Twenty years ago, the American Journal of Preventive Medicine published Felitti and colleagues’ seminal publication on the relationship between adverse childhood experiences (ACEs) and poor mental and physical health.¹ It is astonishing that mainstream medicine is only now taking this finding seriously under the current banner of “trauma informed care.” Better late than never.

In this issue of JFP, Stillerman provides a cogent summary of the research on diagnosis and treatment of ACEs performed over the past 20 years. There are good data supporting the effectiveness of identifying and treating ACEs to lessen the adverse health outcomes that can result. More important, however, is taking a public health approach to preventing the adverse health effects of ACEs by staging community interventions and providing support to new mothers and families.

Research strongly supports a causal relationship between ACEs and a host of mental and physical ailments. Felitti found that adults with 4 or more ACEs compared with none had a 4- to 12-fold increased health risk for alcoholism, drug abuse, depression, and suicide attempt. ACEs also increased the risk of ischemic heart disease, cancer, chronic lung disease, skeletal fractures, and liver disease.¹

The research strongly supports a causal relationship between adverse childhood experiences and a host of mental and physical ailments.

There is need for further research on screening for, and treating, ACEs. A large randomized trial using one of the practical brief screeners would help us learn more about the impact that screening can have on the mental and physical health of those affected. Does the identification and empathetic acknowledgement of the traumatic events lead to improved health? If it does not, what type of treatment is most effective?

Continue to: Pending further research...

Pending further research, here are 3 steps that family physicians can take today:

1. Be aware of the strength of the relationship between ACEs and health problems.
2. Begin screening adults and children for ACEs using one of the simple, validated screening tools described by Stillerman. In a large follow-up study, screening along with discussion of the results with the patient’s physician led to remarkