UACS

GERD

Spirometry

X

Bronchodilator reversibility

X

Bronchoprovocation challenge

X

Allergy evaluation

X

X

X

Sputum eosinophilia

X

Blood eosinophilia

X

Fractional exhaled nitric oxide (FeNO)

X

Sinus imaging

X

Nasopharyngoscopy

X

Empiric treatment trialsa

X

X

X

X

aDiagnostic-Therapeutic Trials

UACS

First-generation oral antihistamines

Inhaled corticosteroids

Inhaled ipratropium

Asthma or NAEB

Inhaled corticosteroids

Systemic (oral) corticosteroids

Leukotriene receptor antagonist

GERD

High-dose proton pump inhibitor (PPI) acid-suppression therapy

Anti-reflux lifestyle measures

Pro-kinetic agent: metoclopramide

GERD = gastroesophageal reflux disease; NAEB = nonasthmatic eosinophilic bronchitis; UACS = upper airway cough syndrome.

Source: [1,82,83,100]

The ADP has been modified to simplify the clinical workup by emphasizing empiric treatment trials for suspected, but not fully investigated or confirmed, disease [77]. According to the rationale, objective diagnostic methods for upper airway cough syndrome, asthma, nonasthmatic eosinophilic bronchitis, and GERD are technically demanding, sometimes difficult for patients, and require specialized instruments and personnel. Further, with GERD, discerning causal and temporal relationships between acid reflux and cough is difficult. Thus, sequential empirical therapy is frequently considered and is advised by some before embarking on extensive workup [39,102]. Because symptom reduction is said to confirm a diagnosis, empiric treatment has been called a diagnostic-therapeutic trial [1].

DIAGNOSTIC TESTS

If airway disease is suspected, the treatable traits approach is advocated to identify and optimize treatment of pulmonary, extrapulmonary, and behavioral traits (Table 4). Optimizing airway disease treatment is usually the key to managing cough in these patients. Cough hypersensitivity may be a trait in airway disease and require additional specific treatment [5].

Table 4: AIRWAY INVESTIGATIONS IN PATIENTS WITH CHRONIC COUGH

Investigation

Description

Utility

Lower Airway

Chest radiograph

Plain radiograph of the chest from anterior or posterior aspect (occasionally lateral view)

Mandatory. Abnormal findings should be pursued first as potential cause of chronic cough.

Spirometry

Maximal inhalation and exhalation into a spirometer measures forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)

Mandatory test for airflow obstruction. FEV1 ≤80% or FEV1/FVC ratio <70% predicted for age and sex prompts reversibility testing.

Bronchodilator reversibility test

Pre- and post-bronchodilator spirometry in patients with obstructive airflow to measure change 10 to 15 minutes after SABA (e.g., albuterol)

Increase in FEV1 ≥12%, or ≥200 mL, after SABA indicates reversibility. Ideally, perform before starting asthma therapy.

Fractional exhaled nitric oxide (FeNO)

Measurement of nitric oxide levels in exhaled breath to indicate eosinophilic airway inflammation

Increased FeNO levels correlate with type 2 airway inflammation in asthma or nonasthmatic eosinophilic bronchitis. High FeNO (>30 ppb) may predict corticosteroids response.

Induced airway sputum

Patient inhales nebulized hypertonic saline (3% to 5%), inducing sputum expectoration for differential cell count analysis.

The criterion standard assessment of eosinophilic airway, routinely used in cough clinics but not widely adopted

Bronchial challenge/provocation test

Patient inhales histamine or methacholine; a ≥20% drop in FEV1 confirms bronchial hyperresponsiveness (positive test).

Positive test with isolated cough and normal spirometry indicates an anti-asthma therapy trial. A negative test makes asthma improbable.

Chest computed tomography (CT)

Provides better resolution of lung parenchymal and mediastinal structures than chest x-ray

In productive cough, may identify early lung fibrosis or confirm bronchiectasis. Low utility in chronic cough with normal physical exam and chest x-ray.

Bronchoscopy (fiberoptic)

Allows direct visualization of the upper and lower airways and bronchoalveolar lavage to obtain specimens

Mandatory in all patients with suspected inhaled foreign body. Endobronchial appearance typically normal in chronic cough with normal chest x-ray.

Upper Airway

Laryngoscopy (fiberoptic)

Allows direct inspection of laryngopharyngeal area including epiglottis and vocal cords

Typically unremarkable, but may reveal laryngopharyngeal reflux. Suspected laryngeal dysfunction prompts challenge laryngoscopy.

Sinus CT imaging

Visualizes the frontal, ethmoid, and maxillary sinuses and nasal passages

May provide evidence of sinus opacification or mucosal thickening. Unclear role in patients with chronic cough without nasal symptoms.

Other

Peripheral blood eosinophil count

Measures absolute number or relative percentage of eosinophils in peripheral blood

May help predict corticosteroid response in respiratory diseases; utility in chronic cough not established.

ppb = parts per billion, SABA = short-acting beta-agonist.

Source: [10,19,103]

Classic asthma, cough-variant asthma, and nonasthmatic eosinophilic bronchitis are clinical diagnoses with no clear-cut, absolute diagnostic test available to either rule asthma in or out as the cause of a patient's chronic cough [10]. In a stepwise diagnostic approach, initial abnormal lung function testing suggests classic asthma or COPD; normal testing is inclusive of cough-variant asthma, nonasthmatic eosinophilic bronchitis, or chronic bronchitis. Absence of bronchial hyperreactivity to methacholine challenge in patients with normal physical exam and spirometry findings suggests nonasthmatic eosinophilic bronchitis. Negative airway responsiveness can exclude cough-variant asthma. Abnormal spirometry contraindicates bronchial challenge testing [104].

Lung Function Tests

Spirometry can reveal airflow obstruction, variability (>20%) in peak expiratory flow measurements, or an improvement in threshold testing (FEV1 >12%, improvement from baseline of >200 mL) in response to bronchodilators (b-2 agonists). Abnormal spirometry can be seen in patients with classic asthma and COPD, but not cough-variant asthma or nonasthmatic eosinophilic bronchitis [104].

Spirometry

An FEV1/forced vital capacity (FVC) ratio of <70% (or below the lower limit of normal, if available) is a positive test for obstructive airway disease (obstructive spirometry) [103].

Bronchodilator Reversibility Test

Bronchodilator reversibility testing is recommended in patients with obstructive spirometry (FEV1/FVC ratio <70%). Following short-acting beta-agonist bronchodilator administration, improvement in FEV1 of ≥12%, together with an increase in volume of ≥200 mL, is a positive test [103].

Airway Inflammation Measures

Asthma is often, but not always, mediated by eosinophilic inflammation, and measurement of airway inflammation has clinical utility because eosinophilic airway inflammation is associated with favorable inhaled corticosteroid response. Fractional exhaled nitric oxide (FeNO) levels and peripheral blood eosinophil count indirectly estimate airway eosinophilia [5,10,84]

Significant (>3%) sputum eosinophilia is the criterion standard for eosinophilic inflammation, but sputum eosinophilia may not be routinely available. Blood eosinophil count is simple and readily available but has diurnal and seasonal variability so multiple assessments should be performed. A blood eosinophil count >0.3 cells/mcL may indicate eosinophilic airway inflammation.

FeNO is a surrogate marker of eosinophilic airway inflammation and inhaled corticosteroid response in classic asthma. FeNO has a relatively high specificity in predicting asthma among patients with chronic cough, but a cut-off level for diagnosis lacks consensus. Elevated FeNO levels (>40 ppb) support a diagnosis of asthma with typical symptoms, but the usefulness in predicting inhaled corticosteroid response in chronic cough is uncertain [5].

A meta-analysis of studies in patients with chronic cough reported significantly higher inhaled corticosteroid response rates in high (>25 ppb) compared with low FeNO (87.4% vs. 46.3%) [105]. After three weeks of high-dose inhaled corticosteroids, the response rate (defined as a ≥1.3-point increase in LCQ) was 68% in patients with high FeNO and no other apparent etiology; LCQ scores and FeNO significantly improved. However, improvements in cough were unrelated to changes in FeNO levels, challenging their direct mechanistic link [106]. Thus, an inhaled corticosteroid trial should be prompted with FeNO >25 ppb but avoided with FeNO <25 ppb unless other factors suggest eosinophilic airway disease [5]. Treatment decisions should not solely hinge on FeNO values [6].

Airway Hyper-Reactivity Measures

In patients with negative physical examination and spirometry findings, bronchial challenge testing (e.g., methacholine) should be performed to confirm airway hyper-reactivity consistent with symptomatic asthma [84]. Bronchial challenge testing is recommended in patients with reactive airway diseases to help diagnosis of asthma and nonasthmatic eosinophilic bronchitis as a cause of chronic cough. A negative bronchial challenge test (defined as an FEV1 decrease of <20% at the highest methacholine challenge dose [10 mg/mL]) has a high negative predictive value of asthma as an etiological diagnosis in chronic cough [104].

Airway eosinophilic inflammation can be present in both asthma and nonasthmatic eosinophilic bronchitis but can be distinguished by a methacholine inhalational challenge (positive in asthma, negative in nonasthmatic eosinophilic bronchitis) because substantially more mast cells localize in the smooth muscle layer in asthma compared with nonasthmatic eosinophilic bronchitis [6].

9. IDENTIFICATION AND MANAGEMENT OF UNDERLYING ETIOLOGIES

The concept that chronic cough is a disease in its own right has only recently gained acceptance. Different phenotypes of this condition are recognized (e.g., asthmatic cough, reflux cough), but the underlying pathology involves hypersensitivity of the vagus nerve and its central projections. The paradigm of asthma, GERD, and postnasal drip causing the symptom of chronic cough was promulgated from the 1980s onwards. However, after it became apparent that many patients suffering from chronic cough with a particular disease label (e.g., asthma, GERD) failed to respond to treatments for that condition, clinical practice guidance changed [79].

Systematic evaluation and treatment guidelines for chronic cough, based on the anatomic locations of receptors and afferent pathways in the cough reflex, first appeared in 1977 [80]. Using such an approach was estimated to determine the cause of chronic cough in 100% of patients, and the subsequent cause-specific treatment was reportedly almost always successful. Termed the ADP, this stepwise diagnostic approach involves a targeted patient history and physical examination to investigate the possible cause/s of their cough. This information is then used to initiate a stepwise treatment approach until resolution of the cough symptoms [77].

The American College of Chest Physicians (ACCP) recommended the ADP in their comprehensive clinical practice guideline on cough in 1998 and in 2006 [81,82]. More recent ACCP guidelines evaluate ADP components and provide treatment recommendations on the major causes of cough, including chronic cough due to GERD in 2016, asthma and nonasthmatic eosinophilic bronchitis in 2020, stable chronic bronchitis in 2020, and unexplained/refractory chronic cough in 2016 [77,83,84,85,86].

However, the understanding of chronic cough has evolved beyond the ADP, especially since 2020 with incorporation of cough hypersensitivity and the treatable traits approach into clinical practice guidelines and endotyping of many cough-associated chronic inflammatory conditions. These knowledge advances are not efficiently reaching U.S. clinicians, because ACCP guidelines on chronic cough have not kept pace. While the ADP remains an important structure of the diagnostic workup for chronic cough patients, its assumptions have been supplanted in recent international chronic cough guidelines.

THE "TREATABLE TRAITS" APPROACH IN CHRONIC AIRWAY DISEASES

In the late 19th century, Sir William Osler established the modern approach to the diagnosis and treatment of disease, based on the principal organ system where symptoms and signs manifest, with some biological correlates. The Oslerian paradigm of disease classification using diagnostic categories has been in use for more than 100 years, with substantial merit, but limitations of the diagnostic label approach have become evident [16].

As noted, in 2016, the treatable traits approach was introduced to pulmonary medicine to overcome the shortcomings of the diagnostic label approach, which does not consider the biological complexity of airway diseases, the distinct endotypes present in each patient, or common patterns of disease such as chronic cough [14,17].

The treatable traits approach addresses the complexity of chronic airway diseases as heterogeneous, frequently overlapping, and often comorbid conditions. In clinical trials of patients with asthma and COPD, the treatable traits approach led to significantly greater improvements in health-related quality of life and biological outcomes and reductions in primary care visits (compared with usual care) [16].

A trait is defined as clinically relevant, measurable, and treatable. These traits can be identified by their phenotypes and/or endotypes in pulmonary, extrapulmonary, and behavioral/environmental domains, and can coexist, interact, and change over time in the same patient. The treatable traits approach is agnostic to the traditional diagnostic labels of asthma or COPD and can be used in any patient with airway disease. The treatable traits approach often extends beyond the diagnostic label itself to find more treatment targets, especially in complex patients with suboptimal response to conventional guideline-based treatment [87,88]. In other words, the treatable traits approach represents a transdiagnostic model.

In asthma, many extrapulmonary traits present as connected comorbidities, meaning they coexist with asthma and may share mechanisms. Extrapulmonary traits (e.g., chronic rhinosinusitis, GERD, anxiety, atopic dermatitis) are clinically relevant as they predict poor outcomes, confound the management of asthma, and are treatable themselves. Through multidimensional assessment of pulmonary, extrapulmonary, and behavioral/environmental domains, the treatable traits approach identifies and targets extrapulmonary traits with effective treatments, improving both asthma and the comorbidity [89].

In the 1970s, the ADP extended the Oslerian classification system to cough, addressing the three common causes (asthma, postnasal drip, reflux) arising from three different anatomical areas. Refined to four causes (asthma, nonasthmatic eosinophilic bronchitis, upper airway cough syndrome, and GERD), this approach benefitted many patients, but in 30% to 40% of these patients, the coughing continues or a presumed cause cannot be identified [16,90]. In 2023, COPD was added to become a fifth common potential underlying cause of chronic cough [24].

Chronic cough is associated with airway and reflux diseases that are heterogeneous, frequently overlapping, and often comorbid, the same characteristics the treatable traits approach addresses [14,17]. For instance, asthma is a clinical syndrome with varying phenotypes and endotypes, rather than a single disease entity. COPD is an umbrella term encompassing different respiratory conditions sharing airflow obstruction. Asthma is not always eosinophilic, and GERD is not necessarily acidic [15]. Despite its relatively recent appearance, the treatable traits paradigm is endorsed throughout pulmonary medicine and in post-2019 (international) clinical practice guidelines on chronic cough.

ENDOTYPES OF COUGH-RELATED CHRONIC INFLAMMATORY DISEASES

A phenotype is an observed characteristic resulting from interactions between genotype and environment. An endotype is a specific biological pathway that forms the basis of observable traits in the phenotype [56].

In the 2016 treatable traits paper, the authors broadly call for a shift away from the classical Oslerian top-to-bottom approach (i.e., from symptoms to mechanisms) to reclassifying airway diseases bottom-up, by linking causal molecular pathways (i.e., endotypes) to disease phenotypes (i.e., from molecules to symptoms) [14].

This has been unfolding in allergy and immunology, and these advances are highly relevant to pulmonary medicine and to chronic cough. For instance, the chronic inflammatory diseases of asthma, allergic rhinitis, chronic rhinosinusitis with or without nasal polyposis, eosinophilic esophagitis, and atopic dermatitis, are now defined by a constellation of symptoms that may result from different pathological mechanisms and not as homogeneous diseases [91].

The discovery of new endotypes in allergic and immune diseases has prompted the transition from symptom-focused disease descriptions to biomarkers and pathogenetic pathways—from phenotypes to endotypes [91]. The imperative for transitioning to endotypes is heightened by FDA approval of several biologicals that target specific inflammatory pathways important in disease pathophysiology [92]. These include the most common chronic cough-associated disorders.

Immune dysregulation has been endotyped as type 1, type 2, and type 3 responses. Asthma has been commonly dichotomized as type 2 and non-type 2. Type 2 inflammation is the best-characterized endotype [91,93,94,95].

Type 2 inflammation involves eosinophils as the key players, which contribute to chronic allergic inflammation by producing cytokines, or interleukins (IL), with specific roles in the inflammatory pathway. IL-5 promotes eosinophil recruitment to sites of inflammation. IL-4 and IL-13 promote immunoglobulin E (IgE) production and immune cell trafficking to tissue, driving and sustaining the type 2 response, tissue damage, and chronic inflammation. IL-31 activates binding sites on sensory neurons, which release CGRP and nerve growth factor, causing neurogenic inflammation. In non-type 2 asthma, Th2 cells migrate to asthmatic bronchi and change their phenotype to produce T1 effector cytokines, such as interferon-γ(IFN-γ) and tumor necrosis factor-α(TNF-α), inducing bronchial epithelial apoptosis and remodeling. TNF-αpromotes neutrophilic inflammation, which correlates with sputum TNF-αlevels in patients with severe asthma. In type 3 inflammation, innate lymphoid cells type 3 (ILC3), T helper lymphocyte type 17 (Th17), and Th22 cells produce cytokines IL-17, IL-22, and IL-23. This mechanism is particularly relevant in the pathogenesis of chronic rhinosinusitis with nasal polyps and neutrophilic asthma [91,93,94,95].

In 2023, the European Academy of Allergy and Clinical Immunology (EAACI) published an updated disease taxonomy with advances in biomarkers, pathogenetic and metabolic pathways, and pathogenic genetic variants. This expanded nomenclature characterizes the following types with relevance to chronic cough [91].

Type V: Epithelial Barrier Defect

The epithelial barrier defect and microbial dysbiosis lead to dysregulation of the immune response, including extensive activation and release of inflammatory cytokines, chemokines and inflammatory mediators (histamine, leukotrienes, reactive oxygen species). The sequence of events eventually leads to tissue damage in asthma, chronic allergic rhinitis, chronic rhinosinusitis, and chronic rhinosinusitis with nasal polyps.

Type VI: Metabolic-Induced Immune Dysregulation

Obesity is a distinguishing variable for clustering and classifying asthma subtypes, and the number of obese patients with asthma has risen dramatically with increasing obesity rates. The obese asthmatic, more likely to be female with adult-onset asthma and to become corticosteroid resistant, has a higher risk of being hospitalized and more frequently presents with severe disease. Higher body mass index (BMI) is associated with increased circulating inflammatory mediators, blood neutrophils, and eosinophils. An additive effect of asthma and obesity further increases inflammatory mediators and airway inflammation.

An asthma endotype introduced in 2020, IL-6-high asthma, is characterized by elevated plasma IL-6 levels, increased markers of systemic inflammation, metabolic dysfunction, and obesity [96].

Type VII: Inflammatory Drug Reactions

These idiosyncratic reactions include hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) and phenotypes such as NSAIDs-exacerbated respiratory disease in patients with asthma and/or chronic rhinosinusitis ± nasal polyposis. NSAIDs-exacerbated respiratory disease is a chronic inflammatory condition characterized by the triad of asthma, recurrent nasal polyps and hypersensitivity to NSAIDs/aspirin. In the underlying mechanism, cyclooxygenase (COX)-1 inhibition releases eicosanoid mediators, causing bronchoconstriction, increased vascular permeability, mucus production and recruitment of inflammatory cells.

These advances in endotyping chronic inflammatory diseases associated with chronic cough have not yet appeared in practice guidelines on chronic cough, with the exception of eosinophilic airway inflammation, but this science is being translated into practice. For example, cough is the most troublesome symptom for patients with asthma. Older patients with asthma and chronic cough show worse clinical outcomes in asthma control, quality of life, and airway obstruction, and more frequent moderate-to-severe exacerbations, partly explained by the interaction of chronic coughing with aging [97]. Non-type 2 inflammation (e.g., increased neutrophils) is associated with cough in older patients with asthma with chronic cough. Interferon-γis a non-type 2 biomarker that enhances cough reflex sensitivity by inducing calcium influx in vagal sensory neurons and is associated with increased cough in patients with refractory chronic cough. Older patients with asthma show increased levels of sputum IFN-γ. Non-type 2 inflammation (i.e., neutrophils and IFN-γ) is also associated with reduced inhaled corticosteroid response [54,97,98].

10. TREATMENT

CHRONIC AIRWAY INFLAMMATION

Treatment of chronic airway inflammation includes inhaled corticosteroids, long-acting beta-agonists, long-acting muscarinic antagonists, leukotriene receptor antagonists, systemic corticosteroids, and biologicals. Confirmation that chronic cough is due to asthma (or another chronic cough-associated condition) requires a beneficial response to therapy for asthma, as patients with asthma can also have chronic cough due to non-asthmatic causes [44].

For chronic cough due to cough-variant asthma or nonasthmatic eosinophilic bronchitis, the ACCP recommends inhaled corticosteroids as first-line treatment [84]. With incomplete response, the inhaled corticosteroid dose should be escalated and adding a leukotriene receptor antagonist should be considered. Other causes of cough should be reconsidered as well. For cough-variant asthma, adding beta-agonists should be considered.

Evidence Based Practice Recommendation

In adult and adolescent patients with chronic cough due to non-asthmatic eosinophilic bronchitis (NAEB), we suggest inhaled corticosteroids as first-choice treatment

https://journal.chestnet.org/article/S0012-3692(20)30045-3/fulltext

Last Accessed: August 12, 2024

Strength of Recommendation/Level of Evidence: 2B (Weak recommendation based on moderate-quality evidence)

In patients with chronic cough in asthma, the first-line treatment is inhaled corticosteroid with or without long-acting beta-agonist [6]. A leukotriene receptor antagonist or long-acting muscarinic antagonist may be added in for those who do not fully respond to initial treatment. Whether biologics can treat chronic cough related to asthma has not been studied.

When an offending allergen cannot be identified or avoided, chronic cough associated with nonasthmatic eosinophilic bronchitis should be treated with an inhaled corticosteroid. Second-line therapy calls for escalation of the inhaled corticosteroid dose; if response remains incomplete, the patient should be assessed for other causes of cough and a trial of leukotriene receptor antagonist initiated. Occasionally, systemic corticosteroids may needed.

Tiotropium may be another therapeutic option. In 17 patients with chronic asthmatic cough refractory to inhaled corticosteroid/long-acting beta-agonist, four to eight weeks of tiotropium (5 mcg/day) significantly improved cough reflex sensitivity and cough severity in a subgroup of 11 patients [107]. These results were replicated in a randomized comparison to theophylline 400 mg/day over four weeks. Both drugs improved cough severity and cough-specific quality of life. Tiotropium decreased cough reflex sensitivity, which correlated with changes in cough severity, and higher baseline cough reflex sensitivity predicted greater tiotropium response. The authors conclude that tiotropium may modulate cough reflex sensitivity to alleviate chronic cough in asthma refractory to inhaled corticosteroid/long-acting beta-agonist [108].

EMPIRIC TREATMENT APPROACH

Empiric treatment of chronic cough is systematically directed at the four most common causes of cough, starting with upper airway cough syndrome. In its 2006 guideline, the ACCP states that therapy should be given in sequential and additive steps, because more than one cause of cough may be present [82]. Initial empiric treatment should begin with an oral first-generation antihistamine/decongestant.

If chronic cough persists after treatment for upper airway cough syndrome, asthma as the possible cause should be worked up next. If spirometry does not indicate reversible airflow obstruction, bronchoprovocation testing is performed in the evaluation for asthma.

With the diagnoses of upper airway cough syndrome and asthma ruled out or treated without the elimination of cough, nonasthmatic eosinophilic bronchitis should be considered next, with a properly performed induced sputum test for eosinophils. In most patients with suspected cough due to asthma, a bronchoprovocation challenge should be performed and, if the result is positive, some combination of inhaled corticosteroids, inhaled beta-agonists, and/or oral leukotriene inhibitors should be administered.

In patients whose cough responds only partially or not at all to interventions for upper airway cough syndrome and asthma or nonasthmatic eosinophilic bronchitis, treatment for GERD should be instituted next. In patients with cough whose condition remains undiagnosed after all of these conditions has been worked up, referral to a cough specialist is indicated.

When the cause of chronic cough is identified or suspected, there are two options [26,44,57,109]. The first is to pursue one diagnostic and treatment path at a time; with incomplete response of the cough to one line of therapy, adding therapy for the next most likely diagnosis is reasonable. The second option in patients with more than one suspected cause and a cough that is especially disruptive is to empirically treat or evaluate the likely causes simultaneously. After the cough resolves, treatments can be stopped sequentially, starting with the least likely to have been helpful, observing the patient for any return of cough.

BEHAVIORAL TREATABLE TRAITS

Nonadherence and poor inhalation technique strongly influence outcomes in airway disease. Despite their critical importance, the proportion of patients with poor technique is high, unimproved over the past 40 years, and often unaddressed by clinicians. These behavioral treatable traits can be improved using strategies such as patient-centered communication, motivational interviewing, shared decision-making, and simplification of drug regimens; and should be assessed in every follow-up visit [110].

Smoking cessation improves cough by resolving chronic bronchitis. Nicotine suppresses the cough reflex, and nicotine withdrawal due to smoking cessation may enhancement cough hypersensitivity; hence, patients may experience more coughing for a period after quitting. This can be attenuated and quit rates improved by using nicotine replacement [5].

LOWER AIRWAY ETIOLOGIES OF CHRONIC COUGH AND MANAGEMENT

Lower airway diseases commonly associated with chronic cough are classic asthma, cough-variant asthma, nonasthmatic eosinophilic bronchitis, and COPD [20].

Chronic cough is a central feature that develops in diverse pulmonary pathologies, such as asthma (an inflammatory airway disease) and idiopathic pulmonary fibrosis (an alveolar fibrosing disease), highlighting the significant role of dysregulated cough pathways in lung disease phenotypes [60]. Chronic cough prevalences have been reported for asthma (8% to 58%), COPD (10% to 74%), bronchiectasis (82% to 98%), interstitial lung disease (50% to 89%) and sarcoidosis (3% to 64%); in all five diseases, patients demonstrate cough reflex hypersensitivity, a cardinal feature of cough hypersensitivity syndrome [111].

Presence of chronic cough generally predicts impaired health status and more severe respiratory disease and is associated with greater symptom burden and disease severity in asthma, COPD, bronchiectasis, and interstitial lung disease. It has also been linked to greater exacerbations in asthma and bronchiectasis and increased mortality and lung transplantation in idiopathic pulmonary fibrosis [111].

Asthma and Nonasthmatic Eosinophilic Bronchitis

Asthma is a complex, chronic airway inflammatory disease of bronchial hyper-responsiveness, intermittent airflow obstruction, and symptoms of wheeze and dyspnea that impacts 26 million people in the United States, results in approximately 10,000 deaths annually, incurs an estimated $56 billion annually in medical care and lost productivity costs, and accounts for cough in 24% to 32% of adult nonsmokers with chronic cough [84,112,113]. Asthma prevalence has increased with rising obesity rates. Obesity often precedes an asthma diagnosis, making it an important modifiable risk factor (or treatable trait) [5,113].

In atopic asthma, the most common type (affecting approximately 50% of adults with asthma), allergens trigger innate and adaptive immune activity, releasing inflammatory mediators such as histamine, prostaglandins, and leukotrienes that promote bronchoconstriction and cough [20,114]. Classic asthma describes symptoms of wheezing, chest tightness, and dyspnea. In these patients, immune response to allergen exposure results in airway inflammation, airflow obstruction, and characteristic symptoms. Increased mucous secretions in narrowing airways induce cough [31,112].

Cough-variant asthma, in contrast, presents with persistent cough as the primary or only symptom. Cough receptor density is highest in the proximal airways, decreasing as the airways get smaller. In cough-variant asthma, inflammation is primarily in the proximal airways, where cough is stimulated, and less so distally, where inflammation and narrowing cause wheezing and dyspnea in classic asthma [31,56]. Some have suggested that asthma-variant cough is a more appropriate term than cough-variant asthma, given that cough hypersensitivity symptoms are the chief complaints, while asthmatic features act as triggers and treatable traits of chronic cough in these patients [115].

Nonasthmatic eosinophilic bronchitis was first described in 1989 as corticosteroid-responsive chronic cough in nonsmokers with airway eosinophilia, but without variable airway obstruction or bronchial hyper-responsiveness [116]. Nonasthmatic eosinophilic bronchitis accounts for 10% to 30% of specialist referrals for chronic cough, but nonasthmatic eosinophilic bronchitis prevalence is uncertain, as its diagnosis requires assessment of eosinophilic airway inflammation [44,84,117]. In nonasthmatic eosinophilic bronchitis, patients have chronic cough, no symptoms or evidence of variable airflow obstruction, sputum eosinophilia, and normal bronchial provocation tests [56,117].

Chronic cough in asthma is mechanistically complex, involving IgE or non-IgE mediated eosinophilic airway (i.e., atopic or nonatopic) inflammation, abnormal neuromechanical properties of the lungs, and presence of cough reflex hypersensitivity independently of airway eosinophilia or bronchial hyper-responsiveness [20].

Nonasthmatic eosinophilic bronchitis and asthma share airway eosinophilia and similar basal membrane thickening, but inflammatory mast cells primarily infiltrate the superficial airway epithelium in nonasthmatic eosinophilic bronchitis versus airway smooth muscle in asthma. Along with lower IL-13 expression in nonasthmatic eosinophilic bronchitis, this partially explains bronchitis and cough with normal airway responsiveness in nonasthmatic eosinophilic bronchitis [116,118]. Nonasthmatic eosinophilic bronchitis lacks the airway hyper-responsiveness of cough-variant asthma, but both share atopic features of eosinophilia and airway inflammation [109].

Eosinophilic airway inflammation in cough-variant asthma is linked to more severe disease. Cough-variant asthma may be a precursor of classic asthma, and both cough phenotypes can manifest overlapping symptoms, airway inflammation, and bronchial hyper-responsiveness [20]. Chronic dry cough, eosinophilic inflammation, and chronic airflow obstruction can present in both cough-variant asthma and nonasthmatic eosinophilic bronchitis [56].

Chronic Obstructive Pulmonary Disease (COPD)

COPD comprises several lung diseases, including emphysema and chronic bronchitis, with persistent and usually progressive airflow limitation associated with an enhanced chronic inflammatory response in the airways and lungs. Exacerbations and comorbidities contribute to the overall severity, while airway and systemic inflammation in COPD is related to disease progression and mortality [119,120].

In the United States, 14.2 million adults had diagnosed COPD in 2021, of whom 25% were never-smokers, and COPD accounted for 354,000 deaths in 2020 [121,122]. Among patients with COPD, 70% experience persistent cough and many consider it extremely severe and impairing [64].

Chronic bronchitis describes productive cough on most days of the week for at least three months total duration in two successive years. Chronic obstructive bronchitis is chronic bronchitis with spirometric evidence of airflow obstruction. Chronic asthmatic bronchitis is a similar condition with chronic productive cough, wheezing, and partially reversible airflow obstruction mostly found in smokers with a history of asthma [123].

Emphysema is defined as the permanent enlargement and damage of the lung air sacs with destruction of the airspace walls, causing symptoms of breathlessness. Emphysema can exist without airflow obstruction but is more common in patients with moderate or severe airflow obstruction [119].

COPD manifests as productive cough with airflow limitation and occasional bronchial hyper-responsiveness [20]. COPD and asthma share symptoms of cough, wheeze, and difficulty breathing. The blurred distinction between chronic obstructive bronchitis and chronic asthmatic bronchitis is termed asthma-COPD overlap [123].

Cigarette smoking is the primary risk factor, but only 15% of smokers develop clinically apparent COPD. Smokers with pre-existing airway reactivity, even in the absence of clinical asthma, have greater risk of developing COPD. Inflammation in the large and small airways can persist after smoking cessation. The genetic disorder alpha-1 antitrypsin deficiency is an important cause of emphysema in nonsmokers and markedly increases susceptibility to COPD in smokers [120,123].

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis is an interstitial lung disease, a group of pulmonary disorders characterized by inflammation and/or fibrosis of the lung parenchyma associated with progressive dyspnea frequently resulting in end-stage respiratory failure. Interstitial lung disease affects 650,000 people and causes 25,000 to 30,000 deaths per year in the United States [124].

Idiopathic pulmonary fibrosis, the most common interstitial lung disease accounting for 35% to 61% of all patients, is a chronic, progressive, invariably fatal fibrotic lung disease [111,124]. Despite approvals of two antifibrotic therapies, the five-year survival rate remains 25%, far worse than many common cancers. Pharmacotherapies slow the disease progression, but none address the significant symptoms of chronic cough, fatigue, and dyspnea suffered by 85% to 95% of patients with idiopathic pulmonary fibrosis [125].

Chronic cough in idiopathic pulmonary fibrosis predicts disease progression and mortality, is as distressing as breathlessness for patients, and remains one of the most difficult symptoms to control [64,125]. Among 1,447 patients with idiopathic pulmonary fibrosis cough, every 1-point decrease in LCQ score increased the risk of respiratory-related hospitalization by 6.5%, death by 7.4%, and lung transplantation by 8.7% over 12 months. Worse cough-specific quality of life independently associated with increased risk of respiratory hospitalization, death, and lung transplantation [126].

Two breakthrough studies demonstrated that low-dose morphine and nalbuphine can safely decrease coughing in idiopathic pulmonary fibrosis patients, as will be described later in this course.

Bronchiectasis

Bronchiectasis is a heterogenous disorder characterized by infection, airway inflammation, failure of mucociliary clearance, and airway structural damage. Absolute suppression of cough is not recommended because bronchiectasis is a suppurative condition with an increased risk of infection. However, much of the cough exceeds what is physiologically needed for sputum clearance and is thus maladaptive or pathological [111]. Cough is a central clinical feature of bronchiectasis that contributes to impaired health status and may be an early indicator of disease exacerbation, but it is almost never evaluated [64].

UPPER AIRWAY ETIOLOGIES OF CHRONIC COUGH AND THEIR MANAGEMENT

In upper airway cough syndrome, diverse chronic infectious, inflammatory, or neurogenic upper airway diseases induce chronic cough [20,127]. While upper airway cough syndrome lacks a uniform definition, its prevalence in chronic cough patients is probably comparable to other major causes like asthma and GERD; in some studies, it is the first or second leading cause [39,127].

Rhinitis, comprising most chronic upper airway diseases in upper airway cough syndrome, has a lifetime prevalence up to 33% in the United States [6]. Nasal mucosa inflammation due to allergic or non-allergic cause leads to mucus secretion, sneezing, nasal pruritus, and postnasal drip that irritates the airways and stimulates coughing [31]. In chronic rhinitis, these symptoms persist at least three months, inducing nasal obstruction and increased nasal discharge [119].

Rhinitis has numerous phenotypes and the nomenclature is not straightforward (Table 5). Allergic rhinitis requires immunoglobulin E (IgE)-mediated sensitization to an allergen exposure [6]. Chronic cough in patients with allergic rhinitis is often related to undiagnosed asthma or nonspecific bronchial hyperreactivity. Bronchial biopsy studies of patients with allergic rhinitis without asthma have shown inflammatory cell infiltration and active structural remodeling of the lower airways similar to that of patients with asthma, thereby potentially contributing to cough in these patients [128].

Table 5: DISTINGUISHING CHARACTERISTICS OF RHINITIS PHENOTYPES

Rhinitis Phenotype

Primary Symptoms

Associated Features

More Responsive to

Less Responsive to

Allergic

Sneezing, nasal pruritis, clear rhinitis

Ocular itching, wheezing, atopic dermatitis

INCS, INAH, FGAH, SGAH, SCS, AIT

Decongestants, ABX

Nonallergic noninfectious

Intermittent congestion, clear rhinitis

Physical triggers (temperature changes, food, irritants)

INCA, INAH, INAC

FGAH, SGAH, SCS, AIT, ABX

GERD-associated

Postnasal drip, throat clearing

Epigastric pain, heartburn, dysphagia

GERD diet and lifestyle changes, INAC

FGAH, SGAH, INCS, INAH, SCS, ABX, AIT

Chronic rhinosinusitis with or without nasal polyposis

Anosmia/hyposmia, unremitting congestion, facial pain/pressure

Wheezing, NSAID hypersensitivity

SCS, biologics, intermittent INCS

FGAH, SGAH, INAH

Infectious

Acute onset, sinus pressure, nasal congestion with purulent discharge

Viral prodrome, episodic nature lasting <2 weeks

Saline nasal lavage, INAH, decongestants, INAC

FGAH, SGAH, INCS, SCS, ABX, AIT

ABX = antibiotics; AIT = allergen immunotherapy; FGAH = first-generation oral antihistamines; GERD = gastroesophageal reflux disease; INAC = intranasal anticholinergics; INAH = intranasal antihistamines; INCS = intranasal corticosteroids, SCS = systemic corticosteroids; SGAH = second-generation oral antihistamines.

Source: [6]

Chronic nonallergic rhinitis syndromes include chronic nonallergic rhinitis, nonallergic rhinitis with eosinophilia syndrome (NARES), atrophic rhinitis, and drug-induced rhinitis; nonallergic rhinitis accounts for up to 80% of cases [129]. Nonallergic rhinitis phenotypes include [6]:

- Vasomotor

- Irritant

- Infectious

- GERD-associated

- Chronic rhinosinusitis with or without nasal polyposis

Rhinosinusitis is preferred to sinusitis because purulent sinus disease without similar rhinitis is rare [130].

Chronic rhinosinusitis is an inflammatory disease of the sinonasal mucosal lining secondary to infectious and allergic etiology, with symptoms of anosmia, nasal obstruction, thick nasal drainage, and facial pressure [92]. Retention of sinus secretions, the key event in chronic rhinosinusitis development, fosters infection and is caused by obstruction or narrowing of sinus ostia, mucociliary dysfunction, or altered mucus composition; 90% of sinus infections involve the maxillary sinus [119]. Cough, one of the important symptoms of chronic rhinosinusitis, occurs in 1% to 5% of U.S. adults [131].

Chronic rhinosinusitis with nasal polyposis, representing up to 20% of chronic rhinosinusitis cases, is more debilitating than the phenotype without nasal polyposis. Comorbidities in chronic rhinosinusitis with nasal polyps are asthma (55% to 56%), allergy (12% to 77%), and allergic rhinitis (17% to 76%). Asthma with nasal polyps is harder to control and more prone to severe exacerbations [92,93].

Chronic cough pathogenesis in upper airway cough syndrome was previously tied to postnasal drip, because the nose and sinuses lack vagal sensory innervation. However, only a minority of patients with postnasal drip have chronic cough, some patients with upper airway cough syndrome do not have postnasal drip, and the pathophysiology is more complex [11,127].

In chronic rhinitis and rhinosinusitis, inflammatory mediators are transmitted via glossopharyngeal and vagal receptors in the pharynx and larynx, and via afferent fibers of the trigeminal nerve, sensitizing the cough reflex centrally [11]. Direct irritation of nasolaryngeal mucosa and stimulation of vagal afferents by postnasal drip lead to hematogenous spread of inflammatory mediators and neurogenic or systemic communication between upper and lower airways, resulting in airway sensory nerve inflammation, cough reflex hypersensitivity, and chronic cough [10,39].

Convergence of trigeminal and vagal afferents in central cough pathways provides a mechanistic/neuronal link between upper airway disease and the development of cough hypersensitivity [5]. In general, upper airway diseases lead to chronic cough only if the cough reflex becomes hypersensitive; therefore, they are generally considered a trigger rather than a cause of chronic cough [11].

In 2024, nonallergic rhinopathy was introduced to replace vasomotor rhinitis as the term describing 80% of the larger nonallergic rhinitis category, prompted by evidence that neuroinflammation and TRPV1 receptor activation play important roles, rather than blood vessels. TRPV1 also contributes to nasal hyper-reactivity in allergic rhinitis, an entity called mixed rhinitis. The management of nonallergic rhinitis requires the correct diagnosis; rhinopathy draws attention to the underlying neuro-immune endotype [129,132].

Chronic cough is triggered in many patients with chronic upper airway disease (usually allergic rhinitis or chronic rhinosinusitis with or without nasal polyps) with common symptoms and signs of postnasal drip, compulsive throat-clearing, nasal stuffiness, globus feeling, headache/facial pain, loss of smell and taste, recurrent hoarseness, and cobblestone appearance of the pharyngeal mucosa on inspection [11]. The most commonly used tool is the SinoNasal Outcome Test (SNOT) [92].

With numerous symptoms and unclear diagnostic criteria, upper airway cough syndrome diagnosis has been based on first-generation oral antihistamine response, which may have central antitussive effects. Upper airway and other airway disease is frequent in patients with chronic cough, making it unclear whether coughing arises from upper or lower airways [5].

A large case series found allergic rhinitis, classic asthma, chronic rhinosinusitis, and nasal polyposis in 46%, 31%, 12%, and 9% of patients with chronic cough, respectively. The high predictive value for concomitant asthma in upper airway cough syndrome calls for investigating lower airway pathology in chronic cough of upper airway origin [20].

Rhinitis is a principal contributor to upper airway cough syndrome. The lengthy differential diagnosis of rhinitis in upper airway cough syndrome includes both allergic and nonallergic diseases; many patients have a combination of both or mixed rhinitis. Distinguishing these will increase treatment success and decrease the time before symptoms improve [6].

Radiological investigations may be useful and are guided by nasal symptoms. Incidental sinus changes may be present in up to 33% of CT and 67% of MRI scans. PPIs should not be used to treat upper airway symptoms [5].

Laryngeal dysfunction and hypersensitivity are common in chronic cough [5]. Consider treatment of laryngeal hypersensitivity as a symptom of cough hypersensitivity. Laryngitis often leads to chronic cough with voice changes (e.g., hoarseness, aphonia). Chronic cough is frequent in functional voice disorders, (e.g., muscle tension dysphonia) [11].

In vocal cord dysfunction, laryngeal hypersensitivity leads to persistent laryngospasm due to different triggering factors, manifesting as cough, wheeze, breathlessness, and voice disturbance. Coughing can be both a trigger and a symptom. Symptoms may be episodic. Diagnosis is based on findings in history, laryngoscopy, and, if possible, spirometry during an attack [5,11]. In a refractory chronic cough population, vocal cord dysfunction is a common finding and may be a manifestation of laryngeal hypersensitivity. Treatment is by speech and language therapy intervention [5].

REFLUX DISORDER ETIOLOGIES OF CHRONIC COUGH AND THEIR MANAGEMENT

In GERD, retrograde transit of gastric contents into the esophagus leads to troublesome symptoms of heartburn, esophageal chest pain, and regurgitation (i.e., "typical" esophageal symptoms) [133,134]. Cough is an extraesophageal symptom of reflux disease [11]. Chronic cough has a low, but potential, pathophysiological relationship to reflux disease [133]. Estimated chronic cough due to GERD vary widely (7% to 85%), with higher prevalence in Western than Asian countries [20]. Chronic cough and GERD are both very common conditions and can therefore co-appear without being causally related [99].

GERD was previously considered a leading chronic cough etiology directly caused by the acidity of proximal esophageal refluxate, but patients with chronic cough and healthy controls show similar proximal reflux events [58,135]. Many patients with chronic cough report GERD symptoms, but PPI therapy is ineffective in those without acidic reflux and only modestly benefit those with typical esophageal symptoms [109].

Reflux can be acidic or non-acidic, liquid or gaseous, and proximal or distal in location. Reflux can trigger cough, coughing can induce reflux, and chronic cough may also cause GERD or increase reflux episodes [20,134]. PPIs decrease reflux acidity but not reflux events and work poorly in patients with airway or extraesophageal reflux [136]. PPI failure in chronic cough treatment suggests the acidic component of reflux has little effect on chronic cough or its etiology [58].

In extraesophageal reflux, troublesome symptoms not normally considered esophageal manifest in the lower and upper airways as chronic cough, asthma, laryngitis, dysphonia, pulmonary fibrosis, sinus disease, ear disease, postnasal drip, throat clearing, non-cardiac chest pain, or dental erosion [20,134].

Laryngopharyngeal reflux is defined as the backflow of weakly or non-acidic "mist" or liquid above the upper esophageal sphincter into the upper airways. Due to weaker mucosal defenses in the upper respiratory tract, inflammation of the mucous membranes and epithelial tissue damage occur with exposure to fewer, and less acidic, reflux events. A significant negative effect from pepsin, a gastric enzyme, on oropharyngeal and respiratory tract tissues is also demonstrated [58,137].

Airway reflux is interchangeably used for laryngopharyngeal, non-acid esophageal, extraesophageal, and silent reflux. But it is important to remember that airway reflux is not GERD. Defined by the symptoms of heartburn and dyspepsia, and associated with esophagitis, GERD is a peptic condition predominantly of liquid acidic reflux [59]. The majority of patients with airway reflux/laryngopharyngeal reflux do not have esophagitis or heartburn [137].

Airway reflux shifts the paradigm from traditional GERD to cough hypersensitivity through sensitization of vagal afferents. Evidence that esophageal irritation by acid and non-acid reflux may directly initiate cough led to the concept of an esophagobronchial reflex based on crosstalk at the nucleus tractus solitarius between esophageal and airway sensory neurons converging in this brainstem area [58].

This led to gastroesophageal reflux-associated cough, a cough-predominant phenotype of GERD, as a chronic airway inflammatory disease. Epithelial damage and airway inflammation in gastroesophageal reflux-associated cough patients suggest micro-aspiration, and the esophagobronchial reflex mediated by distal esophageal vagal afferents [136].

Chronic cough may result from GERD/extraesophageal reflux-induced airway inflammation and supra-esophageal pathology. Whether refluxate causes damage leading to extraesophageal reflux, needs to be acidic or merely contain pepsin, or whether neurogenic signaling leads to inflammation and subsequent symptoms remains unclear [134,136].

In sum, GERD can directly affect the airways when gastric acid backflows into the esophagus, irritating the proximal esophagus and laryngopharyngeal areas, triggering the cough reflex to clear the airways. Gastric content can indirectly cause chronic cough by stimulating the distal esophagus, resulting in vagus nerve irritation and cough reflex sensitization. Airway reflux may comprise most cases of reflux-induced cough, its extraesophageal symptom hampering diagnosis based on symptoms alone [39].

Management

As discussed, the role of reflux, esophageal dysmotility, and aspiration in chronic cough is controversial. Studies suggest non-acidic reflux, both liquid and gaseous, may be an etiological factor. However, no tool reliably detects such reflux and diagnosis relies on clinical history supported by validated questionnaires (e.g., the HARQ). Moreover, the high prevalence of esophageal dysmotility in patients with chronic cough suggests esophagopharyngeal reflux rather than GERD may be the problem [10].

Many of the signs and symptoms associated with chronic cough are explicable by reflux and aspiration, including voice change, nasal symptoms, and dysgeusia. Frequent chest infection bronchitis, even frank bronchiectasis, may be the consequence rather than the cause of cough via repeated aspiration. Unsurprisingly, following aspiration of GI contents there is a neutrophilic or eosinophilic inflammatory response that might be giving rise to asthmatic cough and mucus hypersecretion [10].

The 2016 ACCP clinical practice guideline for reflux-associated chronic cough suggests that esophageal manometry and pH-metry be performed in patients with suspected reflux cough refractory to a three-month antireflux trial and being evaluated for surgical management (antireflux or bariatric); or with strong clinical suspicion warranting diagnostic testing for gastroesophageal reflux (Table 6). Esophageal manometry assesses for major motility disorder. It involves placing the pH electrode 5 cm above the lower esophageal sphincter in the pH monitoring study after the patient is off PPIs for seven days and histamine H2-receptor antagonists for three days [83].

Table 6: REFLUX INVESTIGATIONS IN PATIENTS WITH CHRONIC COUGH

Investigation

Description

Utility

24-hour esophageal pH testing

A catheter is inserted nasally into the esophagus with two pH sensors for 24-hour measurement of proximal and distal acid reflux

Does not reliably predict response to PPI therapy

Barium meal

Radiographic test that visualizes the movement of barium liquid. Can detect structural and motility abnormalities of the esophagus, stomach, and duodenum.

May demonstrate a hiatal hernia and document the extent of non-acid reflux not identified on 24-hour pH testing

Manometry

A catheter is inserted to assess motility patterns by measuring the amplitude of contractile events in the esophagus and its sphincters

Impaired peristalsis is more prevalent in patients with chronic cough, consistent with symptoms of esophageal dysmotility

Impedance testing

Intraesophageal probes measure impedance and pH to record acid, weakly acidic, and non-acid reflux events

Non-acid refluxate may be important in chronic cough etiology, but impedance testing is not validated to investigate chronic cough

Upper GI endoscopy

Allows direct inspection of the upper GI tract and biopsy of stomach and duodenum

Often unrevealing; endoscopic evidence of GERD less common with atypical (e.g., chronic cough) vs. typical symptoms

Source: [19]

For overweight and obese patients, treatment of suspected reflux-cough should include diet change to promote weight loss. In all patients, recommended diet and lifestyle modifications include [6]:

- Eliminate coffee, tea, soda, other carbonated beverages, fish oil supplements, chocolate, mints, alcohol, and energy drinks, sports, or other drinks containing citric acid

- Consume no more than 45 grams of fat daily

- Avoid smoking and vaping

- Avoid exercising that markedly increases intra-abdominal pressure

- Elevate the head of the bed and avoid meals within three hours of bedtime

In patients with heartburn and regurgitation, PPIs, histamine H2-receptor antagonists, alginate, or antacid therapy is often sufficient to control these symptoms. Gastrointestinal symptoms respond within 4 to 8 weeks, but cough may take 12 weeks to improve [83]. PPI monotherapy is not recommended for chronic cough with solely extraesophageal symptoms, as it is unlikely to resolve the cough.

The ACCP suggests against antireflux surgery for patients with chronic cough patients with a major motility disorder and/or normal acid exposure time in the distal esophagus, as the procedural risks and lack of supporting evidence make the risk-benefit ratio unacceptable [83]. However, surgery may be considered for presumed reflux-cough in patients with normal peristalsis, abnormal esophageal acid exposure on pH-metry, and refractory to medical therapy.

TREATABLE TRAITS AND THOROUGHNESS

The variable success in managing chronic cough may be due, in part, to guidelines or protocols not being implemented as planned (Table 7) [6,80]. Failure to recognize the complexity of airway diseases can lead to suboptimal outcomes, as diseases with different endotypes can require different therapeutic strategies (precision medicine). Because the treatable traits approach is a label-free approach, it does not start on the assumption that the diagnosis (e.g., asthma, COPD) is well-established and clear, a situation that is not the case in many instances in clinical practice, particularly in primary care. This is a fundamental, but often overlooked, issue in the current guideline-directed management of airway diseases [14,16].

Table 7: PITFALLS IN THE MANAGEMENT OF CHRONIC COUGH

Upper Airway Cough Syndrome

Failing to recognize that upper airway cough syndrome (also asthma or GERD) can present as a cough-phlegm syndrome, misdiagnosed as chronic bronchitis.

Assuming that all histamine H1 receptor antagonists (H1RAs) are the same. H1RAs without anticholinergic activity do not help nonallergic rhinitis conditions. Further, anticholinergic H1RAs may adversely affect memory, glaucoma, and prostate problems. Instead, consider ipratropium bromide nasal therapy.

Failing to consider:

- "Silent" upper airway cough syndrome when a patient does not sense a postnasal drip or realize their frequent throat clearing

- Allergic rhinitis and recommend the avoidance of allergens because symptoms are perennial

- Sinusitis because it is nonobvious

- NSAID-exacerbated disease

- The potentially beneficial role of upper respiratory endoscopy

Asthma

Failing to recognize that:

Asthma can present as cough alone (i.e., cough-variant asthma)

Inhaled medications may exacerbate cough

Positive methacholine challenge alone is not diagnostic of asthma

Nonasthmatic Eosinophilic Bronchitis

Failing to consider the diagnosis, occupational/environmental causes, or order the correct test

GERD

Failing to recognize that:

- "Silent" reflux disease can be causal and that it may take two to three months of intensive treatment before cough starts to improve and five to six months to resolve

- GERD can be worsened by comorbidities (e.g., obstructive sleep apnea) or their treatment (e.g., nitrates or calcium channel blockers for coronary artery disease, progesterone for hormone replacement)

Assuming that:

- Cough cannot be due to GERD because cough remains unchanged when gastrointestinal symptoms improve

- Vocal cords' appearance can diagnose GERD, when inflammatory changes from coughing can mimic those of reflux

Being unaware that acid suppression alone will not improve cough

Failing to consider:

- Non-acid reflux disease

- The role of diet, intense exercise, and prokinetic therapy

- Adequately treat co-existing causes of cough that perpetuate the cycle of cough and reflux because cough can provoke reflux

Triad of Upper Airway Cough Syndrome, Asthma, and GERD

Failing to consider that more than one condition may be contributing simultaneously to cough, or failing to consider additional contributing conditions because of another "obvious" cause (e.g., COPD)

Failing to appreciate:

- These chronic disorders cannot be cured and will periodically flare, especially with viral illness

- When cough flares after a period of remission, re-evaluate as if a new problem

- Asthma may become a problem when it was not before

Unsuspected Airway Diseases

Failing to perform bronchoscopy when chest x-ray and CT are normal. Transnasal route allows inspection of both upper and lower respiratory tracts.

Failing to appreciate that prolonged IV therapy for suppurative airway disease may succeed when the same drug given orally failed

Source: [6,80]

Pulmonary and Extrapulmonary Traits as "Connected Comorbidities"

As discussed, the treatable traits approach encourages transdiagnostic thinking about chronic cough and associated diseases to identify distinct endotypes and phenotypes within traditional diagnostic categories, as well as shared mechanisms across diagnostic boundaries. For example, asthma and severe chronic rhinosinusitis with nasal polyposis are frequently associated with other, coexisting type 2 inflammatory diseases, such as NSAID-exacerbated respiratory disease, allergic rhinitis, eosinophilic esophagitis, atopic dermatitis, and type 2 eosinophilic COPD [114]. Chronic rhinosinusitis with nasal polyposis has a 7% prevalence in patients with asthma, increasing to 40% in NSAIDs-exacerbated respiratory disease [138]. In predisposed subjects, a dysregulated type-2 inflammation can develop in epithelial barriers (e.g., airways, intestine, skin) in response to various antigens, such as allergens, micro-organisms, and pollutants. This dysregulated epithelial response leads to diseases such as asthma, rhinitis/rhinosinusitis, eosinophilic gastrointestinal disorders, and atopic dermatitis [95].

Allergens are not the only antigens that trigger inflammation. Rather than allergic disorders, type 2 disorders would be a more appropriate definition, also including non-allergic eosinophilic diseases such as nonasthmatic eosinophilic bronchitis, chronic rhinosinusitis, and eosinophilic disorders of the gastrointestinal tract [95].

Targeted biological therapies can also address conditions with shared type 2 pathophysiology. Biologics with FDA approval targeting type 2 inflammatory disease pathophysiology include dupilumab (anti-IL-4 and IL-13), omalizumab (anti-IgE), mepolizumab (anti-IL-5), and benralizumab (anti-IL-5R) [92]. Mepolizumab has proven effective in chronic rhinosinusitis with nasal polyposis and asthma with high eosinophil levels in sputum. Dual targeting of IL-4 and IL-13 by dupilumab has shown efficacy across chronic rhinosinusitis with nasal polyposis, asthma, eosinophilic esophagitis, and atopic dermatitis, and in uncontrolled COPD with high eosinophil counts [93]. Chronic cough, it should be stressed, has not been examined in any study of biological therapies.

The Argument for Thoroughness

The optimal clinical approach in chronic cough and refractory chronic cough continues to evolve. The ERS guideline suggests simplifying the diagnostic process to shorten a patient's journey to a diagnosis of refractory/unexplained chronic cough and limiting sequential empiric trials to two to four weeks unless responses are observed [10]. However, the 2023 BTS guideline and others argue for a more assertive approach to identify all treatable traits and maximize therapy response before diagnosing refractory/unexplained chronic cough [5,78]. This would be the counterargument to the diagnostic-therapeutic empiric trials approach.

In a 2024 study, all 201 patients presenting to a cough center in 2018–2022 were prospectively studied. Refractory chronic cough (defined as persistent cough severity VAS ≥40 with little improvement after at least two treatment attempts) was diagnosed in 30.7% and unexplained chronic cough in 1.5% [78]. The authors suggest a thorough diagnostic algorithm, with frequent second-step investigations, enabled diagnoses of less common cough etiologies and the low (1.5%) unexplained chronic cough rate. As many therapeutic trials as necessary were engaged in order to target all identifiable treatable traits of chronic cough. Treatment followed a stepwise intensification of therapy and introduced add-on treatment of all cough causes, but this was time-consuming and related to difficulties in keeping patients' adherence. In routine practice, the authors usually recommend more than two therapeutic trials before diagnosing refractory chronic cough. When refractory/unexplained chronic cough is diagnosed, additional treatments should be initiated. These patients require nonpharmacologic and/or drug therapies with opioids, neuromodulators, or novel refractory chronic cough agents.

In a separate study conducted at a clinic in China, experts found that among 1,554 patients with chronic cough patients with negative chest x-rays, 58.8% were attributable to common causes, including nonasthmatic eosinophilic bronchitis (18.3%), cough-variant asthma (16.3%), gastroesophageal reflux-associated cough (13.2%), and upper airway cough syndrome (11.1%) [139]. In addition, 18.4% of cases were attributable to other causes: chronic bronchitis (6.1%), bronchiectasis (4.5%), atopic (4.4%), and postinfectious (3.5%) cough; 9.6% had chronic cough of unexplained etiology. Finally, 13.1% of cases were due to rare causes (e.g., bacterial bronchitis, somatic cough syndrome, diffuse panbronchiolitis, obstructive sleep apnea, and interstitial lung disease). These findings suggest that special examinations should be considered after excluding common causes of chronic cough.

It is important to remember that the workup to rule out refractory/unexplained chronic cough is not complete until bronchoscopy has been performed [6]. A study of bronchoscopy involving 54 patients with refractory/unexplained chronic cough with sputum production (more than 1 tbsp/day), atypical urge-to-cough sensations in chest, and unremarkable chest CT revealed bronchoalveolar neutrophilia in 84% and excessive dynamic airway collapse in 31% [140]. Bronchoscopy influenced or changed the management in 89% of patients. Bronchoscopy findings in this specific population have rarely been described, and treatment strategies in these patients differ from typical refractory/unexplained chronic cough. Bronchoscopy provides high diagnostic value in refractory/unexplained chronic cough with mucus production, identifying specific treatable traits of neutrophilic airway inflammation and excessive dynamic airway collapse [140].

Another argument for moving away from the routine use of empiric therapeutic-diagnostic trials is to spare patients with chronic cough from exposure to minimally helpful or unhelpful medications with potentially adverse effects. For example, PPIs are recommended against for chronic cough in patients who lack classic GERD symptoms. Cumulative doses of PPIs dose-dependently increase the risk of developing hypomagnesemia and other side effects. Both hypomagnesemia and its consequent decrease in melatonin production can decrease lower esophageal sphincter tone and trigger a paradoxical iatrogenic cough. Rather than PPI dose escalation for partial responders, magnesium and melatonin supplementation is recommended to curtail side effects of long-term PPIs [104].

Oral corticosteroids, due to their substantial cumulative side effects, are now recommended only as a last resort in the most recent asthma treatment guidelines [141,142]. Even occasional short courses of oral corticosteroids are associated with significant short-term and cumulative long-term adverse effects, with a pronounced dose-response. Short-term adverse effects of oral corticosteroids include sleep disturbance, increased appetite, reflux, mood changes, sepsis, pneumonia, and thromboembolism. As few as four to five lifetime courses of oral corticosteroids are associated with a significantly increased dose-dependent risk of diabetes, cataracts, heart failure, osteoporosis, and several other conditions [142].

11. TREATMENT OF REFRACTORY CHRONIC COUGH

Refractory and unexplained chronic cough are diagnoses of exclusion. For cases with no clear etiology after an extensive workup, or when guideline-based treatment improves the presumed underlying cause of coughing but not the chronic cough itself, cough hypersensitivity syndrome is the most likely explanation [39].

A variety of organizations have published guideline recommendations for the treatment of refractory and/or unexplained chronic cough (Table 8). The British Thoracic Society asserts that cough hypersensitivity is a treatable trait of many conditions and often the foremost problem in patients with chronic dry/unproductive cough [5]. However, there are currently no tools to positively identify cough hypersensitivity. If the condition does not improve with treatment of treatable traits, it is considered refractory chronic cough. In these patients, the most effective treatments are those addressing cough hypersensitivity and include low-dose morphine, gabapentin, and nonpharmacological therapy. In addition, novel therapies are in development, with P2X3 antagonists the most promising [5].

Table 8: GUIDELINE RECOMMENDATIONS FOR NEUROMODULATOR TREATMENT OF REFRACTORY/UNEXPLAINED CHRONIC COUGH

Drug

Guideline Organization (Year)

ACCP (2016)

ERS (2020)

GRS (2020)a

FRS (2023)

BTS (2023)

NEURO-COUGH (2023)

Low-dose morphine slow-release

Not reportedb

Strong recommendation

Strong recommendation

Recommended: Grade B

Recommended

Recommended, very high consensus

Codeine

Not reported

Not recommended

Not reported

Not reported

Recommended against

Not reported

Gabapentin

Recommended

Conditional recommendation

Can be used

Recommended: Grade B

Recommended

Recommended, high consensus

Pregabalin

Not reported

Conditional recommendation

Can be used

Recommended: Grade B

Recommended

Not reported

Amitriptyline

Not reported

Not reported

Can be used

Recommended: Grade C

Not reported

Recommended, high consensus

Baclofen

Not reported

Not reported

Not reported

Not reported

Not reported

Not reported

a"Can be used" is a weaker endorsement than "recommendation" (i.e., "should be used").

b75% of expert panelists endorsed a recommendation of morphine, falling short of 80% required for inclusion; thus, morphine is neither recommended for nor against.

ACCP = American College of Chest Physicians; BTS = British Thoracic Society; ERS = European Respiratory Society; FRS = French-Speaking Society of Respiratory Diseases; GRS = German Respiratory Society; NEURO-COUGH = New Understanding in the treatment Of COUGH Clinical Research Collaboration; SR = sustained-release.

Source: [5,10,11,12,18,86]

PHARMACOTHERAPY

Neuromodulators are centrally acting agents for refractory chronic cough that can downregulate the hypersensitive cough reflex to decrease coughing. Neuromodulators are first-line options for refractory chronic cough [39,57]. However, some of the literature on neuromodulator use in patients with refractory chronic cough might seem counterintuitive.

Clinical trials of P2X3 antagonists have shown efficacy in reducing cough frequency in many patients with refractory/unexplained chronic cough, but the exact mechanisms underlying refractory/unexplained chronic cough remain poorly understood. Although data also suggest central mechanisms may be a key component in the pathophysiology of refractory/unexplained chronic cough, antitussive drug development has focused on peripheral targets [143].

Among patients with unexplained chronic cough started on amitriptyline and contacted by mail two to three years later, 64% had stopped the medication due to no improvement (40%) and/or side effects (48%). The most common side effects triggering treatment nonadherence were sedation (18%), dry mouth (18%), anxiety (8%), difficulty sleeping (8%), and dizziness (5%). Combining patients who continued and stopped amitriptyline, 53% reported cough improvement of at least 50%. There is some evidence that as treatment duration increases, amitriptyline efficacy may decrease [144].

Opioid Medications

The concept of chronic cough as a neuropathic condition, treated with neuromodulators, is not new. In 1856, Edward Smith described chronic cough as a "disease in itself" due to "irritability of the nerves" that could be treated with "morphia," 164 years before expert consensus in the European Respiratory Society chronic cough guidelines concluded the same, albeit for refractory chronic cough [10,111]. Opioids are thought to exert antitussive effects through opioid receptors within inhibitory cortical descending pathways [59].

Codeine

Codeine is a weak opioid that is metabolized to morphine (5% to 10%) by the enzyme cytochrome P450 2D6 (CYP2D6) in the liver to produce its antitussive effects [145]. Codeine has long been used as an antitussive, but a minority of the population possess a genetic variation in CYP2D6 activity, with variable and unpredictable metabolism that increases unpleasant side effects and decreases efficacy. Codeine is now considered an unreliable antitussive and should not be used in chronic cough [5].

Low-Dose Morphine Slow-Release (SR)

Morphine is not affected by interindividual variability in CYP2D6 metabolism; thus, its biological effects are more predictable than codeine [146]. In the first positive results from a double-blind randomized controlled trial for any drug therapy of refractory chronic cough, morphine was selected to minimize the variability of codeine [25,147]. This study compared twice-daily slow-release morphine 5 mg with placebo for four weeks, followed by four weeks of crossover to the alternate treatment. A three-month open-labeled extension of the randomized controlled trial allowed dose escalation to 10 mg twice per day if patients thought their cough was inadequately controlled [147].

The mean LCQ score significantly improved on morphine but not placebo, with significant improvement in physical, psychological, and social subdomains. A 40% reduction in daily cough scores was noted with morphine; placebo had no discernable effect over baseline. Of patients entering the extension, 67% opted for dose escalation and, after three months, had cough outcome improvements similar to 5-mg full-responder patients. Side-effects of constipation (40%) and drowsiness (25%) were tolerable; no patient dropped out from adverse events. Sedation, previously believed to explain the antitussive action of morphine, was transient, but the antitussive effect continued throughout the core and extension study phases [147].

The authors of this study state that side effects and dependence are obvious concerns with opioid therapy for what is a disabling but non-life-threatening condition. However, they note that the risk-benefit ratio makes low-dose slow-release morphine a credible therapeutic option in patients with refractory chronic cough for whom other treatments have failed. Comparisons of similar therapeutic options were made with patients who require long-term oral corticosteroids for severe nonasthmatic eosinophilic bronchitis or cough-variant asthma with a consequently worse adverse event profile [147].

Another double-blind crossover study randomized previous morphine responders to slow-release morphine 5–10 mg twice daily or placebo. After five days, morphine reduced 24-hour cough frequency by 72% over placebo, including overnight (83%) and daytime (71%) cough frequency [148]. Morphine also significantly reduced noxious somatic sensations driving the urge to cough, suggesting this may be an important component of opioid modality in refractory chronic cough [149].

In a real-world effectiveness and tolerability study of long-term, low-dose opioids, 100 patients were prescribed twice daily slow-release morphine 5–10 mg (72%), oxycodone, or oxycodone/naloxone for a median 52 weeks for refractory/unexplained chronic cough. Median cough severity score (CSS, on a 0–10 scale) decreased from 8 pre-treatment to 4. In all, 60% had good-to-excellent response, while 25% had no response. Side effects (present in 38%) were most commonly constipation (25%), which was managed with dose reduction or constipation therapy; however, 15% stopped treatment due to side effect intolerance. Low-dose opioids improved long-term cough outcomes and were tolerated by most patients with refractory/unexplained chronic cough, but managing constipation allowed more patients to continue therapy [150].

Clinical experience with low-dose, slow-release morphine suggests that up to 50% to 60% of patients with refractory chronic cough obtain benefit [5,59,150]. Response dichotomizes into either a large effect on cough symptoms or no effect at all and is usually apparent within five days. The main side effect, constipation, can be managed with laxatives or adding oral low-dose naloxone. Once-daily dosing may be sufficient if cough symptoms are mainly troublesome during waking hours or overnight. Antitussive tolerance does not seem to develop. Unlike in severe chronic pain, there appears to be a dose ceiling for slow-release morphine of twice daily 10 mg, with no further antitussive effect beyond this. Concerns remain about misuse/addiction potential, and patients must be carefully monitored [5,59]. As noted in a 2024 review, it is unclear why such low doses, compared with those used for analgesia, are effective in some patients with refractory chronic cough [25].

Gabapentinoids

Gabapentin and pregabalin are synthetic analogs of gamma-aminobutyric acid (GABA) that bind theα2δsubunit of voltage-gated calcium channels to block excitatory neurotransmitter release. Both were developed originally for epilepsy treatment and subsequently found to ameliorate chronic neuropathic pain, which is associated with central sensitization. The similar pathophysiologic mechanisms of chronic neuropathic pain and chronic cough suggested that gabapentin and pregabalin may also be beneficial in patients with refractory chronic cough [151].

Evidence Based Practice Recommendation

The European Respiratory Society suggests a trial of gabapentin or pregabalin in adults with chronic refractory cough.

https://erj.ersjournals.com/content/55/1/1901136

Last Accessed: August 12, 2024

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

Gabapentin (1,800 mg/day or the maximum tolerable dose) was compared with placebo for eight weeks in a double-blind randomized controlled trial of 62 patients with refractory chronic cough. Gabapentin significantly improved LCQ score over placebo by 1.8 points, and significantly reduced objective cough frequency and cough severity over placebo. Gabapentin response was greater in patients with symptoms of central sensitization (e.g., laryngeal paresthesia, allotussia, hypertussia). The onset of action of gabapentin took up to four weeks [152]. It was subsequently noted that cough frequency differed between gabapentin and placebo groups at baseline (45.3 vs. 68.8 coughs per hour) and was measured only for one hour at each assessment visit, making interpretation of cough frequency outcomes difficult [25,146].

An open-label randomized trial compared gabapentin (300 mg three times per day) to baclofen (20 mg three times per day), an antispasticity drug, in 234 patients with refractory gastroesophageal reflux-associated cough over nine weeks. Compared with baseline, gabapentin and baclofen similarly led to decreased cough symptom scores and patients with success for cough resolution (57.3% vs. 53.0%). Gabapentin led to lower side effect rates than baclofen of somnolence (20% vs. 35%) and dizziness (11% vs. 24%) [151]. In addition to other burdensome side effects, sudden discontinuation of baclofen can result in seizures [5].

In another study, twice daily pregabalin 75 mg was prescribed to 50 consecutive patients with refractory or unexplained chronic cough for three months. Pregabalin response, defined as LCQ total score improvement of ≥1.3, was attained by 56% of patients. Responders were more likely to have refractory (with underlying pulmonary disease) than unexplained chronic cough, and on average were more symptomatic at baseline. There was no information on side effects or dropout [153].

In another study, 40 patients with refractory chronic cough were randomized to speech pathology treatment plus pregabalin 300 mg/day or speech pathology treatment plus placebo for four weeks. Compared with the placebo group, those who received speech pathology treatment/pregabalin experienced a statistically significant improvement [154]. However, CNS adverse effects (e.g., dizziness, disorientation, confusion, fatigue, blurred vision) were common and sometimes intolerable. The effects of pregabalin on 24-hour cough frequency outcome were non-significant [146].

Because gabapentinoids have beneficial effects on anxiety, improvements in mood may contribute to the apparent benefit or changes in symptom perception or cough intensity. Side effects are common, wide ranging, and can be difficult for patients to tolerate. Slow dose escalation may help minimize this, and maximal doses may not be needed to afford some improvement in cough. Gabapentin and pregabalin may have abuse potential in susceptible patients [5].

Gabapentin should be started at a low dose (e.g., 100 mg three times per day) and titrated up to a maximum dose (600 mg three times per day), depending on clinical effects and tolerability. The usual starting dose of pregabalin for chronic cough is 25 mg twice daily, with increases in increments to a maximum 75 mg twice daily. Patients should be reassessed during dose titration and therapy stopped if there are significant side effects or inadequate response to treatment [5].

In clinical experience, the minority of patients who achieve cough suppression often do so at the expense of intolerable adverse effects, usually sedation [57]. Among 38 patients prescribed gabapentin (maximum: 1,800 mg per day) or pregabalin (maximum: 300 mg per day) for refractory chronic cough, 24% developed immediate intolerable side effects and 37% tolerated the drugs but had no response and stopped the medication. Among the 39% with an initial favorable response, 18% eventually developed intolerable side effects and 21% were able to continue with therapy long-term. The most common side effect was drowsiness/sedation. In real-world practice, gabapentinoids are effective in a subgroup of patients with refractory chronic cough, but side effects may outweigh their potential benefits, which were intolerable for 42% of patients [155].

Tricyclic Antidepressants

Amitriptyline and nortriptyline are tricyclic antidepressants with a broad range of pharmacologic actions effecting adrenergic, serotonergic, muscarinic, and histaminergic systems. Amitriptyline is also used in chronic neuropathic pain (e.g., migraine, postherpetic neuralgia, painful diabetic neuropathy) and has been suggested to be effective in the treatment of chronic cough, with anticholinergic properties thought to underlie the antitussive effect [57,156]. However, clinical experience with amitriptyline in refractory chronic cough suggests more limited value [5].

In a small randomized trial of patients attending an otolaryngology clinic with postviral refractory chronic cough, amitriptyline 10 mg per day was compared with codeine 10 mg/guaifenesin 100 mg combined in a syrup taken every six hours. The majority of patients reported a 75% to 100% improvement in cough with amitriptyline, while most reported no improvement with codeine/guaifenesin. Compared with the control arm, amitriptyline was significantly associated with a response greater than 50% [157]. In a randomized controlled trial of patients with chronic pharyngolaryngeal neuropathy, 67% had subjective improvement with amitriptyline (up to 50 mg/day), compared with 44% with placebo. The mean Voice Handicap Index-10 (VHI-10) score worsened with amitriptyline but was unchanged with placebo. Attrition over the eight-week trial was 40% [158].

Nortriptyline was studied in 42 patients with neurogenic chronic cough, of whom 45% discontinued nortriptyline due to side effect intolerance or lack of response. The average time to clinical response was 5.5 months. The average minimum effective dose was 21 mg per day in responders. Laryngeal asymmetry was present in 85.7% of all patients. Side effects included sedation, xerostomia, and anxiety. The intolerability was surprising, because nortriptyline is both a metabolite of amitriptyline and reported to be better tolerated [159].

Pharmacotherapy for Chronic Cough in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis is a chronic, progressive, and invariably fatal fibrotic lung disease, and 85% of patients with idiopathic pulmonary fibrosis experience cough, a distressing symptom associated with rapid disease progression. Available treatments for idiopathic pulmonary fibrosis slow disease progression but do not improve symptoms or quality of life. Thalidomide benefitted idiopathic pulmonary fibrosis cough in one randomized controlled trial, but its side effect profile renders it practically useless, as only 20% of patients were able to tolerate it [125]. Worse still, the potentially severe adverse effect of peripheral neuropathy suggests it may damage sensory nerves (vagal afferents). Thalidomide should not be considered even as second-line therapy for idiopathic pulmonary fibrosis cough until further evaluation of the benefit/risk ratio has been undertaken [160].

Although studies on refractory chronic cough can help inform the treatment of idiopathic pulmonary fibrosis cough, the biological mechanisms that contribute to cough probably differ in these conditions, as evidenced by the contrasting results with gefapixant, a P2X3 receptor antagonist, in refractory chronic cough (positive findings) and idiopathic pulmonary fibrosis cough (negative findings) [161].

Nalbuphine

Nalbuphine extended-release (ER) is an opioid agonist-antagonist. In a double-blind randomized controlled trial of patients with idiopathic pulmonary fibrosis and chronic cough, nalbuphine ER tablets (titrated up to 162 mg twice daily) led to 75.1% reduction in daytime objective cough frequency, compared with 22.6% with placebo, a 50.8% placebo-adjusted reduction in 24-hour cough frequency, and similar improvements in patient reported outcomes [162]. Nalbuphine ER was the first therapy to show robust effects on chronic cough in idiopathic pulmonary fibrosis [25]. However, nalbuphine side effects of nausea (42.1%), fatigue (31.6%), constipation (28.9%), and dizziness (26.3%) led to a 24% dropout during the drug initiation phase, partially attributed to the inflexible forced-titration study design [162].

Low-Dose Morphine SR

In a multicenter randomized controlled trial of patients with idiopathic pulmonary fibrosis and chronic cough, low-dose, slow-release morphine (5 mg twice daily) reduced objective awake cough frequency by 39.4% over placebo, and all cough-related patient-reported outcomes remained significantly improved when adjusted for placebo. Morphine side effects of nausea (14%) and constipation (21%) resulted in only one participant discontinuing morphine, indicating tolerability for these patients. The authors note that the safety assessments during study visits were reassuring and there appeared to be no changes in mood or excessive fatigue with morphine [161]. The authors advocate for rapid implementation in clinical practice due to the well-established safety profile and worldwide availability [163].

A 2024 study reported variable effectiveness of slow-release morphine (8–32 mg per day) in reducing breathlessness in patients with COPD. But, it provided reassuring safety data by observing no evidence of harm and no worsening of subjective daytime sleepiness, alertness, or sleep quality at one and four weeks in these severely ill patients [164].

INVESTIGATIONAL PHARMACOTHERAPIES

Low-dose, slow-release morphine has the strongest observational and empirical evidence of antitussive benefit in refractory chronic cough of any commercially available (although off-label) medication and may be used safely in this population when patients are carefully screened and monitored. Because as many as 50% of patients with refractory chronic cough have no response to low-dose morphine and with substantial restrictions on opioid prescribing in the United States, effective peripherally acting antitussives are an urgent priority for investigators.

P2X3 Receptor Antagonists

P2X3 receptors form ion channels containing ATP-binding sites. In the lungs and airway, ATP activates P2X3 receptors localized on vagal sensory nerve terminals, resulting in bronchoconstriction, cough, and localized release of inflammatory neuropeptides [165].

A breakthrough occurred when gefapixant, a P2X3 receptor antagonist, demonstrated a dramatic reduction in chronic cough. Other P2X3 antagonists confirmed the efficacy of this drug class in refractory chronic cough. The endogenous ligand for P2X3 is ATP. Epithelial damage is believed to release ATP. Evidence suggests that ATP largely mediates peripheral hypersensitivity; therefore, gefapixant is peripherally acting in refractory chronic cough [166].

P2X3 receptors are ion channels found on sensory afferent nerve fibers, activated by ATP. In preclinical studies, vagal C fibers, including those thought to be important in mediating cough, have been shown to express P2X3 and P2X2. At present, it is unclear whether ATP concentrations are elevated or P2X3 receptor expression increased in the airways of patients with refractory chronic cough, or how antagonism of P2X3 plays a role in reducing coughing to a range of chemical irritants, temperature changes, and mechanical stimuli. Nonetheless, in clinical trials, P2X3 receptor antagonism has provided robust reductions in cough frequency and patient-reported outcomes [25].

Gefapixant

The first novel therapy to have significant effects in patients with refractory chronic cough was gefapixant, a first-in-class P2X3 antagonist that was originally planned to be developed as an analgesic. Gefapixant has become the first therapeutic to undergo systematic development as a treatment for refractory chronic cough following unprecedented reductions in cough frequency.

In a landmark study, twice daily gefapixant 600 mg showed remarkable therapeutic effects in patients with refractory chronic cough [167]. Objective 24-hour cough frequency was reduced 74% compared with placebo, and daytime cough severity VAS score and CQLQ score reduced by −25.6 and −9.2, respectively. However, another important finding was that virtually all treated patients reported ageusia, or loss of taste, and 24% withdrew because of the adverse effect. These taste side effects are likely attributable to the inhibition of P2X2/3 channels on the nerve fibers innervating the taste buds by high-dose gefapixant [146].

Subsequent studies suggest that antitussive effects are retained at much lower doses (30–50 mg twice daily), at which taste was altered rather than lost and hence the therapy was better tolerated. Larger multi-center parallel group studies were performed in the UK and the United States followed by the first-ever global phase 3 trials of an antitussive treatment for refractory chronic cough, which reported positive findings over placebo for a 45-mg twice daily dose [25].

Eliapixant and Filapixant

Following the taste side effects reported for gefapixant, more selective P2X3 antagonists were evaluated for the treatment of refractory chronic cough; however, there was some uncertainty about whether effects at both P2X3 and P2X2/3 channels were both contributing to antitussive efficacy and hence whether more selective agents would have similar efficacy. Eliapixant and filapixant both demonstrated efficacy in dose-ranging studies, but eliapixant appeared to cause less taste disturbance (up to 21% of patients) and was therefore progressed to a phase 2b parallel trial. Although this trial reported positive findings, a small number of cases of liver toxicity prevented further development of this therapy for refractory chronic cough [25].

Sivopixant

Another more selective P2X3 antagonist, sivopixant, exhibited promising findings in a single-dose crossover study, very similar in design to the first gefapixant study. The reduction in daytime cough frequency of 32% over placebo (the primary endpoint) was not quite statistically significant, but taste adverse effects were only reported in 6.4% of patients. In a follow-up, multicenter parallel group study assessing a range of doses for four weeks, no dose of sivopixant could be discriminated from the very large placebo effect—there was 60% placebo reduction in cough frequency from baseline. The largest absolute change in cough frequency was observed for the highest dose (300 mg), but 30% of patients reported taste adverse effects. No further studies of sivopixant in refractory chronic cough have been planned [25].

Camlipixant

Finally, thought to be the most selective P2X3 antagonist, camlipixant is the second compound in this class to be evaluated in phase 3 trials. The first double-blind randomized controlled crossover trial of camlipixant studied escalating doses from 25 mg to 200 mg versus matched placebo. Although the primary endpoint of awake cough frequency did not reach statistical significance, preplanned subgroup analysis in patients with a cough frequency of at least 20 coughs per hour (80% of patients) and those with greater than the median cough frequency (≥32 coughs per hour, 50% of patients) exhibited significant improvements versus placebo for all doses tested. This preplanned analysis was based on observations from several of the gefapixant studies that suggested P2X3 antagonism was most efficacious in patients with the highest baseline cough frequency [25].

In post-hoc analysis of a phase 2a study, among patients who reported cough-related urinary incontinence at baseline, 11%, 15%, and 21% of those treated with 12.5 mg, 50 mg, and 200 mg camlipixant, respectively, reported no cough-related urinary incontinence at day 29 (compared with 3% with placebo) [168]. As of 2024, camlipixant is being evaluated in two large-scale phase 3 studies, again in patients selected for higher cough frequencies [25].

Other Novel Antitussives Under Investigation

The studies completed to date investigating P2X3 antagonists have typically found that between one-quarter and one-third of patients do not experience the 30% reduction in cough frequency thought to be the meaningful clinical threshold, suggesting some heterogeneity in the mechanisms underlying refractory chronic cough. Furthermore, patients with less frequent/severe coughing than those recruited to these trials may not benefit from treatments interrupting the ATP-P2X3 axis. Therefore, treatments with alternative modes of action are required to optimally manage patients with refractory chronic cough [25].

Sodium Channel Blockade

Lidocaine non-selectively blocks voltage-gated sodium channels important in the initiation of action potentials and their conduction and is a local anesthetic agent in routine topical use to reduce coughing during bronchoscopy. Case reports and case series have also described the use of nebulized lidocaine as an antitussive to treat refractory chronic cough [169].

In a three-way crossover study of single-dose lidocaine in refractory chronic cough, lidocaine throat spray reduced coughing by about 50% and was more effective than nebulized lidocaine, probably because nebulization into the lower airways has an irritant effect and evokes coughing initially [169]. The antitussive effects of lidocaine spray are relatively short lived and also associated with numbness in the mouth and lips, preventing patients from safely eating after treatment. Efforts have been made to develop similar therapies with a longer duration of action and without loss of sensation [25].

A novel approach to sodium channel blockade has been developed using a compound that is only active in blocking sodium channels after entering neurons via large-pore ion channels, such as P2X3 channels. As of 2024, a phase 2a clinical trial has been performed but the results are not yet published.

TRPM8 Agonism

Activation of TRPM8 ion channels produces cooling sensations. One new therapy has used an orally dissolving tablet containing a TRPM8 agonist (AX-8) placed on the back of the tongue to act as a counter irritant to the sensations of throat irritation reported by many patients with refractory chronic cough. In a randomized controlled trial, AX-8 reduced cough frequency, but not significantly over eight hours, the duration of action suggested by a previous open-label study. However, the effect was significant over four hours and exaggerated in those patients reporting greater throat discomfort, consistent with the proposed mechanism of action. Further studies in this subgroup of patients are hoped to confirm efficacy [25].

On day 1, AX-8 reduced cough frequency within 15 minutes and more than placebo over two and four hours, but not eight hours. In participants with baseline throat discomfort, reduction in cough frequency was significant over 24 hours, with a maximum reduction compared to placebo of 43% over two hours. Over 14 days, AX-8 significantly improved patient-reported outcomes and the safety profile was good with no serious adverse events. This suggests that TRPM8 agonism has potential for control of refractory/unexplained chronic cough as an alternative or adjunct to other therapies, especially in those patients complaining of cough driven by throat sensations [170].

NK-1 Antagonism

Following a positive study testing aprepitant as a cough treatment in patients with lung cancer, there has been interest in the potential antitussive effects of centrally acting neurokinin-1 (NK-1) antagonists. Following a negative trial in refractory chronic cough, a double-blind randomized controlled trial is in progress testing the effects of orvepitant in patients with cough associated with idiopathic pulmonary fibrosis [25].

NONPHARMACOLOGIC THERAPY

Speech and Language Therapy

Speech and language therapy techniques were first described as improving chronic cough in a randomized controlled trial in 87 patients with refractory chronic cough. The intervention appeared to have positive impact on cough, voice, throat symptoms, and symptom limitation after four therapy sessions over two months. Another study investigated a similar intervention delivered by speech and language therapists and physiotherapists. Compared with sham therapy, LCQ score improved by 1.5 points. Cough frequency improved by 40% more than in the sham-treated arm at four weeks and seemed to be maintained at three months. No larger-scale trials have been completed [25].

Evidence Based Practice Recommendation

The European Respiratory Society suggests a trial of cough control therapy (physiotherapy/speech and language therapy) in adult patients with chronic cough.

https://erj.ersjournals.com/content/55/1/1901136

Last Accessed: August 12, 2024

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

Speech and language therapy is a complex intervention, comprising components of education, cough suppression techniques, vocal hygiene, and psychoeducational counseling. Thus, it is difficult to standardize the intervention, and it is not clear whether all or just some of the components are essential for efficacy. In practice, the therapy seems to be most effective when delivered by experienced therapists, who may not be widely available. There is also a question about the durability of the effects over longer timescales when patients may not continue to practice the techniques [25].

The speech and language therapy approach to the management of chronic cough involves four steps: education, vocal hygiene, cough control/suppression training, and psychoeducational counseling [19].

Education

Patients are provided education on the biology of coughing, chronic cough, and cough hypersensitivity. The negative effects of repeated coughing and throat clearing are explained [19].

Vocal Hygiene

Vocal and laryngeal hygiene and hydration are advised with a reduction in caffeine and alcohol intake. Nasal breathing with nasal douching may be recommended with nasal steam inhalation [19].

Cough Control/Suppression Training

Following identification of patient cough triggers, patients are taught a range of suppression strategies, including forced/dry swallow, sipping water, chewing gum, or sucking non-medicated sweets. Breathing pattern re-education is used to promote relaxed abdominal breathing while inhaling through the nose [19].

Psychoeducational Counseling

Behavior modification is used to reduce over-awareness of the need to cough and facilitate an individual's internalization of control over their cough and to help manage stress and anxiety [19].

Local Injection Therapies

The experience of superior laryngeal nerve block by the injection of local anesthetic agents and corticosteroids has been described retrospectively following implementation in several clinics. In 2024, a small single-blind placebo-controlled study was performed comparing this treatment in 10 patients injected with active treatment and 7 with placebo, finding improvements in cough VAS and LCQ scores. Transient sensations of globus (lump in the throat) and soreness at the site of inject were the main adverse effects. Laryngeal botulinum toxin injections have also been reported to produce improvements in series of patients in clinical care, but no controlled studies have been performed. The broad safety of these interventions and duration of any effect currently remains unclear [25].

12. CONCLUSION

Chronic cough affects roughly 10% of adults in the United States [32]. These individuals can cough hundreds to thousands of times every day, often with uncontrollable bouts of coughing triggered by laughing, speaking, or changes in ambient temperature. This can continue for many years or decades, leading to substantial physical and emotional symptoms, including fatigue, urinary incontinence, cough syncope, dysphonia, depression, anxiety, embarrassment, social isolation, and severely diminished quality of life [28,40,64].

In 20% to 59% of patients with chronic cough, coughing persists despite extensive guideline-recommended evaluation and treatment of comorbidities or an underlying cause of cough cannot be identified. In these cases, a diagnosis of refractory or unexplained chronic cough is rendered [7,36].

Chronic cough is a distinct pathologic entity (cough hypersensitivity syndrome) that develops when repetitive activation of airway cough receptors (typically by inflammatory mediators) induces neuroplastic changes, resulting in peripheral and central sensitization with symptoms of allotussia, hypertussia, and/or laryngeal paresthesia [3,19,20]. Hypersensitivity of vagal afferent neurons in the airways and their central projections, and deterioration in cortical inhibitory control of cough, explain the chronicity characteristics of this condition [33,78].

According to current best evidence, clinical management of patients with chronic cough requires that clinicians perform thorough history, physical examination, and diagnostic testing to identify any potential underlying causes, with asthma, COPD, nonasthmatic eosinophilic bronchitis, upper airway cough syndrome, and GERD the top diagnoses to consider. After assessment is complete, clinicians should treat any identified airway and esophageal conditions according to practice guidelines. As part of the treatment approach, behavioral treatable traits, including cigarette smoking, use of ACE inhibitors and NSAIDs, poor inhaler technique (when relevant), and treatment adherence in general should be identified and addressed [5,6,10,18,24,25,79,171].

It is important to recognize that cough hypersensitivity syndrome is present when cough persists despite etiologically based treatment or no etiology can be identified. Clinicians can make a diagnosis of refractory or unexplained chronic cough and refocus management to downregulating a hyper-reactive cough reflex using commercially available medication prescribed off-label and cough-specific speech and language therapy [5,6,10,18,24,25,79,171].

Despite showing the best effectiveness, safety, and tolerability of commercially available medications evaluated in patients with refractory/unexplained chronic cough patients and despite recommended by international clinical practice guidelines, use of low-dose, slow-release morphine may be untenable or unrealistic. In light of this fact, gabapentin, pregabalin, and amitriptyline remain options for effective pharmacotherapy. Clinicians should also stay informed about possible FDA approval of gafapixant, the first-ever drug approved for refractory/unexplained chronic cough in several other countries, and about phase 3 trials of campilixant. Approval of these agents could expand the treatment options for these patients and potentially improve patient quality of life.

Works Cited

1. Dicpinigaitis P. New developments in the treatment and management of chronic cough: managed care considerations on the role of new and emerging therapie. J Manag Care Med. 2022;25(4):16-19.

2. Dicpinigaitis P. Understanding the foundations of chronic cough. Am J Manag Care. 2020;26(11 Suppl):S232-S238.

3. McGarvey L, Gibson PG. What is chronic cough? Terminology. J Allergy Clin Immunol Pract. 2019;7(6):1711-1714.

4. Hull JH, Langerman H, Ul-Haq Z, Kamalati T, Lucas A, Levy ML. Burden and impact of chronic cough in UK primary care: a data-set analysis. BMJ Open. 2021;11(12):e054832.

5. Parker SM, Smith JA, Birring SS, et al. British Thoracic Society clinical statement on chronic cough in adults. Thorax. 2023;78(Suppl 6):s3-s19.

6. Irwin RS, Oppenheimer JJ, Dunlap W, Lieberman JA, Chang AB. Yardstick for managing cough, part 1: in adults and adolescent patients older than 14 years of age. Ann Allergy Asthma Immunol. 2023;130(3):379-391.

7. Song WJ, Morice AH. Cough hypersensitivity syndrome: a few more steps forward. Allergy Asthma Immunol Res. 2017;9(5):394-402.

8. Smith JA, Woodcock A. Chronic cough. N Engl J Med. 2016;375(16):1544-1551.

9. Morice AH, Millqvist E, Belvisi MG, et al. Expert opinion on the cough hypersensitivity syndrome in respiratory medicine. Eur Respir J. 2014;44(5):1132-1148.

10. Morice AH, Millqvist E, Bieksiene K, et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136.

11. Kardos P, Dinh QT, Fuchs K-H, et al. German Respiratory Society guidelines for diagnosis and treatment of adults suffering from acute, subacute and chronic cough. Respir Med. 2020:170:105939.

12. Guilleminault L, Demoulin-Alexikova S, de Gabory L, et al. Guidelines for the management of chronic cough in adults. Endorsed by the French speaking society of respiratory diseases (Société de Pneumologie de Langue Française, SPLF), the Société Française d'Oto-Rhino-Laryngologie et de Chirurgie de la Face et du Cou (SFORL), the Société Française de Phoniatrie et de Laryngologie (SFPL), the Société Nationale Française de Gastro-entérologie (SNFGE). Respir Med Res. 2023:83:101011.

13. Joo H, Moon J-Y, An TJ, et al. Revised Korean cough guidelines, 2020: recommendations and summary statements. Tuberc Respir Dis (Seoul). 2021;84(4):263-273.

14. Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J. 2016;47(2):410-419.

15. Lee J-H, Lee J-H, Park S-Y, Koskela HO, Song WJ. Is fractional exhaled nitric oxide a treatable trait in chronic cough: a narrative review. J Thorac Dis. 2023;15(10):5844-5855.

16. McDonald VM, Gibson PG. Treatable traits in asthma: moving beyond diagnostic labels. Med J Aust. 2022;216(7):331-333.

17. Agusti A, Gibson PG, McDonald VM. Treatable traits in airway disease: from theory to practice. J Allergy Clin Immunol Pract. 2023;11(3):713-723.

18. Song W-J, Dupont L, Birring SS, et al. Consensus goals and standards for specialist cough clinics: the NEUROCOUGH international Delphi study. ERJ Open Res. 2023;9(6):00618-2023.

19. Chung KF, McGarvey L, Song W-J, et al. Cough hypersensitivity and chronic cough. Nat Rev Dis Primers. 2022;8(1):45.

20. Rouadi PW, Idriss SA, Bousquet J, et al. WAO-ARIA consensus on chronic cough. Part II: phenotypes and mechanisms of abnormal cough presentation: updates in COVID-19. World Allergy Organ J. 2021;14(12):100618.

21. Driessen AK, Devlin A-C, Lundy FT, et al. Perspectives on neuroinflammation contributing to chronic cough. Eur Respir J. 2020;56(4):2000758.

22. Chung KF, McGarvey L, Mazzone SB. Chronic cough as a neuropathic disorder. Lancet Respir Med. 2013;1(5):414-422.

23. Sykes DL, Zhang M, Morice AH. Treatment of chronic cough: P2X3 receptor antagonists and beyond. Pharmacol Ther. 2022;237:108166.

24. Wallace DV. Evaluation and management of chronic cough in adults. Allergy Asthma Proc. 2023;44(6):382-394.

25. Smith JA. The therapeutic landscape in chronic cough. Lung. 2024;202(1):5-16.

26. Blaiss MS. Innovations in the treatment and management of chronic cough: expert perspectives on the role of new and emerging therapies. J Manag Care Med. 2023;26(4):12-17.

27. Nguyen AM, Schelfhout J, Muccino D, et al. Leicester Cough Questionnaire validation and clinically important thresholds for change in refractory or unexplained chronic cough. Ther Adv Respir Dis. 2022:16:1-13.

28. Morice A, Dicpinigaitis P, McGarvey L, Birring SS. Chronic cough: new insights and future prospects. Eur Respir Rev. 2021;30(162):210127.

29. Kum E, Guyatt GH, Munoz C, et al. Assessing cough symptom severity in refractory or unexplained chronic cough: findings from patient focus groups and an international expert panel. ERJ Open Res. 2022;8(1):00667-2021.

30. Irwin RS, Madison JM. Gefapixant for refractory or unexplained chronic cough? JAMA. 2023;330(14):1335-1336.

31. Sharma S, Hashmi MF, Alhajjaj MS. Cough. Treasure Island, FL: StatPearls Publishing; 2023.

32. Shields JB, Callen E, Loskutova NY, Schelfhout J, Hester CM. Chronic cough diagnosis, treatment, and referral practices among family physicians in the United States: a survey study. BMC Prim Care. 2024;25(1):181.

33. Drake MG, McGarvey LP, Morice AH. From bench to bedside: the role of cough hypersensitivity in chronic cough. Clin Transl Med. 2023;13(8):e1343.

34. Yang X, Chung KF, Huang K. Worldwide prevalence, risk factors and burden of chronic cough in the general population: a narrative review. J Thorac Dis. 2023;15(4):2300-2313.

35. Kang MG, Song WJ, Kim HJ, et al. Point prevalence and epidemiological characteristics of chronic cough in the general adult population: the Korean national health and nutrition examination survey 2010–2012. Medicine (Baltimore). 2017;96(13):e6486.

36. van Boemmel-Wegmann S, Altman KW, Herrera R, Vieira Pires P, Pichardo PFA, Vora P. Characteristics of adults with potential refractory chronic cough identified using an algorithm designed for administrative claims databases: a descriptive study. Sci Prog. 2024;107(1):1-15.

37. Zeiger RS, Schatz M, Butler RK, Weaver JP, Bali V, Chen W. Burden of specialist-diagnosed chronic cough in adults. J Allergy Clin Immunol Pract. 2020;8(5):1645-1657.e7.

38. Zeiger RS, Schatz M, Hong B, et al. Patient-reported burden of chronic cough in a managed care organization. J Allergy Clin Immunol Pract. 2021;9(4):1624-1637.

39. Alhajjaj MS, Bajaj P. Chronic Cough. Treasure Island, FL: StatPearls Publishing; 2024.

40. Dicpinigaitis PV. Thoughts on one thousand chronic cough patients. Lung. 2012;190(6):593-596.

41. Dicpinigaitis PV, Allusson VR, Baldanti A, Nalamati JR. Ethnic and gender differences in cough reflex sensitivity. Respiration. 2001;68(5):480-482.

42. Zhang J, Perret JL, Chang AB, et al. Risk factors for chronic cough in adults: a systematic review and meta-analysis. Respirology. 2022;27(1):36-47.

43. Mai Y, Zhan C, Zhang S, et al. Arnold nerve reflex: vagal hypersensitivity in chronic cough with various causes. Chest. 2020;158(1):264-271.

44. Weinberger SE, Saukkonen K. Evaluation and Treatment of Subacute and Chronic Cough in Adults. Available at https://www.uptodate.com/contents/evaluation-and-treatment-of-subacute-and-chronic-cough-in-adults. Last accessed July 29, 2024.

45. Irwin RS, Dudiki N, French CL, CHEST Expert Cough Panel. Life-threatening and non-life-threatening complications associated with coughing: a scoping review. Chest. 2020;158(5):2058-2073.

46. 46. Alhatemi AQM, Hashim HT, Hashim AT. Rib fracture secondary to cough-induced trauma. Clin Case Rep. 2024;12(5):e8823.

47. Dicpinigaitis PV. Prevalence of stress urinary incontinence in women presenting for evaluation of chronic cough. ERJ Open Res. 2021;7(1):2012-2021.

48. Dicpinigaitis PV, Lim L, Farmakidis C. Cough syncope. Respir Med. 2014;108(2):244-251.

49. Everett CF, Kastelik JA, Thompson RH, Morice AH. Chronic persistent cough in the community: a questionnaire survey. Cough. 2007:3:5.

50. García-Vicente P, Rodríguez-Valiente A, Górriz Gil C, et al. Chronic cough in post-COVID syndrome: laryngeal electromyography findings in vagus nerve neuropathy. PLoS One. 2023;18(3):e0283758.

51. 51. Chamberlain SAF, Garrod R, Douiri A, et al. The impact of chronic cough: a cross-sectional European survey. Lung. 2015;193(3):401-408.

52. Yousaf N, Montinero W, Birring SS, Pavord ID. The long term outcome of patients with unexplained chronic cough. Respir Med. 2013;107(3):408-412.

53. Abozid H, Kirby M, Nasir N, et al. CT airway remodelling and chronic cough. BMJ Open Respir Res. 2023;10(1):e001462.

54. Deng SJ, Wang J, Liu L, et al. Chronic cough in asthma is associated with increased airway inflammation, more comorbidities, and worse clinical outcomes. Allergy Asthma Proc. 2022;43(3):209-219.

55. Beech A, Portacci A, Herrero-Cortina B, et al. ERS International Congress 2022: highlights from the Airway Diseases Assembly. ERJ Open Res. 2023;9(3):00034-2023.

56. 56. Wicaksono MBA, Yunus F. Diagnosis and management of cough-variant asthma. Pneumologia. 2021;70:111-116.

57. Dicpinigaitis PV, Altman KW, Isci IU, Ke X, Blaiss M. Interdisciplinary collaboration in the diagnosis and management of chronic cough: the role and importance of primary care providers. Curr Med Res Opin. 2023;39(10):1375-1381.

58. Sykes DL, Morice AH. The cough reflex: the Janus of respiratory medicine. Front Physiol. 2021;12:684080.

59. Zhang M, Morice AH. Unravelling vagal hypersensitivity in chronic cough: a distinct disease. J Physiol. 2023; [Epub ahead of print].

60. Kornfield J, De La Torre U, Mize E, Drake MG. Illuminating airway nerve structure and function in chronic cough. Lung. 2023;201(6):499-509.

61. 61. Farooqi MAM, Cheng V, Wahab M, Shahid I, O'Byrne PM, Satia I. Investigations and management of chronic cough: a 2020 update from the European Respiratory Society Chronic Cough Task Force. Pol Arch Intern Med. 2020;130(9):789-795.

62. Smith JA, Badri H. Cough: new pharmacology. J Allergy Clin Immunol Pract. 2019;7(6):1731-1738.

63. Smith JA, Satia I, Badri H, Marsden P. Mini-review: hypertussivity and allotussivity in chronic cough endotypes. Neurosci Lett. 2023;792:136934.

64. Mazzone S, Chung KF, McGarvey L. The heterogeneity of chronic cough: a case for endotypes of cough hypersensitivity. Lancet Respir Med. 2018;6(8):636-646.

65. Tamasauskiene L, Sitkauskiene B. Immune system in the pathogenesis of chronic cough. Immunol Lett. 2020;218:40-43.

66. 66. Turner RD, Hirons B, Cortese A, Birring SS. Chronic cough as a genetic neurological disorder? Insights from cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Lung. 2023;201(6):511-519.

67. Ando A, Smallwood D, McMahon M, Irving L, Mazzone SB, Farrell MJ. Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control. Thorax. 2016;71(4):323-329.

68. Moe AAK, Singh N, Dimmock M, et al. Brainstem processing of cough sensory inputs in chronic cough hypersensitivity. EBioMedicine. 2024:100:104976.

69. Smith JA, West PW. Branching out in chronic cough: evidence for increased airway nerve density. Am J Respir Crit Care Med. 2021;203(3):283-284.

70. Dockry RJ, Farrelly CL, Mitchell J, Corfield DR, Smith JA. Chronic cough is associated with increased reporting of autonomic symptoms. ERJ Open Res. 2021;7(3):00105-2021.

71. 71. Mazzone SB. Chronic cough: a disorder of response inhibition? Eur Respir J. 2019;53(5):1900254.

72. Namgung E, Song W-J, Kim Y-H, An J, Cho YS, Kang D-W. Structural and functional correlates of higher cortical brain regions in chronic refractory cough. Chest. 2022;162(4):851-860.

73. Diab N, Patel M, O'Byrne P, Satia I. Narrative review of the mechanisms and treatment of cough in asthma, cough variant asthma, and non-asthmatic eosinophilic bronchitis. Lung. 2022;200(6):707-716.

74. Sundar KM, Stark AC, Hu N, Barkmeier-Kraemer J. Is laryngeal hypersensitivity the basis for unexplained or refractory chronic cough? ERJ Open Res. 2021;7(1):00793-2020.

75. Demirjian NL, Lever A, Yip H. Identifying practice gaps among otolaryngology providers for the treatment of chronic cough. OTO Open. 2024;8(2):e143.

76. 76. Al-Hajjaj MS. Tips and pitfalls in the diagnosis and treatment of bronchial asthma. Advances in Biomedical and Health Sciences. 2023;2(2):58-61.

77. Ryan NM, Vertigan AE, Birring SS. An update and systematic review on drug therapies for the treatment of refractory chronic cough. Expert Opin Pharmacother. 2018;19(7):687-711.

78. Kukiełka P, Moliszewska K, Białek-Gosk K, Grabczak EM, Dąbrowska M. Prevalence of refractory and unexplained chronic cough in adults treated in cough centre. ERJ Open Res. 2024;10(4).

79. Morice A. A survey of UK respiratory specialists' opinion on the management of chronic cough. ERJ Open Res. 2024;10(4).

80. Irwin RS, Rosen MJ, Braman SS. Cough. A comprehensive review. Arch Intern Med. 1977;137(9):1186-1191.

81. Irwin RS, Boulet LP, Cloutier MM, et al. Managing cough as a defense mechanism and as a symptom: a consensus panel report of the American College of Chest Physicians. Chest. 1998;114(2 Suppl Managing):133S-181S.

82. Irwin RS, Baumann MH, Bolser DC, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 Suppl):1S-23S.

83. Kahrilas PJ, Altman KW, Chang AB, et al. Chronic cough due to gastroesophageal reflux in adults: CHEST guideline and expert panel report. Chest. 2016;150(6):1341-1360.

84. Côté A, Russell RJ, Boulet LP, et al. Managing chronic cough due to asthma and NAEB in adults and adolescents: CHEST guideline and expert panel report. Chest. 2020;158(1):68-96.

85. Malesker MA, Callahan-Lyon P, Madison JM, Ireland B, Irwin RS, CHEST Expert Cough Panel. Chronic cough due to stable chronic bronchitis: CHEST Expert Panel Report. Chest. 2020;158(2):705-718.

86. Gibson P, Wang G, McGarvey L, et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149(1):27-44.

87. Agustí A, Rapsomaniki E, Beasley R, et al. Treatable traits in the NOVELTY study. Respirology. 2022;27(11):929-940.

88. Zhang Q, Wu WW, Li L, et al. Workup of difficult-to-treat asthma: implications from treatable traits. Precis Clin Med. 2023;6(1):pbad003.

89. McDonald VM, Hamada Y, Agusti A, Gibson PG. Treatable traits in asthma: the importance of extrapulmonary traits: GERD, CRSwNP, atopic dermatitis, and depression/anxiety. J Allergy Clin Immunol Pract. 2024;12(4):824-837.

90. 90. Morice AH, Fontana GA, Sovijarvi ARA, et al. The diagnosis and management of chronic cough. Eur Respir J. 2004;24:481-492.

91. Jutel M, Agache I, Zemelka-Wiacek M, et al. Nomenclature of allergic diseases and hypersensitivity reactions: adapted to modern needs: an EAACI position paper. Allergy. 2023;78(11):2851-2874.

92. Rank MA, Chu DK, Bognanni A, et al. The joint task force on practice parameters GRADE guidelines for the medical management of chronic rhinosinusitis with nasal polyposis. J Allergy Clin Immunol. 2023;151(2):386-398.

93. Toppila-Salmi S, Bjermer L, Cardell L-O, et al. Multi-disciplinary expert perspective on the management of type 2 inflammation-driven severe CRSwNP: a brief overview of pathophysiology and recent clinical insights. J Asthma Allergy. 2024;17:431-439.

94. Jiang Y, An R, Cheng L, et al. Classification of non-acute bronchial asthma according to allergy and eosinophil characteristics: a retrospective study. Allergy Asthma Clin Immunol. 2021;17(1):45.

95. 95. Marra AM, Rossi CM, Piga MA, Moroncini G, Bilò MB. Eosinophil-associated diseases: the allergist's and clinical immunologist's perspective. Eur Ann Allergy Clin Immunol. 2024;[Epub ahead of print].

96. Kalchiem-Dekel O, Yao X, Levine SJ. Meeting the challenge of identifying new treatments for type 2-low neutrophilic asthma. Chest. 2020;157(1):26-33.

97. Jin FD, Wang J, Deng SJ, et al. Interaction effect of chronic cough and ageing on increased risk of exacerbation in patients with asthma: a prospective cohort study in a real-world setting. ERJ Open Res. 2023;9(6):00461-2023.

98. Sun J, Zhan C, Deng Z, et al. Expression of interferon-γand its effect on cough hypersensitivity in chronic refractory cough patients. Thorax. 2022;77(6):621-624.

99. Dicpinigaitis PV. Chronic cough and refractory chronic cough: an important distinction. J Precis Respir Med. 2023;6(1):10-13.

100. Irwin RS, French CL, Chang AB, Altman KW, CHEST Expert Cough Panel. Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report. Chest. 2018;153(1):196-209.

101. Shim J-S, Song W-J, Morice AH. Drug-induced cough. Physiol Res. 2020;69(Suppl. 1):S81-S92.

102. Song DJ, Song WJ, Kwon JW, et al. KAAACI evidence-based clinical practice guidelines for chronic cough in adults and children in Korea. Allergy Asthma Immunol Res. 2018;10(6):591-613.

103. National Institute for Health and Care Excellence. Asthma: Diagnosis, Monitoring and Chronic Asthma Management. Available at http://www.nice.org.uk/guidance/ng80. Last accessed July 26, 2024.

104. Rouadi PW, Idriss SA, Bousquet J, et al. WAO-ARIA consensus on chronic cough. Part III: management strategies in primary and cough-specialty care: updates in COVID-19. World Allergy Organ J. 2022;15(5):100649.

105. 105. Ambrosino P, Accardo M, Mosella M, et al. Performance of fractional exhaled nitric oxide in predicting response to inhaled corticosteroids in chronic cough: a meta-analysis. Ann Med. 2021;53(1):1659-1672.

106. Lee JH, Kang S-Y, Yu I, et al. Cough response to high-dose inhaled corticosteroids in patients with chronic cough and fractional exhaled nitric oxide levels ≥ 25 ppb: a prospective study. Lung. 2024;202(3):275-280.

107. Fukumitsu K, Kanemitsu Y, Asano T, et al. Tiotropium attenuates refractory cough and capsaicin cough reflex sensitivity in patients with asthma. J Allergy Clin Immunol Pract. 2018;6(5):1613-1620.

108. Fukumitsu K, Kanemitsu Y, Kurokawa R, et al. Tiotropium for refractory cough in asthma via cough reflex sensitivity: a randomized, parallel, open-label trial. Ann Allergy Asthma Immunol. 2023;131(1):59-68.

109. Weinberger SE, Saukkonen K. Causes and Epidemiology of Subacute and Chronic Cough in Adults. Available at https://www.uptodate.com/contents/causes-and-epidemiology-of-subacute-and-chronic-cough-in-adults. Last accessed July 29, 2024.

110. Papi A, Faner R, Pavord I, et al. From treatable traits to GETomics in airway disease: moving towards clinical practice. Eur Respir Rev. 2024;33(171):230143.

111. Hirons B, Rhatigan K, Kesavan H, Turner RD, Birring SS, Cho PSP. Cough in chronic lung disease: a state of the art review. J Thorac Dis. 2023;15(10):5823-5843.

112. Lai K, Satia I, Song W-J, et al. Cough and cough hypersensitivity as treatable traits of asthma. Lancet Respir Med. 2023;11(7):650-662.

113. Ortega VE, Izquierdo M. Asthma. Available at https://www.merckmanuals.com/professional/pulmonary-disorders/asthma-and-related-disorders/asthma. Last accessed July 26, 2024.

114. Maspero J, Adir Y, Al-Ahmad M, et al. Type 2 inflammation in asthma and other airway diseases. ERJ Open Res. 2022;8(3):00576-2021.

115. Kim M-Y, Won H-K, Oh J-Y, et al. Could cough hypersensitivity symptom profile differentiate phenotypes of chronic cough? ERJ Open Res. 2024;10(4).

116. Villalobos-Violan V, Betancor D, Mahíllo-Fernández I, Sastre J. Nonasthmatic eosinophilic bronchitis and asthma: analysis of biomarkers. J Investig Allergol Clin Immunol. 2022;32(3):216-217.

117. Michaudet C, Malaty J. Chronic cough: evaluation and management. Am Fam Physician. 2017;96(9):575-580.

118. Gonlugur U, Gonlugur TE. Eosinophilic bronchitis without asthma. Int Arch Allergy Immunol. 2008;147(1):1-5.

119. World Health Organization. ICD-11 for Mortality and Morbidity Statistics 2024-01. Available at https://icd.who.int/browse/2024-01/mms/en. Last accessed July 29, 2024.

120. 120. Brightling C, Greening N. Airway inflammation in COPD: progress to precision medicine. Eur Respir J. 2019;54(2):1900651.

121. Liu Y, Carlson SA, Watson KB, Xu F, Greenlund KJ. Trends in the prevalence of chronic obstructive pulmonary disease among adults aged ≥18 years—United States, 2011–2021. MMWR. 2023;72(46):1250-1256.

122. Syamlal G, Kurth LM, Dodd KE, Blackley DJ, Hall NB, Mazurek JM. Chronic obstructive pulmonary disease mortality by industry and occupation—United States, 2020. MMWR. 2022;71(49):1550-1554.

123. Wise RA. Chronic Obstructive Pulmonary Disease (COPD). Available at https://www.merckmanuals.com/professional/pulmonary-disorders/chronic-obstructive-pulmonary-disease-and-related-disorders/chronic-obstructive-pulmonary-disease-copd. Last accessed July 29, 2024.

124. Maher TM. Interstitial lung disease: a review. JAMA. 2024;331(19):1655-1665.

125. Wu Z, Banya W, Chaudhuri N, et al. PAciFy cough—a multicentre, double-blind, placebo-controlled, crossover trial of morphine sulphate for the treatment of pulmonary fibrosis cough. Trials. 2022;23:184.

126. Lee J, White E, Freiheit E, et al. Cough-specific quality of life predicts disease progression among patients with interstitial lung disease: data from the Pulmonary Fibrosis Foundation patient registry. Chest. 2022;162(3):603-613.

127. Dąbrowska M, Arcimowicz M, Grabczak EM, et al. Chronic cough related to the upper airway cough syndrome: one entity but not always the same. Eur Arch Otorhinolaryngol. 2020;277(10):2753-2759.

128. Dykewicz MS, Wallace DV, Amrol DJ, et al. Rhinitis 2020: a practice parameter update. J Allergy Clin Immunol. 2020;146(4):721-767.

129. Baroody FM, Gevaert P, Smith PK, Ziaie N, Bernstein JA. Nonallergic rhinopathy: a comprehensive review of classification, diagnosis, and treatment. J Allergy Clin Immunol Pract. 2024:12(6):1436-1447.

130. 130. Battisti AS, Modi P, Pangia J. Sinusitis. Treasure Island, FL: StatPearls Publishing; 2023.

131. Zhao P, Kariya S, Higak T, et al. Chronic rhinosinusitis possibly associated with decreased lung function in chronic cough patients. Braz J Otorhinolaryngol. 2024;90(4):101424.

132. Naclerio RM, Bousquet J. Nose woes. J Allergy Clin Immunol Pract. 2024;12(6):P1493-P1494.

133. Gyawali CP, Yadlapati R, Fass R, et al. Updates to the modern diagnosis of GERD: Lyon consensus 2.0. Gut. 2024;73(2):361-371.

134. Chen JW, Vela MF, Peterson KA, Carlson DA. AGA clinical practice update on the diagnosis and management of extraesophageal gastroesophageal reflux disease: expert review. Clin Gastroenterol Hepatol. 2023;21(6):1414-1421.

135. 135. Decalmer S, Stovold R, Houghton LA, et al. Chronic cough: relationship between microaspiration, gastroesophageal reflux, and cough frequency. Chest. 2012;142(4):958-964.

136. Zhang L, Zhang M, Aierken A, Dong R, Chen Q, Qiu Z. Role of alveolar nitric oxide in gastroesophageal reflux-associated cough: prospective observational study. Ther Adv Respir Dis. 2024;18:1-16.

137. Hránková V, Balner T, Gubová P, Staníková L, Zeleník K, Komínek P. Narrative review of relationship between chronic cough and laryngopharyngeal reflux. Front Med (Lausanne). 2024:11:1348985.

138. Pérez-Pazos J, García-Sánchez A, Estravís M, et al. Beyond T2-asthma biomarkers: risk stratification for NSAID-exacerbated respiratory disease. ERJ Open Res. 2024;10(4).

139. Lai K, Tang J, Zhan W, et al. The spectrum, clinical features and diagnosis of chronic cough due to rare causes. J Thorac Dis. 2021;13(4):2575-2582.

140. 140. Wingfield Digby J, King J, Al-Sheklly B, Marsden P, Fowler S, Smith J. Bronchoscopy for refractory/unexplained cough with mucus. Respir Med. 2023;217:107335.

141. Levy ML, Bacharier LB, Bateman E, et al. Key recommendations for primary care from the 2022 Global Initiative for Asthma (GINA) update. NPJ Prim Care Respir Med. 2023;33(1):7.

142. Global Initiative for Asthma. 2024 GINA Main Report: Global Strategy for Asthma Management and Prevention. Available at https://ginasthma.org/2024-report/. Last accessed July 25, 2024.

143. King J, Al-Sheklly B, Wingfield Digby J, et al. Refractory chronic cough patients are indiscriminately hyper-responsive to inhaled tussive irritants/agents. Am J Respir Crit Care Med. 2022;205:A2809.

144. Ryan MA, Cohen SM. Long-term follow-up of amitriptyline treatment for idiopathic cough. Laryngoscope. 2016;126(12):2758-2763.

145. Peechakara BV, Tharp JG, Eriator II, Gupta M. Codeine. Treasure Island, FL: StatPearls Publishing; 2023.

146. Song W-J, Chung KF. Pharmacotherapeutic options for chronic refractory cough. Expert Opin Pharmacother. 2020;21(11):1345-1358.

147. Morice AH, Menon MS, Mulrennan SA, et al. Opiate therapy in chronic cough. Am J Respir Crit Care Med. 2007;175(4):312315.

148. Al-Sheklly B, Mitchell J, Issa B, et al. S35 Randomised control trial quantifying the efficacy of low dose morphine in a responder group of patients with refractory chronic cough. Thorax. 2017;72(Suppl 3):A24-A25.

149. Mitchell J, Al-Sheklly B, Issa B, et al. P104 Sensations associated with experimentally evoked cough: influence of low dose morphine sulphate in opioid responders. Thorax. 2017;72(Suppl 3):A139-A140.

150. King J, Wingfield-Digby J, Hennessey S, et al. Real world effectiveness and tolerability of low-dose opiates for refractory/unexplained chronic cough (RCC/UCC) in a tertiary clinic. Eur Respir J. 2022;60(Suppl 66):1159.

151. Zhang M, Zhu Y, Dong R, Qiu Z. Gabapentin versus baclofen for treatment of refractory gastroesophageal reflux-induced chronic cough. J Thorac Dis. 2020;12(9):5243-5250.

152. Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380(9853):1583-1589.

153. Saint-Pierre MD. Predictors of treatment response to pregabalin in unexplained or refractory chronic cough. Respir Med. 2023:218:107396.

154. Vertigan AE, Kapela SL, Ryan NM, Birring SS, McElduff P, Gibson PG. Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial. Chest. 2016;149(3):639-648.

155. Al-Sheklly B, Badri H, Satia I, Woodcock A, Smith JA. P106 The use of gabapentin and pregabalin for the management of chronic cough in a tertiary cough clinic. Thorax. 2017;72(Suppl 3):A140-A142.

156. Dicpinigaitis PV, Morice AH, Birring SS, et al. Antitussive drugs: past, present, and future. Pharmacol Rev. 2014;66(2):468-512.

157. Jeyakumar A, Brickman TM, Haben M. Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. Laryngoscope. 2006;116(12):2108-2112.

158. Jang M, Rubin SJ, Stein DJ, Noordzij JP. Randomized double blind trial of amitriptyline versus placebo in treatment of chronic laryngopharyngeal neuropathy. Am J Otolaryngol. 2017;38(6):683-687.

159. Song SA, Choksawad K, Franco RA Jr. The effectiveness of nortriptyline and tolerability of side effects in neurogenic cough patients. Ann Otol Rhinol Laryngol. 2021;130(7):781-787.

160. Lečić SK, Javorac J, Živanović D, et al. Management of musculoskeletal pain in patients with idiopathic pulmonary fibrosis: a review. Ups J Med Sci. 2022;127:e8739.

161. Wu Z, Spencer LG, Banya W, et al. Morphine for treatment of cough in idiopathic pulmonary fibrosis (PACIFY COUGH): a prospective, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial. Lancet Respir Med. 2024;12(4):P273-P280.

162. Maher TM, Avram C, Bortey E, et al. Nalbuphine tablets for cough in patients with idiopathic pulmonary fibrosis. NEJM Evid. 2023;2(8):EVIDoa2300083.

163. Fabbri L, Guiot J, Vermant M, et al. ERS International Congress 2023: highlights from the Interstitial Lung Diseases Assembly. ERJ Open Res. 2024;10(2):00839-2023.

164. Domnik NJ, Yaggi HK. Lessons about low-dose morphine at the intersection of sleep and breathlessness. Am J Respir Crit Care Med. 2024; [Epub ahead of print].

165. Pelleg A, Sirtori E, Rolland J-F, Mahadevan A. DT-0111: a novel P2X3 receptor antagonist. Purinergic Signal. 2023;19(3):467-479.

166. Morice AH, Kitt MM, Ford AP, et al. The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study. Eur Respir J. 2019;54(1):1900439.

167. Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015;385(9974):1198-1205.

168. Iyer VN, Dicpinigaitis P, Taliercio R, et al. Camlipixant reduces burden of cough-related urinary incontinence in patients with refractory chronic cough in post-hoc analysis of a phase 2b trial. Am J Respir Crit Care Med. 2024;209:A7083.

169. Abdulqawi R, Satia I, Kanemitsu Y, et al. A randomized controlled trial to assess the effect of lidocaine administered via throat spray and nebulization in patients with refractory chronic cough. J Allergy Clin Immunol Pract. 2021;9(4):1640-1647.

170. Smith J, Hull J, Birring SS, et al. Randomized proof-of-concept study of AX-8, a TRPM8 agonist, in refractory or unexplained chronic cough. Am J Respir Crit Care Med. 2023;207:A2532.

171. Krüger K, Holzinger F, Trauth J, Koch M, Heintze C, Gehrke-Beck S. Chronic cough. Dtsch Arztebl Int. 2022;119(5):59-65.

Evidence-Based Practice Recommendations Citations

1. Alyn H Morice 1, Eva Millqvist 2, Kristina Bieksiene, et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. Available at https://erj.ersjournals.com/content/55/1/1901136. Last accessed August 12, 2024.

2. Côté A, Russell RJ, Boulet L-P, et al. Managing chronic cough due to asthma and NAEB in adults and adolescents: CHEST Guideline and Expert Panel report. Chest. 2020;158(1):68-96. Available at https://journal.chestnet.org/article/S0012-3692(20)30045-3/fulltext. Last accessed August 12, 2024.

97510 • Intercultural Competence and Patient-Centered Care

Alice Yick Flanagan, PhD, MSW

www.netce.com

Copyright © 2023 NetCE, All rights reserved.

Culture serves as a lens through which patients and practitioners filter their experiences and perceptions. Patients will bring their unique life stories and concerns to the practitioner, and their cultural values and belief systems will inevitably shape how the problem is defined and their beliefs about what is effective in solving the problem. However, the cultural backgrounds and values of patients are not necessarily scripts that define behavior, and when practitioners view culture as a strength and not a pathology, practitioners will be able to more effectively join with patients to mobilize change.

Table of Contents

97510 • Intercultural Competence and Patient-Centered Care

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Individual State Behavioral Health Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. DEFINITIONS

CULTURAL COMPETENCE

CULTURAL HUMILITY

DISCRIMINATION

DIVERSITY

INTERSECTIONALITY

PREJUDICE

RACISM

3. BIAS: IMPLICIT AND EXPLICIT

4. ROLE OF INTERPROFESSIONAL COLLABORATION AND PRACTICE

5. SOCIAL DETERMINANTS OF HEALTH

ECONOMIC STABILITY

HEALTH CARE ACCESS AND QUALITY

SOCIAL AND COMMUNITY CONTEXT

6. BARRIERS TO PROVIDING CARE

7. BEST PRACTICES FOR CULTURALLY RESPONSIVE CARE

RACIAL BACKGROUNDS

RELIGIOUS, CULTURAL, AND ETHNIC BACKGROUNDS

GENDER

GENDER AND SEXUAL MINORITIES

AGE

PERSONS WITH MENTAL OR PHYSICAL DISABILITY

VETERANS

DIETARY CONSIDERATIONS

8. PROMOTING CULTURALLY SENSITIVE COMMUNICATION

9. CULTURALLY SENSITIVE ASSESSMENT GUIDELINES

10. CREATING A WELCOMING AND SAFE ENVIRONMENT

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

97510 • Intercultural Competence and Patient-Centered Care

Education Category. Ethics - Human Rights

Release Date. 10/01/2023

Expiration Date. 09/30/2026

Course Overview

Culture serves as a lens through which patients and practitioners filter their experiences and perceptions. Patients will bring their unique life stories and concerns to the practitioner, and their cultural values and belief systems will inevitably shape how the problem is defined and their beliefs about what is effective in solving the problem. However, the cultural backgrounds and values of patients are not necessarily scripts that define behavior, and when practitioners view culture as a strength and not a pathology, practitioners will be able to more effectively join with patients to mobilize change.

Audience

This course is designed for all members of the interprofessional healthcare team.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE has been approved by NBCC as an Approved Continuing Education Provider, ACEP No. 6361. Programs that do not qualify for NBCC credit are clearly identified. NetCE is solely responsible for all aspects of the programs. NetCE is approved by the California Nursing Home Administrator Program as a provider of continuing education. Provider number 1622. As a Jointly Accredited Organization, NetCE is approved to offer social work continuing education by the Association of Social Work Boards (ASWB) Approved Continuing Education (ACE) program. Organizations, not individual courses, are approved under this program. Regulatory boards are the final authority on courses accepted for continuing education credit. Continuing Education (CE) credits for psychologists are provided through the co-sponsorship of the American Psychological Association (APA) Office of Continuing Education in Psychology (CEP). The APA CEP Office maintains responsibility for the content of the programs. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU. NetCE is recognized by the New York State Education Department's State Board for Social Work as an approved provider of continuing education for licensed social workers #SW-0033. This course is considered self-study, as defined by the New York State Board for Social Work. NetCE is recognized by the New York State Education Department's State Board for Mental Health Practitioners as an approved provider of continuing education for licensed mental health counselors #MHC-0021. This course is considered self-study by the New York State Board of Mental Health Counseling. NetCE is recognized by the New York State Education Department's State Board for Mental Health Practitioners as an approved provider of continuing education for licensed marriage and family therapists. #MFT-0015.This course is considered self-study by the New York State Board of Marriage and Family Therapy. Materials that are included in this course may include interventions and modalities that are beyond the authorized practice of licensed master social work and licensed clinical social work in New York. As a licensed professional, you are responsible for reviewing the scope of practice, including activities that are defined in law as beyond the boundaries of practice for an LMSW and LCSW. A licensee who practices beyond the authorized scope of practice could be charged with unprofessional conduct under the Education Law and Regents Rules.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 4 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 4 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 4 ANCC contact hour(s). NetCE designates this continuing education activity for 4.8 hours for Alabama nurses. NetCE designates this continuing education activity for 3 NBCC clock hour(s). Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 4 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Social workers participating in this intermediate to advanced course will receive 4 Clinical continuing education clock hours. NetCE designates this activity for 4 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-23-021-H04-P. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 4 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 4 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. This course is approved by the California Nursing Home Administrator Program for 4 hour(s) of continuing education credit - NHAP#1622004-9450/P. California NHAs may only obtain a maximum of 10 hours per course. NetCE designates this continuing education activity for 4 credit(s). AACN Synergy CERP Category B. NetCE is authorized by IACET to offer 0.4 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Individual State Behavioral Health Approvals

In addition to states that accept ASWB, NetCE is approved as a provider of continuing education by the following state boards: Alabama State Board of Social Work Examiners, Provider #0515; Florida Board of Clinical Social Work, Marriage and Family Therapy and Mental Health Counseling, CE Broker Provider #50-2405; Illinois Division of Professional Regulation for Social Workers, License #159.001094; Illinois Division of Professional Regulation for Licensed Professional and Clinical Counselors, License #197.000185; Illinois Division of Professional Regulation for Marriage and Family Therapists, License #168.000190;

Special Approvals

This course has been approved by the Nevada State Board of Nursing to meet the requirement for cultural competency education. This course has been approved by NetCE, as a NAADAC Approved Education Provider, for educational credits, NAADAC Provider #97847. NetCE is responsible for all aspects of their programming. NetCE is approved as a provider of continuing education by the California Consortium of Addiction Programs and Professionals. Provider Number 5-08-151-0626. NetCE is approved as a provider of continuing education by the California Association of DUI Treatment Programs (CADTP). Provider Number 185. NetCE is approved as a provider of continuing education by the California Association for Alcohol/Drug Educators. Provider Number CP40 889 H 0626. This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency. NetCE designates this continuing education activity for 4 continuing education hours for addiction professionals.

Course Objective

The purpose of this course is to provide members of the interprofessional healthcare team with the knowledge, skills, and strategies necessary to provide culturally competent and responsive care to all patients.

Learning Objectives

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

1. Define cultural competence, implicit bias, and related terminology.

2. Outline social determinants of health and barriers to providing care.

3. Discuss best practices for providing culturally competent care to various patient populations.

4. Discuss key aspects of creating a welcoming and safe environment, including avoidance of discriminatory language and behaviors.

Faculty

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

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

Faculty Disclosure

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

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

Margaret Donohue, PhD

Randall L. Allen, PharmD

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Culturally competent care has been defined as "care that takes into account issues related to diversity, marginalization, and vulnerability due to culture, race, gender, and sexual orientation" [1]. A culturally competent person is someone who is aware of how being different from the norm can be marginalizing and how this marginalization may affect seeking or receiving health care [1]. To be effective cross-culturally with any diverse group, healthcare professionals must have awareness, sensitivity, and knowledge about the culture involved, enhanced by the use of cross-cultural communication skills [2,3].

Healthcare professionals are accustomed to working to promote the healthy physical and psychosocial development and well-being of individuals within the context of the greater community. For years, these same professionals have been identifying at-risk populations and developing programs or making referrals to resources to promote the health and safety of at-risk groups. But, because of general assumptions, persistent stereotypes, and implicit and explicit biases, culture-related healthcare disparities persist [2]. In the increasingly diverse landscape of the United States, assessing and addressing culture-related barriers to care are a necessary part of health care. This includes seeking to improve one's cultural competence and identifying blind spots and biases.

2. DEFINITIONS

CULTURAL COMPETENCE

In healthcare, cultural competence is broadly defined as practitioners' knowledge of and ability to apply cultural information and appreciation of a different group's cultural and belief systems to their work [4]. It is a dynamic process, meaning that there is no endpoint to the journey to becoming culturally aware, sensitive, and competent. Some have argued that cultural curiosity is a vital aspect of this approach.

CULTURAL HUMILITY

Cultural humility refers to an attitude of humbleness, acknowledging one's limitations in the cultural knowledge of groups. Practitioners who apply cultural humility readily concede that they are not experts in others' cultures and that there are aspects of culture and social experiences that they do not know. From this perspective, patients are considered teachers of the cultural norms, beliefs, and value systems of their group, while practitioners are the learners [5]. Cultural humility is a lifelong process involving reflexivity, self-evaluation, and self-critique [6].

DISCRIMINATION

Discrimination has traditionally been viewed as the outcome of prejudice [7]. It encompasses overt or hidden actions, behaviors, or practices of members in a dominant group against members of a subordinate group [8]. Discrimination has also been further categorized as lifetime, which consists of major discreet discriminatory events, or everyday, which is subtle, continual, and part of day-to-day life and can have a cumulate effect on individuals [9].

DIVERSITY

Diversity "encompasses differences in and among societal groups based on race, ethnicity, gender, age, physical/mental abilities, religion, sexual orientation, and other distinguishing characteristics" [10]. Diversity is often incorrectly conceptualized into singular dimensions as opposed to multiple and intersecting diversity factors [11].

INTERSECTIONALITY

Intersectionality is a term to describe the multiple facets of identity, including race, gender, sexual orientation, religion, sex, and age. These facets are not mutually exclusive, and the meanings that are ascribed to these identities are inter-related and interact to create a whole [12]. This term also encompasses the ways that different types and systems of oppression intersect and affect individuals.

PREJUDICE

Prejudice is a generally negative feeling, attitude, or stereotype against members of a group [13]. It is important not to equate prejudice and racism, although the two concepts are related. All humans have prejudices, but not all individuals are racist. The popular definition is that "prejudice plus power equals racism" [13]. Prejudice stems from the process of ascribing every member of a group with the same attributes [14].

RACISM

Racism is the "systematic subordination of members of targeted racial groups who have relatively little social power…by members of the agent racial group who have relatively more social power" [15]. Racism is perpetuated and reinforced by social values, norms, and institutions.

There is some controversy regarding whether unconscious (implicit) racism exists. Experts assert that images embedded in our unconscious are the result of socialization and personal observations, and negative attributes may be unconsciously applied to racial minority groups [16]. These implicit attributes affect individuals' thoughts and behaviors without a conscious awareness.

Structural racism refers to the laws, policies, and institutional norms and ideologies that systematically reinforce inequities, resulting in differential access to services such as health care, education, employment, and housing for racial and ethnic minorities [17,18].

3. BIAS: IMPLICIT AND EXPLICIT

In a sociocultural context, biases are generally defined as negative evaluations of a particular social group relative to another group. Explicit biases are conscious, whereby an individual is fully aware of his/her attitudes and there may be intentional behaviors related to these attitudes [19]. For example, an individual may openly endorse a belief that women are weak and men are strong. This bias is fully conscious and is made explicitly known. The individual's ideas may then be reflected in his/her work as a manager.

FitzGerald and Hurst assert that there are cases in which implicit cognitive processes are involved in biases and conscious availability, controllability, and mental resources are not [20]. The term "implicit bias" refers to the unconscious attitudes and evaluations held by individuals. These individuals do not necessarily endorse the bias, but the embedded beliefs/attitudes can negatively affect their behaviors [21,22,23,24]. Some have asserted that the cognitive processes that dictate implicit and explicit biases are separate and independent [24].

Implicit biases can start as early as 3 years of age. As children age, they may begin to become more egalitarian in what they explicitly endorse, but their implicit biases may not necessarily change in accordance to these outward expressions [25]. Because implicit biases occur on the subconscious or unconscious level, particular social attributes (e.g., skin color) can quietly and insidiously affect perceptions and behaviors [26]. According to Georgetown University's National Center on Cultural Competency, social characteristics that can trigger implicit biases include [27]:

- Age

- Disability

- Education

- English language proficiency and fluency

- Ethnicity

- Health status

- Disease/diagnosis (e.g., human immunodeficiency virus [HIV])

- Insurance

- Obesity

- Race

- Socioeconomic status

- Sexual orientation, gender identity, or gender expression

- Skin tone

- Substance use

An alternative way of conceptualizing implicit bias is that an unconscious evaluation is only negative if it has further adverse consequences on a group that is already disadvantaged or produces inequities [20,28]. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages [28].

When the concept of implicit bias was introduced in the 1990s, it was thought that implicit biases could be directly linked to behavior. Despite the decades of empirical research, many questions, controversies, and debates remain about the dynamics and pathways of implicit biases [21].

Specific conditions or environmental risk factors have been associated with an increased risk for certain implicit biases, including [130,131]:

- Stressful emotional states (e.g., anger, frustration)

- Uncertainty

- Low-effort cognitive processing

- Time pressure

- Lack of feedback

- Feeling behind with work

- Lack of guidance

- Long hours

- Overcrowding

- High-crises environments

- Mentally taxing tasks

- Juggling competing tasks

4. ROLE OF INTERPROFESSIONAL COLLABORATION AND PRACTICE

The study of implicit bias is appropriately interdisciplinary, representing social psychology, medicine, health psychology, neuroscience, counseling, mental health, gerontology, gender/sexuality studies, religious studies, and disability studies [28]. Therefore, implicit bias empirical research and curricula training development lends itself well to interprofessional collaboration and practice (ICP).

The main characteristics of ICP allow for implicit and explicit biases to be addressed by the interprofessional team. One of the core features of ICP is sharing—professionals from different disciplines share their philosophies, values, perspectives, data, and strategies for planning of interventions [29]. ICP also involves the sharing of roles, responsibilities, decision making, and power [30]. Everyone on the team employs their expertise, knowledge, and skills, working collectively on a shared, patient-centered goal or outcome [30,31].

Another feature of ICP is interdependency. Instead of working in an autonomous manner, each team member's contributions are valued and maximized, which ultimately leads to synergy [29]. At the heart of this are two other key features: mutual trust/respect and communication [31]. In order to share responsibilities, the differing roles and expertise are respected.

Experts have recommended that a structural or critical theoretical perspective be integrated into core competencies in healthcare education to teach students about implicit bias, racism, and health disparities [32]. This includes [32]:

- Values/ethics: The ethical duty for health professionals to partner and collaborate to advocate for the elimination of policies that promote the perpetuation of implicit bias, racism, and health disparities among marginalized populations.

- Roles/responsibilities: One of the primary roles and responsibilities of health profes-sionals is to analyze how institutional and organizational factors promote racism and implicit bias and how these factors contribute to health disparities. This analysis should extend to include one's own position in this structure.

- Interprofessional communication: Ongoing discussions of implicit bias, perspective taking, and counter-stereotypical dialogues should be woven into day-to-day practice with colleagues from diverse disciplines.

- Teams/teamwork: Health professionals should develop meaningful contacts with marginalized communities in order to better understand whom they are serving.

Adopting approaches from the fields of education, gender studies, sociology, psychology, and race/ethnic studies can help build curricula that represent a variety of disciplines [33]. Students can learn about and discuss implicit bias and its impact, not simply from a health outcomes perspective but holistically. Skills in problem-solving, communication, leadership, and teamwork should be included [33].

5. SOCIAL DETERMINANTS OF HEALTH

Social determinants of health are the conditions in the environments where people are born, live, learn, work, play, worship, and age that affect a wide range of health, functioning, and quality-of-life outcomes and risks. These circumstances are shaped by the distribution of money, power, and resources at global, national, and local levels. Healthy People 2030 groups social determinants of health into five categories [34]:

- Economic stability

- Education access and quality

- Health care access and quality

- Social and community context

- Neighborhood and built environment

These factors have a major impact on people's health, well-being, and quality of life. Examples of social determinants of health include [34]:

- Safe housing, transportation, and neighborhoods

- Racism, discrimination, and violence

- Education, job opportunities, and income

- Access to nutritious foods and physical activity opportunities

- Polluted air and water

- Language and literacy skills

Social determinants of health also contribute to wide health disparities and inequities. For example, people who lack access to grocery stores with healthy foods are less likely to have good nutrition, which raises the risk of heart disease, diabetes, and obesity and lowers life expectancy compared with those who have easier access to healthy foods [34].

Promoting healthy choices will not eliminate these and other health disparities. Instead, public health organizations and their partners must take action to improve the conditions in people's environments. Healthcare providers play a role by identifying factors affecting the health of their patients, providing resources (when appropriate), and advocating for healthy environments.

ECONOMIC STABILITY

In the United States, 1 in 10 people live in poverty, and many people are unable afford healthy foods, health care, and housing. People with steady employment are less likely to live in poverty and more likely to be healthy, but many people have trouble finding and keeping a job. People with disabilities, injuries, or chronic conditions (e.g., arthritis) may be especially limited in their ability to work. In addition, many people with steady work still do not earn enough to afford the things they need to stay healthy [34].

Employment programs, career counseling, and high-quality childcare opportunities can help more people find and keep jobs. In addition, policies to help people pay for food, housing, health care, and education can reduce poverty and improve health and well-being [34].

HEALTH CARE ACCESS AND QUALITY

Many people in the United States are unable to access the healthcare services they need. About 1 in 10 people in the United States lack health insurance, and people without insurance are less likely to have a primary care provider and be able to afford the healthcare services and medications they need. Strategies to increase insurance coverage rates are critical for making sure more people get important healthcare services, including preventive care and treatment for chronic illnesses [34].

In some cases, patients are not recommended health care services (e.g., cancer screenings) because they do not have a primary care provider or because they live too far away from healthcare providers who offer them. Interventions to increase access to healthcare professionals and improve communication—in person or remotely—can help more people get the care they need [34].

SOCIAL AND COMMUNITY CONTEXT

People's relationships and interactions with family, friends, co-workers, and community members can have a major impact on their health and well-being. Many people face challenges and dangers they are not able to control, including unsafe neighborhoods, discrimination, or trouble affording the things they need. This can have a negative impact on health and safety throughout life.

Positive relationships at home, at work, and in the community can help reduce these negative impacts. But some people (e.g., children whose parents are in jail, adolescents who are bullied) often do not get support from loved ones or others. Interventions to help people access the social and community support they need are critical for improving health and well-being [34]. Healthy People 2030 objectives in this category focus on increasing the proportion of children and adolescents who have an adult they can talk to about serious problems, improving community health literacy, increasing the likelihood that an individual talks to friends or family about their health, and expanding access to online healthcare services [34].

6. BARRIERS TO PROVIDING CARE

Culturally diverse patients experience a variety of barriers when seeking health and mental health care, including:

- Immigration status

- Lower socioeconomic status

- Language barriers

- Cultural differences

- Lack of or poor health insurance coverage

- Fear of or experiences with provider discrimination

- Mistrust of healthcare systems

Such obstacles can interfere with or prevent access to treatment and services, compromise appropriate referrals, affect compliance with recommendations, and result in poor outcomes. Culturally competent providers build and maintain rich referral resources to meet patients' assorted needs.

Encountering discrimination when seeking health or mental health services is a barrier to optimal care and contributor to poorer outcomes in under-represented groups. Some providers will not treat patients because of moral objections, which can affect all groups, but particularly those who are gender and/or sexual minorities, religious minorities, and/or immigrants. In fact, in 2016, Mississippi and Tennessee passed laws allowing health providers to refuse to provide services if doing so would violate their religious beliefs [35]. However, it is important to remember that providers are obligated to act within their profession's code of ethics and to ensure patients receive the best possible care.

7. BEST PRACTICES FOR CULTURALLY RESPONSIVE CARE

The U.S. Department of Health and Human Services has outlined steps important to incorporate in evaluation and treatment planning processes to ensure culturally competent clinical and programmatic decisions and skills [36].

The first step is to engage patients. In nonemergent situations, it is important to establish rapport before asking a series of assessment questions or delving deeply into history taking. Providers should use simple gestures as culturally appropriate (e.g., handshakes, facial expressions, greetings) to help establish a first impression. The intent is that all patients feel understood and seen following each interaction. Culturally responsive interview behaviors and paperwork should be used at all times [36].

When engaging in any patient teaching, remember that individuals may be new to the specific language or jargon and expectations of the diagnosis and care process. Patients should be encouraged to collaborate in every step of their care. This consists of seeking the patient's input and interpretation and establishing ways they can seek clarification. Patient feedback can then be used to help identify cultural issues and specific needs. If appropriate, collaboration should extend to include family and community members.

Assessment should incorporate culturally relevant themes in order to more fully understand patients and identify their cultural strengths and challenges. Themes include [36]:

- Immigration history

- Cultural identity and acculturation

- Membership in a subculture

- Beliefs about health, healing, and help-seeking

- Trauma and loss

In some cases, it may be appropriate and beneficial to obtain culturally relevant collateral information, with the patient's permission, from sources other than the patient (e.g., family or community members) to better understand beliefs and practices that shape the patient's cultural identity and understanding of the world.

Practitioners should work to identify screening and assessment tools that have been translated into or adapted for other languages and have been validated for their particular population group(s). An instrument's cultural applicability to the population being served should be assessed, keeping in mind that research is limited on the cross-cultural applicability of specific test items or questions, diagnostic criteria, and concepts in evaluative and diagnostic processes [36].

Typically, culturally responsive care establishes holistic treatment goals that include objectives to improve physical health and spiritual strength; utilizes strengths-based strategies that fortify cultural heritage, identity, and resiliency; and recognizes that treatment planning is a dynamic process that evolves along with an understanding of patient history and treatment needs.

In addition to these general approaches, specific considerations may be appropriate for specific populations. While discussion of every possible patient subgroup is outside of the scope of this course, some of the most common factors are outlined in the following sections [36].

RACIAL BACKGROUNDS

Race and color impact the ways in which individuals interact with their environments and are perceived and treated by others. Race is defined as groups of humans divided on the basis of inherited physical and behavioral differences. As part of the cultural competence process and as a reflection of cultural humility, practitioners should strive to learn as much as possible about the specific racial/ethnic populations they serve [37]. However, considerable diversity exists within any specific culture, race, or ethnicity [37]. Cultural beliefs, traditions, and practices change over time, both through generations and within an individual's lifetime. It is also possible for the differences between two members of the same racial/ethnic group to be greater than the differences between two people from different racial/ethnic groups. Within-group variations in how persons interact with their environments and specific social contexts are also often present.

As with all patients, it is vital to actively listen and critically evaluate patient relationships. All practitioners should seek to educate themselves regarding the experiences of patients who are members of a community that differs from their own. Resources and opportunities to collaborate may be available from community organizations and leaders.

Finally, preferred language and immigration/migration status should be considered. Interpreters should be used when appropriate, with adherence to best practices for the use of interpretation services. Stressing confidentiality and privacy is particularly important for undocumented workers or recent immigrants, who may be fearful of deportation.

Black Patients

"Black" or "African American" is a classification that serves as a descriptor; it has sociopolitical and self-identification ramifications. The U.S. Census Bureau defines African Americans or Black Americans as persons "having origins in any of the Black racial groups of Africa" [38].

Evidence Based Practice Recommendation

When providing mental health services for African Americans, the American Psychiatric Association recommends exploring how a patient's present experiences connect to historical trauma for a particular group or community.

https://www.psychiatry.org/psychiatrists/diversity/education/stress-and-trauma/african-americans

Last Accessed: September 26, 2023

Level of Evidence: Expert Opinion/Consensus Statement

According to the U.S. Census, African Americans number 46.9 million as of 2020 [39]. By 2060, it is projected they will comprise 17.9% of the U.S. population [40]. This group tends to be young; 30% of the African American population in the United States is younger than 18 years of age. In 2019, the median age for this group was 35 years [41]. In terms of educational attainment, 89.4% of African Americans 25 years of age or older had a high school diploma or completed college in 2020 [39]. Texas has the largest African American population, at 3.9 million [41].

Historical adversity and institutional racism contribute to health disparities in this group. For the Black population, patient assessment and treatment planning should be framed in a context that recognizes the totality of life experiences faced by patients. In many cases, particularly in the provision of mental health care, equality is sought in the provider-patient relationship, with less distance and more disclosing. Practitioners should assess whether their practices connect with core values of Black culture, such as family, kinship, community, and spirituality. Generalized or Eurocentric treatment approaches may not easily align with these components of the Black community [42]. Providers should also consider the impact of racial discrimination on health and mental health among Black patients. Reports indicate that expressions of emotion by Black patients tend to be negatively misunderstood or dismissed; this reflects implicit or explicit biases.

Asian Patients

As of 2019, 22.9 million Americans identified as Asian [43]. Between 2000 and 2019, Asians experienced the greatest growth compared with any other racial group at 81% [44,45]. The Chinese group represents the largest Asian subgroup in the United States, and it is projected that this population will grow to 35.7 million between 2015 and 2040 [46,47]. In 2019, Chinese Americans (excluding Taiwanese Americans) numbered at 5.2 million [43]. They also have the highest educational attainment; 54.6% of Asians 25 years of age or older had a bachelor's degree or higher in 2019 [43].

"Asian" is a single term widely used to describe individuals who have kinship and identity ties to Asia, including the Far East, Southeast Asia, and the Indian subcontinent [48]. This encompasses countries such as China, Japan, Korea, Vietnam, Cambodia, Thailand, India, Pakistan, and the Philippines. Pacific Islander is often combined with Asian American in census data. The Pacific Islands include Hawaii, Guam, Samoa, Fiji, and many others [48]. There are more than 25 Asian/Pacific Islander groups, each with a different migration history and widely varying sociopolitical environments in their homelands [49].

Asian American groups have differing levels of acculturation, lengths of residency in the United States, languages, English-speaking proficiency, education attainment, socioeconomic statuses, and religions. For example, there are approximately 32 different languages spoken among Asian Americans, and within each Asian subgroup (e.g., Chinese), multiple dialects may be present [49,50]. In 2019, California had the largest Asian American population, totaling 5.9 million [44].

Recommended best practices when caring for Asian American patients include:

- Create an advisory committee using representatives from the community.

- Incorporate cultural knowledge and maintain flexible attitudes.

- Provide services in the patients' primary language.

- Develop culturally specific questionnaires for intake to capture information that may be missed by standard questionnaires.

- Emphasize traditional values and incorporate traditional practices (e.g., acupuncture) into treatment plans, when appropriate and desired.

- Explore patient coping mechanisms that draw upon cultural strengths.

Latino/a/x or Hispanic Patients

In 2020, the Hispanic population in the United States numbered 60.6 million [51]. The majority of the Hispanic population in the United States (63.3%) identify themselves as being of Mexican descent [53]. Approximately 27% of the U.S. Hispanic population identify as Puerto Rican, Cuban, Salvadoran, Dominican, Guatemalan, Colombian, Honduran, Ecuadorian, or Peruvian [54].

In 2020, the Hispanic population comprised 18.7% of the U.S. population [51]. As such, they are the largest ethnic minority group in the United States. By 2060, Hispanics are expected to represent 31% of the U.S. population [55]. They are also a young group, with a median age of 29.8 years [51]. In 2019, the three states with the largest Hispanic population growth were Texas (2 million), California (1.5 million), and Florida (1.4 million); these three states have the largest Hispanic populations overall [52].

When involved in the care of Latinx/Hispanic individuals, practitioners should strive to employ personalismo (warm, genuine communication) and recognize the importance of familismo (the centrality of the family). More flexible scheduling strategies may be more successful with this group, if possible, and some patients may benefit from culturally specific treatment and ethnic and gender matching with providers. Aspects of Latino culture can be assets in treatment: strength, perseverance, flexibility, and an ability to survive.

Native American Patients

The Native American population is extremely diverse. According to the U.S. Census, the terms "Native American," "American Indian," or "Alaskan Native" refer to individuals who identify themselves with tribal attachment to indigenous groups of North and South America [56]. In the United States, there are 574 federally recognized tribal governments and 324 federally recognized reservations [57].

In 2020, it was reported that there were 7.1 million Native Americans in the United States, which is approximately 2% of the U.S. population [57]. By 2060, this number is projected to increase to 10.1 million, or 2.5% of the total population [57].

Evidence Based Practice Recommendation

The American Psychological Association recommends that clinicians aim to understand and encourage Indigenous/ethnocultural sources of healing within professional practice.

https://www.apa.org/about/policy/guidelines-race-ethnicity.pdf

Last Accessed: September 26, 2023

Level of Evidence: Expert Opinion/Consensus Statement

In general, this group is young, with a median age of 31 years, compared with the general median age of 37.9 years [58]. As of 2018, the states with the greatest number of residents identifying as Native American are Alaska, Oklahoma, New Mexico, South Dakota, and Montana [59]. In 2016, this group had the highest poverty rate (26.2%) of any racial/ethnic group [58].

Listening is an important aspect of rapport building with Native American patients, and practitioners should use active listening and reflective responses. Assessments and histories may include information regarding patients' stories, experiences, dreams, and rituals and their relevance. Interruptions and excessive questioning should be avoided if at all possible. Extended periods of silence may occur, and time should be allowed for patients to adjust and process information. Practitioners should avoid asking about family or personal matters unrelated to presenting issues without first asking permission to inquire about these areas. Native American patients often respond best when they are given suggestions and options rather than directions.

White American Patients

In 2021, 76.3% of the U.S. population identified as White alone [60]. The U.S. Census Bureau defines White race as person having origins in any of the original peoples of Europe, the Middle East, or North Africa [38]. While the proportion of population identifying as White only has decreased between 2010 and 2020, the numbers of persons identifying as White and another race/ethnicity increased significantly. The White population in the United States is diverse in its religious, cultural, and social composition. The greatest proportion of this group reports a German ancestry (17%), followed by Irish (13%), English (10%), and Italian (7%) [61].

Providers can assume that most well-accepted treatment approaches and interventions have been tested and evaluated with White American individuals, particularly men. However, approaches may need modification to suit class, ethnic, religious, and other factors.

Providers should establish not only the patient's ethnic background, but also how strongly the person identifies with that background. It is also important to be sensitive to persons multiracial/multiethnic heritage, if present, and how this might affect their family relationships and social experiences. Assumption of White race should be avoided, as White-passing persons of color have their own unique needs.

Multiracial Patients

Racial labels do not always have clear meaning in other parts of the world; how one's race is defined can change according to one's current environment or society. A person viewed as Black in the United States can possibly be viewed as White in Africa. Racial categories also do not easily account for the complexity of multiracial identities. An estimated 3% of United States residents (9 million individuals) indicated in the 2010 Census that they are of more than one race [149]. The percentage of the total United States population who identify as being of mixed race is expected to grow significantly in coming years, and some estimate that it will rise as high as one in five individuals by 2050 [36,150].

Multiracial individuals often report feeling not fully embraced by any racial or ethnic group, and mistaken identity is a common issue. A small study of multiracial patients assessed their healthcare experiences and noted six commonly encountered microaggressions: mistaken identity, mistaken relationships, fixed forms, entitled examiner, pervasive stereotypes, and intersectionality [144]. It is important to avoid assuming race/culture based only on appearance and to take into account the patient's self-reported identity.

RELIGIOUS, CULTURAL, AND ETHNIC BACKGROUNDS

Religion, culture, beliefs, and ethnic customs can influence how patients understand health concepts, how they take care of their health, and how they make decisions related to their health. Without proper training, clinicians may deliver medical advice without understanding how health beliefs and cultural practices influence the way that advice is received. Asking about patients' religions, cultures, and ethnic customs can help clinicians engage patients so that, together, they can devise treatment plans that are consistent with the patients' values [37].

Respectfully ask patients about their health beliefs and customs and note their responses in their medical records. Address patients' cultural values specifically in the context of their health care. For example, one may ask [37]:

- "Is there anything I should know about your culture, beliefs, or religious practices that would help me take better care of you?"

- "Do you have any dietary restrictions that we should consider as we develop a food plan to help you lose weight?"

- "Your condition is very serious. Some people like to know everything that is going on with their illness, whereas others may want to know what is most important but not necessarily all the details. How much do you want to know? Is there anyone else you would like me to talk to about your condition?"

- "What do you call your illness and what do you think caused it?"

- "Do any traditional healers advise you about your health?"

Practitioners should avoid stereotyping based on religious or cultural background. Each person is an individual and may or may not adhere to certain cultural beliefs or practices common in his or her culture. Asking patients about their beliefs and way of life is the best way to be sure you know how their values may impact their care [37].

The following sections provide a glimpse of the beliefs and practices of the major world religions. This overview is meant only to give a very simple, brief summary of the general ideology of each religion. By no means are all of the rites or beliefs described practiced by all members of each religion; likewise, not all religious rites or beliefs are discussed for each religion. As always, individualized assessment is encouraged.

Judaism

Judaism emerged in the Southern Levant (an area in the Middle East) in about 2000 B.C.E. [136]. There are approximately 13 million Jewish people in the world—6 million in North America, 4.3 million in Asia, and 2.5 million in Europe [137]. Jewish descent is traced through the maternal line, but the choice to practice Judaism is made by the individual. In Jewish tradition, the Torah is believed to be the word of God and the ultimate authority.

There are three tenets of Judaism. The first tenet is monotheism; there is one God who created the universe and continues to rule [138]. The second tenet is that the Jews were chosen to receive the law of God (Yahweh) and to serve as role models for humankind [138]. The third tenet refers to the covenant, which is a contractual agreement between God and the Jewish people. According to the agreement, they will be rewarded if they obey God and keep his commandments; failing to do so would result in divine retribution. Also, they believe that studying the Torah and faithfulness to God and his commandments may hasten the arrival of the Messiah [136,138].

Jewish law focuses on dietary practices, the Sabbath, and annual holidays or festivals. Observing the dietary laws is called keeping kosher. One's home is considered the table of the Lord, and therefore certain animals considered unclean (e.g., pork, shellfish) are not to be eaten. However, animals with split hooves and animals that chew their cud are acceptable. Acceptable animals must be slaughtered correctly, must have the blood drained from them, and must not be served with dairy products. Those who adhere to kosher laws have separate sets of dishes and utensils for preparing and serving meat, dairy products, and Passover meals [138,139]. Passover, Hanukkah, Rosh Hashanah, and Yom Kippur are major festivals observed by members of the faith.

Christianity

Christianity emerged in the 1st century C.E. It is the largest religion in North America, and there are approximately 2 billion followers worldwide [136]. There are three major divisions in Christianity: Roman Catholicism, Eastern Orthodoxy, and Protestantism [136,138]. Christianity is based on the life and teachings of Jesus Christ, and followers believe that salvation and eternal life can be obtained through their belief in Jesus [137]. The concept of the Trinity is also basic to Christian belief. Although God is perceived as one, God is also expressed in three roles: Father (Creator), Son (Redeemer), and the Holy Spirit (Sustainer) [138,139].

Baptism and the Eucharist or Holy Communion are the primary sacraments celebrated in most Christian churches [138]. Baptism symbolizes the forgiveness of sins, new life, and initiation into the Christian church. During the baptism, persons are either immersed in water or water is sprinkled or poured over them. Eucharist or Holy Communion is a ritual meal in which bread and wine are taken in remembrance of the body and blood of Jesus that was broken and shed at the cross [136]. Major Christian holidays include Easter (commemorating the death and resurrection of Jesus Christ) and Christmas (celebrating the birth of Jesus).

Christians consider the Bible to be the word of God. It is composed of 66 to 81 separate books (depending on denomination). Christians hold various perspectives on the nature, purpose, and approaches to the interpretation of the Bible.

Islam

Islam is the fastest-growing religion in the United States and throughout the world [140]. Members of Islam are called Muslims, and approximately 3.45 million live in the United States [140]. Islam began in Arabia around 570–632 C.E. and was founded by the prophet Muhammad. It is a monotheistic religion whose followers believe there is one God and that Muhammad was his last Prophet. They believe the Qur'an (or Koran) is the literal word of God (or Allah in Arabic) that was revealed to Muhammad and mediated by Gabriel, the angel of revelation [138]. Arabic is the language used in Islamic prayer/liturgy [137]. Major festivals or holidays include Al-Hijra, Milad un Nabi, Ramadan, Eid al-Fitr, Eid al-Adha, Day of Ashura, and Laylatul Qadr.

Most Muslims are of one of two denominations: Sunni and Shia. While various denominations may have slightly different beliefs or translations, Islam has six major doctrines. The first is the belief in divine unity, or tawhid [136,138]. The second is the belief in angels as agents of God. Angels have many functions, such as carrying messages to prophets and watching over and keeping track of people. The third is a belief in prophecy as revealed in the Qur'an. The fourth involves belief in scripture (Qur'an), and the fifth is the belief in Judgment Day and life after death [136,138]. On the Last Day (or final judgment), both the living and the dead will be judged. The faithful will be rewarded, and the unfaithful will be cast into hell. Finally, the sixth doctrine is the Divine Decree and Predestination. It suggests that Allah has already determined who will receive eternal salvation [136,138].

The Five Pillars are the core beliefs and practices of Islam. The first is the Shahada (profession of faith)—the belief that there is no god but Allah, and Muhammad is his messenger [136]. The second pillar is the Salat (ritual prayer). Muslims pray facing Mecca five times every day: at dawn, noon, mid-afternoon, sunset, and evening [138]. The prayers are usually performed on a rug or mat specifically for this purpose. Zakat (almsgiving) is the third pillar of Islam. Muslims are expected to donate a certain portion of their income to community members in need [138]. Sawm (or fasting) is the fourth pillar of Islam. During the daylight hours of Ramadan, healthy adult Muslims are expected to abstain from food, drink, and sexual relations. This is a time of reflecting, renewing faith, and being grateful for everything Allah has given [138]. The fifth pillar of Islam is Hajj (pilgrimage). After 16 years of age, every Muslim in good health and whose finances permit is expected to visit the holy city of Mecca, located in present-day Saudi Arabia.

Hinduism

Hinduism is one of the world's oldest religions, dating back to about 1500 B.C.E. [138]. Unlike other major religions, it was not founded by a single person but was born of many religious beliefs and philosophies [138]. Hinduism originated in India, and today it is the third-largest religion in the world. There are approximately 1.1 billion adherents worldwide and 2.3 million adherents in the United States [141]. Hinduism is a polytheistic religion with three major deities: Shiva, Vishnu, and Brahma [138]. There are many sacred texts in Hinduism, including The Ramayana, an epic tale of Lord Rama's victory over the 10-headed demon Ravana, and The Mahabharata, the world's longest epic poem that is an historical account of the birth of Hinduism along with a code of ethics for the faithful [136]. Major Hindu festivals include Makar Sankranti, Holi, Diwali, Mahashivratri, Vasant Panchami, Rama Navami, and Janmashtami/Krishna Jayanti.

Two concepts are central to Hinduism: karma and reincarnation. Karma refers to the spiritual principle of cause and effect. In short, people's circumstances are the result of present and past-life actions of good or evil [136]. Hindus also believe in the continuous cycle of life, death, and rebirth (reincarnation) that continues until the soul "transcends all pain and pleasure and release itself from all fears and attachments" [138]. This state is called samsara or transmigration [138].

The Hindu temple is a cultural center where people come to sing, read sacred texts, and perform rituals [136]. The chanting of mantra called pathas is a traditional Hindu practice and is believed to have transformative power. Puja or daily worship is an important aspect of Hinduism. It entails the offering of food, incense, flowers, fruits, ashes, and other articles to an image of a deity [138]. Tirthas refer to pilgrimage sites and holy places in Hinduism [138].

Buddhism

There are approximately 3 million Buddhists in the United States and about 488 million worldwide [141]. Buddhism was founded in northeastern India by Siddhartha Gautam, whose name was later changed to the Buddha or Enlightened One. At 29 years of age, the Buddha sought knowledge from several forest yogis and learned meditation techniques. After six years, Buddhists believe Gautama found enlightenment while meditating under a Bodhi tree and was released from the cycle of rebirths [138]. He began promoting the idea of a middle path that focused on purity of thought and deed. Buddha believed awareness was the path to overcoming death [136]. He did not want to be worshiped as a god or savior. Instead, he believed his role was to help people find their path to freedom and enlightenment.

The Four Noble Truths and the Eightfold Path are essential to understanding Buddhism. The Four Noble Truths have been identified as the first teaching given by Buddha [137]:

- There is suffering in life.

- Human desire is the cause of suffering.

- The end of human suffering is possible.

- The Eightfold Path is how one achieves nirvana.

Collectively, the Four Noble Truths explain why humans suffer and how to overcome suffering. Within the Four Noble Truths is found the Eightfold Path. Wangu describes the Eightfold Path as consisting of the right opinion, right intentions, right speech, right conduct, right livelihood, right effort, right mindfulness, and right concentration [138]. These eight paths are grouped into three key elements of Buddhist practice: morality, wisdom, and concentration [138].

Buddhists engage in rituals such as chanting and placing flowers, candles, and incense before an image of Buddha. Buddhists celebrate many holidays and festivals, most of which commemorate important events in the life of the Buddha. Every year, Buddhists celebrate Vesak, a festival that commemorates Buddha's birth, enlightenment, and death. During each quarter of the moon, followers of Buddhism participate in a ceremony called Uposatha [136]. This observance allows Buddhists to renew their commitment to their teachings. Buddhist New Year is a time for reflection of past lives and identifying and rectifying mistakes [136].

Confucianism

Confucianism is described as a way of life, philosophy, religion, or ethical code by which to live [138]. It was developed from the teachings of Confucius, who was born around 551 B.C.E. [138]. These teachings focus on good conduct, wisdom, and proper social relationships. Confucius has had a great influence on Chinese culture. Although temples were built to honor him, he is not perceived as a god. The temples are used for public ceremonies only and not as places of worship [138].

Confucianism advocates eight key concepts. The first is Jen, which translates as love, human-heartedness, and goodness [138]. The second concept is Chun-tzu, which refers to a state of centeredness whereby one exhibits Confucians' values effortlessly and without the need for self-monitoring. The third concept is Li, or a sense of order in one's life that coincides with social convention. The fourth concept is Te, or the appropriate use of power by leaders and authority figures. The fifth concept is Wen, which refers to the cultural arts (e.g., music, drama, poetry) that help to maintain unity in society [138]. The remaining concepts are Chi (the wisdom of proper action), Hsin (integrity), and Yi (righteousness or justice).

Taoism

Taoism (pronounced DOW-ism) is a Chinese philosophy and religion dating back to the fourth century B.C.E. [136]. Tao means "the way," and it has no founder or central figures. Taoists do not worship a god. Instead, they focus on coming into harmony with Tao, the cosmic energy that blows through everything. Taoism emphasizes what is natural and going with the flow of life. Today, there are about 20 million Taoists, and most followers live in China, Taiwan, or Southeast Asia [136].

Meditation is an important practice, and the goal of meditation is to come into harmony with the universe [136]. The philosophy is found in a text, the Tao-te-Ching (Classic Way and Its Power), dating back to the third century B.C.E. and attributed to Lao Tzu [138].

Shintoism

Shintoism began during prehistoric times on the Japanese islands [138]. Today, Shinto is the religion of Japan, and it has approximately 112 million followers; more than 75% of them follow Buddhism as well [138]. Like Taoism, Shinto has no founder or central figure. It teaches that all things in the world are imbued with a spirit (kami). Therefore, Shinto followers revere nature in all forms [138].

Most of the deities associated with Shinto are related to nature, such as the sky, earth, heavenly bodies, and storms [136]. However, deities are not different from humans, because everything is imbued with spirit. Everything is connected, including rocks, trees, dust, water, animals, and humans [138].

Shinto has no fixed doctrine and no scripture or sacred text. However, ancient prayers are passed down via oral tradition. Shinto followers worship primarily individually rather than in groups, and followers engage in purification rituals (e.g., handwashing) [138]. Worship occurs outside the shrine, and worshipers usually bring offerings of food or coins for the spirit (kami). These offerings are not given as sacrifices but as signs of gratitude [138]. Some followers write prayers on slips of paper and leave them nearby.

New Age Spirituality

The New Age movement became popular in Western society in the 1970s [142]. The precise definition of the term differs among scholars largely due to its highly eclectic range of spiritual beliefs and practices [142,143]. The movement takes many shapes and is continually changing. However, there are some common features that distinguish it from other religions, such as followers who [136]:

- Look forward to a society that reunites the wisdom of both science and religion

- Adopt holistic and alternative healing methods

- Embrace a wide array of traditional and nontraditional spiritual beliefs and practices

- Accept the existence of a universal energy that undergirds and permeates all of existence

Adherents believe healing can occur when individuals connect with this universal energy and learn to use it. This energy has been called by many names by different cultures, including chi (Chinese), ki (Japanese), prana (Sanskrit), mana (Pacific Islander), or the use of self as a final authority [136].

GENDER

Gender identity is a vital aspect of a person's experience of the world and of themselves. It also impacts the ways in which the world perceives and treats individuals, with a clear effect on the effective provision of health and mental health care. This section will focus on persons presenting as cisgender male or female; special considerations for those who are transgender, non-binary, or gender nonconforming will be explored in the next section.

An increasing amount of research is supporting a relationship between men's risk for disease and death and male gender identity, and the traditional male role has been shown to conflict with the fostering of healthy behaviors [62,63]. Male gender identity is related to a tendency to take risks, and the predilection for risky behavior begins in boyhood [63,64,65]. In addition, boys are taught that they should be self-reliant and independent and should control their emotions, and societal norms for both boys and men dictate that they maintain a strong image by denying pain and weakness [62,64,65].

Issues related to male gender identity have several important implications for health. First, risky behavior is associated with increased morbidity and mortality. Second, the concept of masculinity leads to inadequate help- and information-seeking behavior and a reduced likelihood to engage in behavior to promote health [62,64,65]. These behaviors appear to be rooted in a decreased likelihood for men to perceive themselves as being ill or at risk for illness, injury, or death [62]. Third, male gender identity, coupled with lower rates of health literacy, creates special challenges for effectively communicating health messages to men [66,67,68]. Gender differences in health-related behaviors are consistent across racial/ethnic populations, although specific behaviors vary according to race/ethnicity [63].

Men's beliefs about masculinity and traditional male roles affect health communication, and healthcare practitioners should consider male-specific beliefs and perceptions when communicating with male patients. For example, because men tend to focus on present rather than future health, concepts of fear, wellness, and longevity often do not work well in health messages [69]. Instead, healthcare practitioners should focus more on "masculine" concepts, such as strength, safety, and performance, all of which tie into men's perceptions of their roles as providers and protectors.

Although men are more likely than women to lack a regular healthcare provider and to avoid seeking help or information, women are more likely to have a chronic condition requiring regular monitoring and are more likely to have forgone necessary health care due to the cost [70]. In general, women are disproportionately affected by stresses related to caregiving, and this can be a barrier to help-seeking. Caregiving has been socialized as a feminine role, and two out of every three caregivers in the United States are women, meaning they provide daily or regular support to children, adults, or people with chronic illnesses or disabilities [145]. Women who are caregivers have a greater risk for poor physical and mental health, including depression and anxiety.

Women are more likely than men to be diagnosed with a mental health disorder, and more than 20% of women in the United States experienced a mental health condition in the past year [146]. In addition to being disproportionately affected, mental health conditions, such as depression and bipolar disorder, can manifest differently in or have different impacts on women than men. Much of the research into women's health has focused on the perinatal period, which limits our knowledge of how mental illness affects women's lives.

There is also some evidence that women's pain is less likely to be taken seriously and controlled than male patients. A series of four studies found a relative gender-pain exaggeration bias, wherein perceivers believe women, relative to men, to be emotionally dramatizing and therefore more likely to exaggerate versus downplay their pain [147]. This bias may lead perceivers to interpret women's, relative to men's, pain reports as overstatements, inauthentic, or dramatized.

Providing gender-sensitive care to women involves overcoming the limitations imposed by the dominant medical model in women's health. This requires theoretical bases that do not reduce women's health and illness experience into a disease. This philosophy incorporates explanations of health and empowers women to effectively and adequately deal with their situations. The major components incorporated into the development of sensitive care include:

- Gender is a central feature.

- Women's own voices and experiences are reflected.

- Diversities and complexities are incorporated into women's experiences.

- Theorists reflect about underlying androcentric and ethnocentric assumptions.

- Sociopolitical contexts and constraints of women's experiences are considered.

- Guidelines for practice with specific groups of women are provided.

GENDER AND SEXUAL MINORITIES

The gender and sexual minority (GSM) population is a diverse group that can be defined as a subculture. It includes homosexual men, lesbian women, bisexual persons, transgender individuals, and those questioning their sexual identity, among others. The GSM population is diverse, representing all ages and all socioeconomic, ethnic, educational, and religious backgrounds. The population has been described as "hidden and invisible," "marginalized," and "stigmatized." As a result, the unique health and safety needs of the population have often been overlooked or ignored. Clear definitions of the concepts related to sexual identity will be helpful. The following is a glossary of terms used in discussions of this group [71,72,73,74,75,76]:

Asexual/aromantic: An individual who does not experience sexual attraction. There is considerable diversity in individuals' desire (or lack thereof) for romantic or other relationships.

Bisexual: An adjective that refers to people who relate sexually and affectionately to both women and men.

Coming-out process: A process by which an individual, in the face of societal stigma, moves from denial to acknowledging his/her sexual orientation. Successful resolution leads to self-acceptance. Coming out is a lifelong process for lesbian, gay, bisexual, and transgender persons and their families and friends as they begin to tell others at work, in school, at church, and in their communities.

Gay: The umbrella term for GSM persons, although it most specifically refers to men who are attracted to and love men. It is equally acceptable and more accurate to refer to gay women as "lesbians."

Gender and sexual minorities (GSM): A term meant to encompass lesbian, gay, bisexual, trans, queer/questioning, intersex/intergender, asexual/ally (LGBTQIA) people as well as less well-recognized groups, including aromantic, two-spirited, and gender-fluid persons.

Heterosexism: An institutional and societal reinforcement of heterosexuality as the privileged and powerful norm.

Heterosexuality: Erotic feelings, attitudes, values, attraction, arousal, and/or physical contact with partners of the opposite gender.

Homophobia: A negative attitude or fear of non-straight sexuality or GSM individuals. This may be internalized in the form of negative feelings toward oneself and self-hatred. Called "internalized homophobia," it may be manifested by fear of discovery, denial, or discomfort with being LGBTQIA, low self-esteem, or aggression against other lesbians and gay men.

Homosexuality: The "persistent sexual and emotional attraction to members of one's own gender" as part of the continuum of sexual expression. Typically not used to describe people.

LGBTQIA: An acronym used to refer to the lesbian, gay, bisexual, transgender/transsexual, queer/questioning, intersex/intergender, asexual/ally community. In some cases, the acronym may be shortened for ease of use or lengthened for inclusivity. Members of this group may also be referred to as gender and sexual minorities (GSM).

Queer: An umbrella term to describe persons with a spectrum of identities and orientations that are outside of the heteronormative standard.

Sexual identity: The inner sense of oneself as a sexual being, including how one identifies in terms of gender and sexual orientation.

Sexual orientation: An enduring emotional, romantic, sexual, and/or affectionate attraction to another person. Individuals may experience this attraction to someone of the same gender, the opposite gender, both genders, or gender nonconforming.

Transgender: An umbrella term describing a number of distinct gender positions and identities including: crossdressing, transsexual, nonbinary, and intersex.

One's intrapersonal acceptance or rejection of societal stereotypes and prejudices, the acceptance of one's self-identity as a sexual minority, and how much one affiliates with other members of the GSM community varies greatly among individuals [77]. Some authors stress the diversity within the GSM community by discussing "GSM populations" [78]. For example, it is understandable that a GSM population living in rural areas of the United States would have little in common with a GSM population living in urban areas or "gay-friendly" neighborhoods. Additionally, mental health experts have suggested that "GSM community" symbolizes a single group of individuals who express their sexuality differently than the majority of heterosexual individuals. However, many distinct communities have been identified, including lesbian, gay, bisexual, and transgender [79]. Each community is different from the other as well as different from the heterosexual community. A culturally competent healthcare provider should keep this diversity in mind so that vital differences among these smaller groups are not lost when thinking of the GSM population in general.

Commonalities exist among the GSM communities as well. For example, many adolescents, whether gay, lesbian, bisexual, transgender, or questioning their sexual identity, lack sexual minority role models to assist with successful psychosocial development [79].

The subtle and pervasive ways that discomfort with GSM individuals may be manifested have been examined and, in some instances, categorized as "cultural heterosexism," which is characterized by the stigmatization in thinking and actions found in our nation's cultural institutions, such as the educational and legal systems [80]. "Cultural heterosexism fosters individual antigay attitudes by providing a ready-made system of values and stereotypical beliefs that justify such prejudice as natural" [81]. Perhaps the paucity of information about the GSM community in basic professional education has been a reflection of cultural heterosexism. Writers, funding sources, and publishers have been exposed to the same cultural institutions for many years.

Individuals generally begin to absorb these institutional attitudes as children and may consequently develop "psychologic heterosexism," which may also manifest as antigay prejudice. Many individuals, as children, have little contact with someone who is openly gay and, as a result, may not be able to associate homosexuality with an actual person. Instead, they may associate it with concepts such as "sin," "sickness," "predator," "outsider," or some other negative characteristic from which the individual wants to maintain distance [81]. Psychologic heterosexism involves (among other factors) considering sexual identity and determining that one does not want to think further about it. The direction of this thinking is undeniably negative, resulting in an environment that allows antigay hostility [81]. The impact of antigay prejudice on the physical and mental health of members of the LGBTQIA community and their families should not be underestimated [82,83].

Sexual minority individuals also are not immune to societal attitudes and may internalize negative aspects of the antigay prejudice experience. Anxiety, depression, social withdrawal, and other reactions may result [2,84]. While the study of psychologic heterosexism, both blatant and subtle, is in the early stages of research, it has had a measurable impact on the mental health of the GSM community [85,86,87,88].

Examples of the range of manifestations of heterosexism and/or homophobia in our society are readily available. Without difficulty, each example presented here may be conceptualized as related to the emotional or physical health of a GSM individual or family member:

- A kindergarten student calls another child an LGBTQ+ slur but does not really know what he is saying.

- A teenage girl allows herself to become pregnant, "proving" her heterosexuality to herself, her family, and her friends.

- A parent worries that her 12-year-old daughter is still a "tomboy."

- An office employee decides to place a photo of an old boyfriend in her office rather than a photo of her gender- nonconforming partner of five years.

- A college student buries himself in his studies in an effort to ignore his same-sex feelings and replace feelings of isolation.

- Two teenage girls, thought by peers to be transgender individuals, are assaulted and killed while sitting together in an automobile.

- A female patient is told by a healthcare provider that her haircut makes her look like a lesbian and is examined roughly.

- A gay man chooses not to reveal his sexual identity to his healthcare provider out of fear of a reduction or withdrawal of healthcare services.

The manifestations of heterosexism have inhibited our learning about the LGBTQIA population and its needs [78]. Gay patients have feared open discussion about their health needs because of potential negative reactions to their self-disclosure. Prejudice has impacted research efforts by limiting available funding [77]. All of these factors emphasize that the healthcare education system has failed to educate providers and researchers about the unique aspects of LGBTQIA health [83,89].

Common Myths

Many myths surround homosexuality; a few are outlined below. The origin of these myths may be better understood after examining the history of homosexuality as well as the attitudes toward human sexuality in general. The history of the development of societal norms related to homosexuality includes misconceptions developed during times when research was not available on which to build a scientific knowledge base [82,90,91,92].

Myth: Sexual orientation is a choice.

Fact: No consensus exists among scientists about the reasons that an individual develops his/her sexual orientation. Some research has shown that the bodies and brains of gay men and women differ subtly in structure and function from their heterosexual counterparts; however, no findings have conclusively shown that sexual orientation is determined by any particular factor or set of factors. Many people confuse sexual orientation with sexual identity. The reader may consider reviewing the definitions of these terms when further considering this myth.

Myth: Gay men and lesbians can be easily identified because they have distinctive characteristics.

Fact: Most gay and lesbian individuals conform to the majority of society in the way they dress and act. Further, a person's appearance is not necessarily an indication of sexual or romantic interests.

Myth: Gay individuals are child molesters.

Fact: This is a very damaging and heterosexist position. According to experts in the field of sexual abuse, the vast majority of those who molest children are heterosexual. The average offender is a White heterosexual man whom the child knows.

Myth: Gay people want to come into our schools and recruit our children to their "lifestyle."

Fact: Efforts to bring issues related to LGBTQIA history and rights into schools are not efforts to "convert," just as education on European history is not an effort to glamorize or "convert" to European identity. The intent has been to teach a more complete history of the world and to prevent children from mistreating LGBTQIA individuals, who are often the subjects of harassment and physical attacks. There is no evidence that people could be "recruited" to a gay sexual orientation, even if someone wanted to do this.

AGE

Elderly patients should be routinely screened for health and mental health conditions using tools specifically developed for this population, in spite of some practitioners' discomfort with asking questions about sensitive topics. These population-appropriate assessments may be included in other health screening tools [93].

Wellness and purpose have become important emphases when working with older adults [94]. In the past, aging was associated with disability, loss, decline, and a separation from occupational productivity. Although patient growth and positive change and development are values that practitioners embrace, the unconscious acceptance of societal myths and stereotypes of aging may prevent practitioners from promoting these values in elderly individuals [95].

Common Myths of Aging

Society holds several myths about the elderly. Many of these myths may be easily disputed based on data from the U.S. Census and other studies.

Myth: Most older adults live alone and are isolated.

Fact: In 2018, 70% of men and 46% of women 65 years and older were married. An estimated 28% lived alone [96]. According to a survey conducted in 2009, 9 out of 10 individuals 65 years of age and older stated they talked to family and friends on a daily basis [97]. In 2016, an estimated 20% of the U.S. population lived in a household comprised of two adult generations or a grandparent or at least one other generation, compared with 12% in 1980 [97,98]. This multigenerational household trend particularly affects those 65 years and older, with 21% of these individuals living in multigenerational households in 2016. This group was second only to individuals 25 to 29 years of age (33%) [98]. Several factors have contributed to this trend, including growing racial and ethnic diversity and adults getting married later [97,98].

Myth: Most older adults engage in very minimal productive activity.

Fact: In 2016, 18.6% of persons 65 years and older were employed or actively looking for work, and this population represents approximately 8% of the total labor force in the United States [99]. The elderly are more engaged in self-employed activities than younger persons. In 2016, 16.4% of those 65 years of age and older were self-employed, compared with an average of 5.5% of those 16 years to 64 years of age [100].

Myth: Life satisfaction is low among the elderly.

Fact: Data from the Berkeley Older Generation Study indicate that many elders are quite satisfied with their life [101]. More than one-third (36%) of persons older than 59 years of age and 15% of those older than 79 years of age stated they were currently experiencing the best time in their lives. A 2009 survey found that 60% of individuals 65 years of age and older stated they were very happy. A 2012 survey found that 65% of individuals 65 years of age and older indicated that the past year of their life has been normal or better than normal, and more than 80% of respondents agreed with the statement, "I have a strong sense of purpose and passion about my life and my future" [102]. Most of the factors that predict happiness for the young, such as good health and financial stability, also apply to the elderly. Older adults tend to report higher levels of well-being in part due to the quality of their social relationships [103].

PERSONS WITH MENTAL OR PHYSICAL DISABILITY

Americans with disabilities represent a large and heterogeneous segment of the population. The prevalence of disability varies by age group and definition. Based on the U.S. Census Bureau's 2013 American Community Survey (ACS), which describes disability in terms of functional limitations, 12.6% of the civilian U.S. noninstitutionalized population has a disability, defined as difficulty in hearing or vision, cognitive function, ambulation, self-care, or independent living [104]. The U.S. Department of Education, which uses categorical disability labels, estimates that 13% of children and youth 3 to 21 years of age have a disability (defined as specific learning disabilities, speech or language impairments, intellectual disability, emotional disturbance, hearing impairments, orthopedic impairments, other health impairments, visual impairments, multiple disabilities, deaf-blindness, autism, traumatic brain injury, or developmental delay) [104].

People with disabilities experience many health disparities. Some documented disparities include poorer self-rated health; higher rates of obesity, smoking, and inactivity; fewer cancer screenings (particularly mammography and Pap tests); fewer breast-conserving surgeries when breast cancer is diagnosed; and higher rates of death from breast or lung cancer [104].

Disability cultural competence requires appreciation of social model precepts, which recognize patients' rights to seek care that meets their expectations and values. The social model of disability has been characterized as centering disability as a social creation rather than an attribute of the patient [105]. As such, disability requires a social/political response in order to improve environmental factors affecting access and acceptance [105]. This involves adoption of person-first language, acknowledgement of social and environmental factors impacting persons abilities, and confronting disability-associated stigma.

VETERANS

The effects of military service and deployment to military combat on the individual and the family system are wide-reaching. According to the U.S. Department of Defense, there were 3.5 million current military personnel in 2020 and 18.3 million veterans in 2017 [132,133]. The Army has the largest number of active duty members, followed by the Navy, the Air Force, and the Marine Corps [132]. 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.

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 [133].

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 [134]. 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 [135]. This program provides pocket cards, posters, and resource links for professionals working with veterans and their families. Recommended questions for intake include [135]:

- 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?

DIETARY CONSIDERATIONS

Cultural or personal beliefs can also impact the dietary needs of patients, which, in turn, can affect their health and adherence to prescribed treatments. For example, health issues related to fasting may arise among Buddhists, Hindus, Muslims, and some Christian patients, as well as persons of other faiths. This may particularly become an issue during extended fasts, such as the Muslim observance of Ramadan, which continues for one month [148]. Fasting is done during Ramadan as a spiritual exercise and is mandatory for all healthy adults. Those exempt from Ramadan fasting include children (prior to the onset of puberty); developmentally disabled individuals; the elderly; those who are acutely or chronically ill, for whom fasting would be detrimental to health; travelers who have journeyed more than approximately 50 miles; and pregnant, menstruating, or breastfeeding women [148]. Practitioners should advise all patients for whom fasting would prevent healing or adequate care (e.g., inability to take medication) to postpone or abstain from the ritual, if possible [148].

Another dietary consideration for some patients is whether medications contain animal-sourced ingredients. Vegetarians, vegans, Jewish people, Muslims, and others may need to know which products are from animal sources. Common examples of meds that contain ingredients from animals include:

- Desiccated thyroid from pig thyroid glands

- Heparin from pig intestines

- Pancreatic enzymes from pig pancreases

- Certain vaccines grown in eggs

- Conjugated estrogens from pregnant mares' urine

In addition, the gelatin used to make capsules and even some tablets and vaccines is often hydrolyzed collagen from animal tissues. Over-the-counter medications and supplements that may have animal-source ingredients include glucosamine (from shellfish), vitamin D3 (from lanolin, or sheep's wool), calcium (from oyster shells or bone meal), and omega-3 fatty acids (from fish oils).

8. PROMOTING CULTURALLY SENSITIVE COMMUNICATION

Communication, the process of sending a message from one party to another, consists of both verbal and nonverbal components. Verbal and nonverbal communications are embedded within the culture of the parties disseminating the information and within the culture of the parties receiving the information. Communication is complex and multilayered because it involves unstated, implicit rules about a variety of factors, including physical distance between parties, tone of voice, acceptable topics of discussion, physical contact, and amount of eye contact [106]. Each of these variables is influenced by the perception of the level of formality/informality of the situation. Frequently, misunderstandings occur because the decoding and interpretation of these nonverbal cues are not accurate.

The verbal component of communication is just as complicated. Certainly, similarity in language shared by both parties enhances communication, but assuming that both parties in a conversation speak the same language, how the information is interpreted is still influenced by a host of factors. Linguists have posited that approximately 14,000 different meanings and interpretations can be extracted from the 500 most common English words [107]. Consequently, practitioners must be aware of the different communication styles held by diverse ethnic minority patients, as the clinical communication process is the primary vehicle by which problems and solutions are identified and conveyed [108].

Styles of communication can be classified from high- to low-context [109]. High-context cultures are those cultures that disseminate information relying on shared experience, implicit messages, nonverbal cues, and the relationship between the two parties [107,110]. Members of these cultural groups tend to listen with their eyes and focus on how something was said or conveyed [106,109]. On the other hand, low-context cultures rely on verbal communication or what is explicitly stated in the conversation [107]. Consequently, low-context communicators listen with their ears and focus on what is being said [106,109,110]. Western culture, including the United States, can be classified as a low-context culture. On the other hand, groups from collectivistic cultures, such as Asian/Pacific Islanders, Hispanics, Native Americans, and African Americans, are from high-context cultures [109].

Communicators from high-context cultures generally display the following characteristics [106,107,110,111]:

- Use of indirect modes of communication

- Use of vague descriptions

- Less talk and less eye contact

- Interpersonal sensitivity

- Use of feelings to facilitate behavior

- Assumed recollection of shared experiences

- Reliance on nonverbal cues such as gestures, tone of voice, posture, voice level, rhythm of speaking, emotions, and pace and timing of speech

- Assimilation of the "whole" picture, including visual and auditory cues

- Emotional speech

- Use of silence

- Use of more formal language, emphasizing hierarchy between parties

On the other hand, low-context communicators can typically be described as [106,107,110]:

- Employing direct patterns of communication

- Using explicit descriptions and terms

- Assuming meanings are described explicitly

- Utilizing and relying minimally on nonverbal cues

- Speaking more and often raising their voices (more animated, dramatic)

- Often being impatient to get to the point of the discussion

- Using more informal language; less emphasis on hierarchy, more equality between parties (more friendly)

- Being more comfortable with fluidness and change

- Uncomfortable using long pauses and storytelling as a means of communicating

Understanding the distinctions between individuals who come from high- and low-context cultures can promote cultural sensitivity. However, it is vital that practitioners take heed of several words of caution. First, it is important not to assume that two individuals sharing the same culture (e.g., low-context culture) will automatically have a shared script for communicating. Second, it is important to not immediately classify an individual into a low- or high-context culture because of their ethnicity. A Chinese American man may not necessarily be a high-context communicator because he is Asian. A host of factors, such as level of acculturation, upbringing and socialization, education, and family immigration history, will all play a role in how one learns to communicate. Third, a major criticism of the discussion of low-/high-context cultures is that they reinforce dualism and ultimately oversimplify the complexities and nuances of communication [112].

Learning to communicate effectively also requires an understanding of how different conversational traits influence the communication process, or how information is conveyed and interpreted. Again, the goal of this section is not to simply dichotomize individuals' conversational styles into categories, but rather to understand the factors that play a role in how someone makes a decision on how to communicate [106].

As long as there are two parties involved in a conversation, nonverbal communication is inevitable, and it becomes salient particularly when it is processed from one culture to another. Nonverbal communication is any behavior (including gestures, posture, eye contact, facial expressions, and body positions) that transcends verbal or written forms of communication [113]. Nonverbal communication can enhance or reinforce what is said verbally, and conversely, it can completely contradict the message communicated verbally. It can also end up replacing what was verbally communicated if both parties do not share a native language [114].

In Western culture, communication is more direct and eye contact is highly valued. When eye contact is not maintained, many Westerners assume that the party is hiding pertinent information. However, in some cultures, reducing eye contact is a sign of respect [108]. Conversely, patients may interpret direct and indirect gazes differently. For example, in one study, Japanese individuals tended to rate faces with a direct gaze as angry and less pleasant compared with Finnish participants [115].

The amount of social space or distance between two communicating parties is culturally charged as well. Depending upon the social context, Westerners tend to maintain a distance of about three feet, or an arm's length, in conversations [107]. In a public setting, where both parties are engaged in a neutral, nonpersonal topic, Westerners will feel encroached upon and uncomfortable if an individual maintains a closer conversational distance. However, in other cultures, such as Latino and Middle Eastern, a closer distance would be the norm [107]. Chung recommends that in a clinical setting the practitioner allow patients to set the tone and social distance [116]. The practitioner can sit first and permit the patient to select where they want to sit.

Cross-cultural communication is by no means simple, and there is no set of rules to merely abide by. Instead, promoting culturally sensitive communication is an art that requires practitioners to self-reflect, be self-aware, and be willing to learn. Therefore, as practitioners become skilled in noticing nonverbal behaviors and how they relate to their own behaviors and emotions, they will be more able to understand their own level of discomfort and comprehend behavior from a cultural perspective [106].

9. CULTURALLY SENSITIVE ASSESSMENT GUIDELINES

Practitioners may be categorized as either disease-centric or patient-centric [117]. Disease-centered practitioners are concerned with sign/symptom observation and, ultimately, diagnosis. On the other hand, patient-centered practitioners focus more on the patient's experience of the illness, subjective descriptions, and personal beliefs [117]. Patient-centered practice involves culturally sensitive assessment. It allows practitioners to move assessment and practice away from a pathology-oriented model and instead acknowledge the complex transactions of the individual's movement within, among, and between various systems [118].

Practitioners who engage in culturally sensitive assessment nonjudgementally obtain information related to the patient's cultural beliefs, overall perspective, and specific health beliefs [119]. They also allow the patient to control the timing [120].

The goal is to avoid the tendency to misinterpret health concerns of ethnic minority patients. Panos and Panos have developed a qualitative culturally sensitive assessment process that focuses on several domains [119]. Each domain includes several questions a practitioner may address in order to ensure that he or she is providing culturally responsive care.

Alternatively, Kleinman suggests that the practitioner ask the patient what he or she thinks is the nature of the problem [121]. He highlights the following types of questions that may be posed to the patient [121]:

- Why has the illness/problem affected you?

- Why has the illness had its onset now?

- What course do you think the illness will follow?

- How does the illness affect you?

- What do you think is the best or appropriate treatment? What treatment do you want?

- What do you fear most about the illness and its treatment?

Similar to Kleinman's culturally sensitive assessment questions, Galanti has proposed the 4 Cs of Culture [122]:

- What do you call the problem?

- What do you think caused it?

- How do you cope with the problem?

- What questions or concerns do you have about the problem or treatment?

Pachter proposed a dynamic model that involves several tiers and transactions, similar to Panos and Panos' model [123]. The first component of Pachter's model calls for the practitioner to take responsibility for cultural awareness and knowledge. The professional must be willing to acknowledge that they do not possess enough or adequate knowledge in health beliefs and practices among the different ethnic and cultural groups they come in contact with. Reading and becoming familiar with medical anthropology is a good first step.

The second component emphasizes the need for specifically tailored assessment [123]. Pachter advocates the notion that there is tremendous diversity within groups. Often, there are many intersecting variables, such as level of acculturation, age at immigration, educational level, and socioeconomic status, that influence health ideologies. Finally, the third component involves a negotiation process between the patient and the professional [123]. The negotiation consists of a dialogue that involves a genuine respect of beliefs. The professional might recommend a combination of alternative and Western treatments.

Beckerman and Corbett further recommend that recently immigrated families be assessed for [124]:

- Coping and adaptation strengths

- Issues of loss and adaptation

- The structure of the family in terms of boundaries and hierarchies after immigration

- Specific emotional needs

- Acculturative stress and conflict for each family member

Practitioners should seek to understand the sociopolitical context of the origin country [125]. A migration narrative is also recommended, whereby an individual provides a story of their migration history. Asking about how long the family has been in the United States, who immigrated first, who was left behind, and what support networks are lacking gives the practitioner an overview of the individual's present situation [126]. The theme of loss is very important to explore. Types of losses may include family and friends left behind, social status, social identity, financial resources, and familiarity [126]. For refugees and newly immigrated individuals and families, assessment of basic needs (e.g., food, housing, transportation) is necessary [125].

Culturally sensitive assessment involves a dynamic framework whereby the practitioner engages in a continual process of questioning. Practitioners should work to recognize that there are a host of factors that contribute to patients' multiple identities (e.g., race, gender, socioeconomic status, religion) [127].

10. CREATING A WELCOMING AND SAFE ENVIRONMENT

Improving access to care can be facilitated, in part, by providing a welcoming environment. The basis of establishing a safe and welcoming environment for all patients is security, which begins with inclusive practice and good clinician-patient rapport. Shared respect is critical to a patient's feeling of psychological well-being. Security can also be fostered by a positive and safe physical setting. For patients who are acutely ill, both the illness experience and treatment process can produce trauma. This is particularly true if involuntary detainment or hospitalization is necessary, but exposure to other individuals' narratives of experienced trauma or observing atypical behaviors from individuals presenting as violent, disorganized, or harmful to themselves can also be traumatic. As such, care environments should be controlled in a way to minimize traumatic stress responses. Providers should keep this in mind when structuring the environment (e.g., lighting, arrangement of space), creating processes (e.g., layout of appointments or care systems, forms), and providing staff guidance (e.g., nonverbal communication, intonation, communication patterns). During each encounter, the patient's perception of safety is impacted by caretakers and ancillary staff.

Experts recommend the adoption and posting of a nondiscrimination policy that signals to both healthcare providers and patients that all persons will be treated with dignity and respect [128]. Also, checklists and records should include options for the patient defining their race/ethnicity, preferred language, gender expression, and pronouns; this can help to better capture information about patients and be a sign of acceptance to that person. If appropriate, providers should admit their lack of experience with patient subgroups and seek guidance from patients regarding their expectations of the visit.

Front office staff should avoid discriminatory language and behaviors. For example, staff should avoid using gender-based pronouns, both on the phone and in person. Instead of asking, "How may I help you, sir?" the staff person could simply ask, "How may I help you?" Offices that utilize electronic health records should have a system to track and record the gender, name, and pronoun of all patients. This can be accomplished by standardizing the notes field to document a preferred name and pronoun for all patients [129]. Some persons who identify as non-binary (i.e., neither or both genders) may prefer that plural pronouns (e.g., they) be used.

Questions should be framed in ways that do not make assumptions about a patient's culture, gender identity, sexual orientation, or behavior. Language should be inclusive, allowing the patient to decide when and what to disclose. Assurance of confidentiality should be stressed to the patient to allow for a more open discussion, and confidentiality should be ensured if a patient is being referred to a different healthcare provider. Asking open-ended questions can be helpful during a history and physical.

The FACT acronym may be helpful for healthcare providers. Providers should:

- Focus on those health issues for which the individual seeks care

- Avoid intrusive behavior

- Consider people as individuals

- Treat individuals according to their gender

Training office staff to increase their knowledge and sensitivity toward persons will also help facilitate a positive experience for patients.

11. CONCLUSION

Culture serves as a lens through which patients and practitioners filter their experiences and perceptions. Patients will bring their unique life stories and concerns to the practitioner, and their cultural values and belief systems will inevitably shape how the problem is defined and their beliefs about what is effective in solving the problem. However, the cultural backgrounds and values of patients are not necessarily scripts that define behavior, and when practitioners view culture as a strength and not a pathology, practitioners will be able to more effectively join with patients to mobilize change.

Works Cited

1. Meleis AI. Culturally competent care. J Transcultural Nurs. 1999;10(1):12.

2. Baker K, Beagan B. Making assumptions, making space: an anthropological critique of cultural competency and its relevance to queer patients. Med Anthropol Q. 2014;28(4):578-598.

3. U.S. Department of Health and Human Services Office of Minority Health. Cultural and Linguistic Competency. Available at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=1&lvlid=6. Last accessed September 21, 2023.

4. DeAngeles T. In Search of Cultural Competence. Available at https://www.apa.org/monitor/2015/03/cultural-competence. Last accessed September 21, 2023.

5. Lekas H-M, Pahl K, Lewis CF. Rethinking cultural competence: shifting to cultural humility. Health Services Insights. 2020;13:1178632920970580.

6. Velott D, Sprow FK. Toward health equity: mindfulness and cultural humility as adult education. New Directions for Adult & Continuing Education. 2019;161:57-66.

7. Allport GW. The Nature of Prejudice. New York, NY: Bacon Press; 1954.

8. Feagin J, Feagin CBR. Racial and Ethnic Relations. 9th ed. Boston, MA: Pearson; 2011.

9. Essed P. Everyday Racism: Reports for Women of Two Cultures. Dutch ed. Claremont, CA: Hunter House; 1990.

10. Lum D. Culturally Competent Practice: A Framework for Understanding Diverse Groups and Justice Issues. 4th ed. Belmont, CA: Cengage; 2010.

11. Baker DL, Schmaling K, Fountain KC, Blume AW, Boose R. Defining diversity: a mixed-method analysis of terminology in faculty applications. The Social Science Journal. 2016;53(1):60-66.

12. Crenshaw K. Mapping the margins: intersectionality, identity politics, and violence against women of color. Stanford Law Rev. 1991;43(6):1241-1299.

13. Diller JV. Cultural Diversity: A Primer for the Human Services. 5th ed. Stamford, CT: Cenage Learning; 2014.

14. Gasner B, McGuigan W. Racial prejudice in college students: a cross-sectional examination. College Student Journal. 2014;48(2):249-256.

15. Wijeyesinghe CL, Griffin P, Love B. Racism-curriculum design. In: Adams M, Bell LA, Griffin P (eds). Teaching for Diversity and Social Justice. 2nd ed. New York, NY: Routlege; 2007: 123-144.

16. Quillian L. Does unconscious racism exist? Soc Psychol Q. 2008;71(1):6-11.

17. Gee G, Ford C. Structural racism and health inequities: old issues, new directions. Du Bois Review: Social Science Research on Race. 2011;8(1):115-132.

18. Johnson TJ. Intersection of bias, structural racism, and social determinants with health care inequities. Pediatrics. 2020;146(2):e2020003657.

19. Georgetown University National Center for Cultural Competence. Conscious and Unconscious Biases in Health Care. Available at https://nccc.georgetown.edu/bias. Last accessed September 21, 2023.

20. FitzGerald C, Hurst S. Implicit bias in healthcare professionals: a systematic review. BMC Med Ethics. 2017;18(1):19.

21. Amodio DM. The social neuroscience of intergroup relations. Eur Rev Soc Psychol. 2008;19(1):1-54.

22. Blair IV, Steiner JF, Havranek EP. Unconscious (implicit) bias and health disparities: where do we go from here? Perm J. 2011;15(2):71-78.

23. Hall WJ, Chapman MV, Lee KM, et al. Implicit racial/ethnic bias among health care professionals and its influence on health care outcomes: a systematic review. Am J Public Health. 2015;105(12):e60-e76.

24. Matthew DB. Toward a structural theory of implicit racial and ethnic bias in health care. Health Matrix. 2015;5(1)61-85.

25. Baron AS, Banaji MR. The development of implicit attitudes: evidence of race evaluations from ages 6 and 10 and adulthood. Psychol Sci. 2006;17(1):53-58.

26. Ogungbe O, Mitra AK, Roberts JK. A systematic review of implicit bias in health care: a call for intersectionality. IMC Journal of Medical Science. 2019;13(1):1-16.

27. Georgetown University National Center for Cultural Competence. What the Literature Is Telling Us. Available at https://nccc.georgetown.edu/bias/module-2/2.php. Last accessed September 21, 2023.

28. FitzGerald C, Martin A, Berner D, Hurst S. Interventions designed to reduce implicit prejudices and implicit stereotypes in real world contexts: a systematic review. BMC Psychol. 2019;7(1):29.

29. D'Amour D, Oandasan I. Interprofessionality as the field of interprofessional practice and interprofessional education: an emerging concept. J Interprof Care. 2005;(Suppl 1):8-20.

30. Petri L. Concept analysis of interdisciplinary collaboration. Nursing Forum. 2010;45(2):73-82.

31. Lam AHY, Wong JTL, Ho ECM, Choi RYY, Fung MST. A concept analysis of interdisciplinary collaboration in mental healthcare.COJ Nurse Healthcare. 2017;1(2).

32. Cahn PS. How interprofessional collaborative practice can help dismantle systemic racism. J Interprof Care. 2020;34(4):431-434.

33. Bennett CJ, Dielmann KM. Weaving the threat of implicit bias through health administration curricula to overcome gender disparities in the workforce. J Health Adm Educ. 2017;34(2):277-294.

34. Healthy People 2030. Social Determinants of Health. Available at https://health.gov/healthypeople/objectives-and-data/social-determinants-health. Last accessed September 21, 2023.

35. Wang T, Cahill S. Antitransgender political backlash threatens health and access to care. Am J Public Health. 2018;108(5):609-610.

36. Substance Abuse and Mental Health Services Administration. Improving Cultural Competence: Quick Guide for Clinicians. Available at https://store.samhsa.gov/sites/default/files/d7/priv/sma16-4931.pdf. Last accessed September 21, 2023.

37. Agency for Healthcare Quality and Research. Health Literacy Universal Precautions Toolkit, 2nd Edition. Available at https://www.ahrq.gov/health-literacy/improve/precautions/index.html. Last accessed September 21, 2023.

38. U.S. Census Bureau. About the Topic of Race. Available at https://www.census.gov/topics/population/race/about.html. Last accessed at September 21, 2023.

39. U.S. Census Bureau. National Black (African American) History Month: February 2023. Available at https://www.census.gov/newsroom/facts-for-features/2023/black-history-month.html. Last accessed September 21, 2023.

40. U.S. Census Bureau. National African-American (Black) History Month: February 2018. Available at https://www.census.gov/newsroom/facts-for-features/2018/black-history-month.html. Last accessed September 21, 2023.

41. Tamir C. The Growing Diversity of Black America: 46.8 Million People in the U.S. Identify as Black. Available at https://www.pewresearch.org/social-trends/2021/03/25/the-growing-diversity-of-black-america. Last accessed September 21, 2023.

42. American Psychiatric Association. Working with African American/Black Patients. Available at https://www.psychiatry.org/psychiatrists/diversity/education/best-practice-highlights/working-with-african-american-patients. Last accessed September 21, 2023.

43. U.S. Census Bureau. Asian American, Native Hawaiian and Pacific Islander Heritage Month: May 2023. Available at https://www.census.gov/newsroom/facts-for-features/2023/asian-american-pacific-islander.html. Last accessed September 21, 2023.

44. Budiman A, Ruiz NG. Asian Americans are the Fastest-Growing Racial or Ethnic Group in the U.S. Available at https://www.pewresearch.org/fact-tank/2021/04/09/asian-americans-are-the-fastest-growing-racial-or-ethnic-group-in-the-u-s. Last accessed September 21, 2023.

45. Pew Research Center. U.S. Hispanic Population Growth has Leveled Off. Available at https://www.pewresearch.org/fact-tank/2017/08/03/u-s-hispanic-population-growth-has-leveled-off. Last accessed September 21, 2023.

46. Pew Research Center. The Demographics of Asian Americans. Available at https://www.pewresearch.org/social-trends/2013/04/04/asian-groups-in-the-u-s. Last accessed September 21, 2023.

47. Ong P, Ong E. The Future of Asian America in 2040 Asian American Electorate to Double. Available at https://luskin.ucla.edu/sites/default/files/AA2040_report.pdf. Last accessed September 21, 2023.

48. Lee E. Asian American families: an overview. In: McGoldrick M, Giordano J, Pearce JK (eds). Ethnicity and Family Therapy. 2nd ed. New York, NY: The Guilford Press; 1996: 227-248.

49. U.S. Census Bureau. We the People: Asians in the United States: Census 2000 Special Reports. Available at https://www2.census.gov/library/publications/decennial/2000/briefs/c2kbr01-16.pdf. Last accessed September 21, 2023.

50. Lee E. Working with Asian Americans: A Guide for Clinicians. New York, NY: The Guilford Press; 1997.

51. U.S. Census Bureau. Hispanic Heritage Month 2023. Available at https://www.census.gov/newsroom/facts-for-features/2023/hispanic-heritage-month.html. Last accessed September 21, 2023.

52. Krogstad JM. Hispanics Have Accounted for More than Half of Total U.S. Population Growth Since 2010. Available at https://www.pewresearch.org/fact-tank/2020/07/10/hispanics-have-accounted-for-more-than-half-of-total-u-s-population-growth-since-2010. Last accessed September 21, 2023.

53. Pew Research Center. 2015, Hispanic Population in the United States Statistical Portrait. Available at https://www.pewresearch.org/hispanic/2017/09/18/2015-statistical-information-on-hispanics-in-united-states-trend-data. Last accessed September 21, 2023.

54. Pew Hispanic Center. Hispanic Origin Profiles, 2010. Available at https://www.pewresearch.org/hispanic/2012/06/27/country-of-origin-profiles. Last accessed September 21, 2023.

55. Kagawa Singer M, Dressler W, George S. Culture: the missing link in health research. Soc Sci Med. 2016;170:237-246.

56. U.S. Census Bureau. We the People: American Indians and Alaska Natives in the United States. Available at https://www.census.gov/content/dam/Census/library/publications/2006/dec/censr-28.pdf. Last accessed September 21, 2023.

57. U.S. Census Bureau. Facts for Features: American Indian and Alaska Native Heritage Month: November 2022. Available at https://www.census.gov/newsroom/facts-for-features/2022/aian-month.html. Last accessed September 21, 2023.

58. U.S. Census Bureau. American Indian and Alaska Native Heritage Month: November 2017. Available at https://www.census.gov/newsroom/facts-for-features/2017/aian-month.html. Last accessed September 21, 2023.

59. Center for Disease Control and Prevention. American Indian and Alaska Native Populations. Available at https://www.cdc.gov/nchs/fastats/american-indian-health.htm. Last accessed September 21, 2023.

60. U.S. Census Bureau. QuickFacts: United States. Available at https://www.census.gov/quickfacts/fact/table/US/PST045221. Last accessed September 21, 2023.

61. U.S. Census Bureau. American Community Survey: B04006 People Reporting Ancestry. Available at https://data.census.gov/cedsci/table?q=ancestry&tid=ACSDT1Y2019.B04006. Last accessed September 21, 2023.

62. Addis M, Mahalik JR. Men, masculinity, and the contexts of help seeking. Am Psychol. 2003;58(1):5-14.

63. Courtenay WH. Key determinants of the health and well-being of men and boys. Internat J Mens Health. 2003;2(1):1-30.

64. Mahalik JR, Lagan HD, Morrison JA. Health behaviors and masculinity in Kenyan and US male college students. Psychol Men Masculin. 2006;7(4):191-202.

65. Mahalik JR, Burns SM, Syzdek M. Masculinity and perceived normative health behaviors as predictors of men's health behaviors.Soc Sci Med. 2007;64(11):2201-2209.

66. Galdas PM, Cheater F, Marshall P. Men and health help-seeking behaviour: literature review. J Adv Nurs. 2005;49(6):616-623.

67. Peerson A, Saunders M. Men's health literacy: advancing evidence and priorities. Crit Pub Health. 2009;19(3&4):441-456.

68. Kutner M, Greenberg E, Jin Y, Paulsen C. The Health Literacy of America's Adults: Results from the 2003 National Assessment of Adult Literacy. Washington, DC: National Center for Education Statistics; 2006.

69. Peak T, Gast J, Ahlstrom D. A needs assessment of Latino men's health concerns. Am J Mens Health. 2010;4(1):22-32.

70. U.S. Department of Veterans Affairs. Spotlight: Gender Differences in Healthcare. Available at https://www.hsrd.research.va.gov/news/feature/gender_differences.cfm. Last accessed September 21, 2023.

71. Sears JT, Williams WL (eds). Overcoming Heterosexism and Homophobia: Strategies That Work. 1st ed. New York, NY: Columbia University Press; 1997.

72. Centers for Disease Control and Prevention. The State of Aging and Health in America 2013. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept. of Health and Human Services; 2013.

73. Williamson IR. Internalized homophobia and health issues affecting lesbians and gay men. Health Education Research. 2000;15(1):97-107.

74. Greenberg JS, Bruess CE, Conklin SC. Sexual orientation. In: Greenberg JS, Bruess CE, Conklin SC. Exploring the Dimensions of Human Sexuality. 4th ed. Sudberry, MA: Jones and Bartlett Publishers; 2011:352-356.

75. Centers for Disease Control and Prevention. Health Considerations for LGBTQ Youth. Available at https://www.cdc.gov/healthyyouth/disparities/health-considerations-lgbtq-youth.htm. Last accessed September 21, 2023.

76. National Center for Transgender Equality. Understanding Transgender People: The Basics. Available at https://transequality.org/issues/resources/understanding-transgender-people-the-basics. Last accessed September 21, 2023.

77. Dean L, Meyer IH, Robinson K, et al. Lesbian, gay, bisexual, and transgender health: findings and concerns. J Gay Lesbian Med Assoc. 2000;4(3):102-151.

78. Meyer IH. Why lesbian, gay, bisexual, and transgender public health? Am J Public Health. 2001;91(6):856-859.

79. Jones BE, Hill MJ. Mental Health Issues in Lesbian, Gay, Bisexual, and Transgender Communities. 1st ed. Washington, DC: American Psychiatric Publishing: 2002.

80. Perry B. The sociology of hate: theoretical approaches. In: Levin B, Iganski P, Blazak R, Lawrence FM. Hate Crimes. Volumes 1-5. Westport, CT: Greenwood Publishing Group, Inc.; 2009: 56-57.

81. Herek GM. The context of anti-gay violence: notes on cultural and psychological heterosexism. J Interpersonal Violence. 1990;5(3):316-333.

82. American Psychological Association Committee on Lesbian and Gay Concerns. Avoiding Heterosexual Bias in Language. Available at https://www.apa.org/pi/lgbt/resources/language. Last accessed September 21, 2023.

83. Like RC, Steiner RP, Rubel AJ. Society of Teachers of Family Medicine (STFM) Core Curriculum Guidelines: recommended core curriculum guidelines on culturally sensitive and competent health care. Fam Med. 1996;28(4):291-297.

84. O'Hanlan KA, Cabaj RP, Schatz B, Lock J, Nemrow P. A review of the medical consequences of homophobia with suggestions for resolution. J Gay Lesbian Med Assoc. 1997;1(1):25-39.

85. Kitzinger C. Speaking of oppression: psychology, politics, and the language of power. In: Rothblum ED, Bond LA (eds). Preventing Heterosexism and Homophobia. Thousand Oaks, CA: Sage Publications; 1996.

86. Matthews CR, Adams EM. Using a social justice approach to prevent the mental health consequences of heterosexism. J Prim Prev. 2009;30(1):11-26.

87. Hong JS, Woodford MR, Long LD, Renn KA. Ecological covariates of subtle and blatant heterosexist discrimination among LGBQ college students. J Youth Adolesc. 2016;45(1):117-131.

88. Woodford MR, Kulick A, Sinco BR, Hong JS. Contemporary heterosexism on campus and psychological distress among LGBQ students. The mediating role of self-acceptance. Am J Orthopsychiatry. 2014;84(5):519-529.

89. Misener TR, Sowell RL, Phillips KD, Harris C. Sexual orientation: a cultural diversity issue for nursing. Nurs Outlook. 1997;45(4):178-181.

90. Kirk HW, Weisbrod JA, Ericson KA. Psychosocial and Behavioral Aspects of Medicine. Philadelphia, PA: Lippincott Williams and Wilkins; 2002.

91. Human Rights Foundation. Demystifying Homosexuality: A Teaching Guide About Lesbians and Gay Men. Irvington Publishers; 1984.

92. Meyer IH, Schwartz S. Social issues as public health: promise and peril. Am J Public Health. 2000;90(8):1189-1191.

93. Willenbring M, Spring WD Jr. Evaluating alcohol use in elders. Aging. 1990;361:22-27.

94. Greene RR, Cohen HL. Social work with older adults and their families: changing practice paradigms. Fam Soc. 2005;86(3):367-374.

95. Koenig T, Spano R. Professional hope in working with older adults. J Sociol Soc Welf. 2006;33(2):25-44.

96. Administration on Aging. 2018 Profile of Older Americans. Available at https://acl.gov/sites/default/files/Aging%20and%20Disability%20in%20America/2018OlderAmericansProfile.pdf. Last accessed September 21, 2023.

97. Pew Research Center. The Return of the Multi-Generational Family Household. Available at https://www.pewresearch.org/social-trends/2010/03/18/the-return-of-the-multi-generational-family-household. Last accessed September 21, 2023.

98. Pew Research Center. A Record 64 Million Americans Live in Multigenerational Households. Available at https://www.pewresearch.org/fact-tank/2018/04/05/a-record-64-million-americans-live-in-multigenerational-households. Last accessed September 21, 2023.

99. U.S. Senate. America's Aging Workforce: Opportunities and Challenges. Available at https://www.aging.senate.gov/imo/media/doc/Aging%20Workforce%20Report%20FINAL.pdf. Last accessed September 21, 2023.

100. Toossi M, Torpey E. Older Workers: Labor Force Trends and Career Options. Available at https://www.bls.gov/careeroutlook/2017/article/older-workers.htm. Last accessed September 21, 2023.

101. Denmark FL. Myths of aging. Eye on Psi Chi. 2002;7(1):14-21.

102. National Council on Aging. The United States of Aging Survey: National Findings. Available at https://www.unitedhealthgroup.com/content/dam/UHG/PDF/2015/USofAging-2015-Executive-Summary.pdf. Last accessed September 21, 2023.

103. Bruine de Bruin W, Parker AM, Strough J. Age differences in reported social networks and well-being. Psychology Aging. 2020;35(2):159-168.

104. Butler M, McCreedy E, Schwer N, et al. Improving Cultural Competence to Reduce Health Disparities. Rockville, MD: Agency for Healthcare Research and Quality; 2016.

105. Agaronnik N, Campbell EG, Ressalam J, Iezzoni LI. Exploring issues relating to disability cultural competence among practicing physicians. Disabil Health J. 2019;12(3):403-410.

106. Okun BF, Fried J, Okun ML. Understanding Diversity: A Learning-As-Practice Primer. Pacific Grove, CA: Brooks/Cole Publishing Co.; 1999.

107. Lynch EW, Hanson MJ (eds). Developing Cross-Cultural Competence: A Guide for Working with Children and Their Families. 4th ed. Baltimore, MD: Paul H. Brookes Publishing, Co.; 2011.

108. Ayonrinde O. Importance of cultural sensitivity in therapeutic transactions: considerations for healthcare providers. Disease Management & Health Outcomes. 2003;11(4):233-248.

109. Singh NN, Mckay JD, Singh AN. Culture and mental health: nonverbal communication. J Child Fam Stud. 1998;7(4):403-409.

110. Manrai LA, Manrai AK, Lascu D, Friedeborn S. Determinants and effects of cultural context: a review, conceptual model, and propositions. Journal of Global Marketing. 2019;32(2):67-82.

111. Gudykunst WB. Asian American Ethnicity and Communication. Thousand Oaks, CA: Sage; 2001.

112. Chang H, Chen L. Commonalities as an alternative approach to analyzing Asian Pacific communication. Journal of Asian Pacific Communication. 2015;25(1):1-21.

113. Herring RD. Nonverbal communication: a necessary component of cross-cultural counseling. J Multicult Couns Devel. 1990;18(4):172-179.

114. le Roux J. Effective educators are culturally competent communicators. Intercultural Education. 2002;13(1):37-48.

115. Akechi H, Senju A, Uibo H, et al. Attention to eye contact in the West and East: autonomic responses and evaluative ratings. PLoS One. 2013;8(3):e59312.

116. Chung DK. Asian cultural commonalities: a comparison with mainstream culture. In: Furuto S, Biswas R, Chung DK, Murase K, Ross-Sheriff F (eds). Social Work Practice with Asian Americans. Newbury Park, CA: Sage Publications; 1992: 27-44.

117. Castillo RJ. Culture and Mental Illness: A Client-Centered Approach. Pacific Groves, CA: Brooks/Cole Publishing Company; 1997.

118. Fong R, Furuto S (eds). Culturally Competent Practice: Skills, Interventions, and Evaluations. Needham Heights, MA: Allyn & Bacon; 2001.

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

120. Fondacaro KM, Harder VS. Connecting cultures: a training model promoting evidence-based psychological services for refugees. Training & Education in Professional Psychology. 2014;8(4):320-327.

121. Kleinman A. The Illness Narratives: Suffering, Healing and the Human Condition. New York, NY: Basic Books; 1988.

122. Galanti GA. Caring for Patients from Different Cultures. 5th ed. Philadelphia, PA: University of Pennsylvania Press; 2015.

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

124. Beckerman NL, Corbett L. Immigration and families: treating acculturative stress from a systemic framework. Fam Ther. 2008;35(2):63-81.

125. Ellis BH, Abdi SM, Winer JP. Psychosocial assessment with refugee and immigrant youth and families. In: Mental Health Practice with Immigrant and Refugee Youth: A Socioecological Framework. Washington, DC: American Psychological Association; 2020: 53-76.

126. Weisman A, Feldman G, Gruman C, et al. Improving mental health services for Latino and Asian immigrant elders. Prof Psychol Res Pr. 2005;36(6):642-648.

127. Braun FK, Fine ES, Greif DC, Devenny JM. Guidelines for multicultural assessment: an Asian Indian American case study. J Multicult Couns Devel. 2010;38(3):130-141.

128. Committee on Health Care for Underserved Women. Committee Opinion #512: health care for transgender individuals. Obstet Gynecol. 2011;118(6):1454-1458.

129. National LGBT Health Education Center. Affirmative Care for Transgender and Gender Non-Conforming People: Best Practices for Front-line Health Care Staff. Available at https://www.lgbtqiahealtheducation.org/publication/affirmative-services-for-transgender-and-gender-diverse-people-best-practices-for-frontline-health-care-staff. Last accessed September 21, 2023.

130. Johnson TJ, Hickey RW, Switzer GE, et al. The impact of cognitive stressors in the emergency department on physician implicit racial bias. Acad Emerg Med. 2016;23(3):297-305.

131. National Center for States Courts. Strategies to Reduce the Influence of Implicit Bias. Available at https://horsley.yale.edu/sites/default/files/files/IB_Strategies_033012.pdf. Last accessed September 21, 2023.

132. U.S. Department of Defense. 2020 Demographics Report: Profile of the Military Community. Available at https://download.militaryonesource.mil/12038/MOS/Reports/2020-demographics-report.pdf. Last accessed September 21, 2023.

133. Department of Veterans Affairs. Profile of Veterans: 2017. Available at https://www.va.gov/vetdata/docs/SpecialReports/Profile_of_Veterans_2017.pdf. Last accessed September 21, 2023.

134. Kime P. Experts: Docs Should Ask about Patients' Military History. Available at https://www.militarytimes.com/pay-benefits/military-benefits/health-care/2015/02/16/experts-docs-should-ask-about-patients-military-history. Last accessed September 21, 2023.

135. American Academy of Nursing. Have You Ever Served in the Military? Available at https://www.haveyoueverserved.com. Last accessed September 21, 2023.

136. Cashwell CS, Young JS. Integrating Spirituality and Religion into Counseling: A Guide to Competent Practice. 3rd ed. Alexandria, VA: American Counseling Association; 2020.

137. Miller G. Incorporating Spirituality in Counseling and Psychotherapy. New York, NY: John Wiley & Sons; 2003.

138. Wiggins-Frame M. Integrating Religion and Spirituality into Counseling: A Comprehensive Approach. Pacific Grove, CA: Brooks/Cole-Thomson Learning: 2003.

139. Gold JM. Counseling and Spirituality: Integrating Spiritual and Clinical Orientations. Upper Saddle River, NJ: Pearson; 2010.

140. Pew Research Center. Key Findings About Americans' Belief in God. Available at https://www.pewresearch.org/short-reads/2018/04/25/key-findings-about-americans-belief-in-god. Last accessed September 21, 2023.

141. Pew Research Center. The Future of World Religions: Population Growth Projections, 2010–2050. Available at https://www.pewforum.org/2015/04/02/religious-projections-2010-2050. Last accessed September 21, 2023.

142. Heelas P. The New Age Movement: The Celebration of the Self and the Sacralization of Modernity. Oxford: Blackwell; 2005.

143. Heelas P, Woodhead L. The Spiritual Revolution: Why Religion is Giving Way to Spirituality. Oxford: Blackwell Publishing; 2018.

144. Snyder CR, Wang PZ, Truitt AR. Multiracial patient experiences with racial microaggressions in health care settings. J Patient Cent Res Rev. 2018;5(3):229-238.

145. Centers for Disease Control and Prevention. Women, Caregiving, and COVID-19. Available at https://www.cdc.gov/women/caregivers-covid-19/index.html. Last accessed September 21, 2023.

146. U.S. Department of Health and Human Services. Office on Women's Health. Mental Health. Available at https://www.womenshealth.gov/mental-health. Last accessed September 21, 2023.

147. Paganini GA, Summers KM, ten Brinke L, Lloyd EP. Women exaggerate, men downplay: Gendered endorsement of emotional dramatization stereotypes contributes to gender bias in pain expectations. Journal of Experimental Social Psychology. 2023;109:104520.

148. Sadiq A. Managing the fasting patient: sacred ritual, modern challenges. In: Sheikh A, Gatrad AR (eds). Caring for Muslim Patients. 2nd ed. Abingdon: Radcliffe Publishing Ltd; 2008: 73-79.

149. Humes KR, Jones NA, Ramirez RR. Overview of Race and Hispanic Origin: 2010. Washington, DC: U.S. Census Bureau, 2011.

150. Lee J, Bean FD. America's changing color lines: immigration, race/ethnicity, and multiracial identification. Annual Review of Sociology. 2004;30(1):221-242.

Evidence-Based Practice Recommendations Citations

1. Alves-Bradford J-M, Bailey R, Durham MP. Stress and Trauma Toolkit for Treating African Americans in a Changing Political and Social Environment. Available at https://www.psychiatry.org/psychiatrists/diversity/education/stress-and-trauma/african-americans. Last accessed September 26, 2023.

2. American Psychological Association. APA Guidelines on Race and Ethnicity in Psychology. Available at https://www.apa.org/about/policy/guidelines-race-ethnicity.pdf. Last accessed September 26, 2023.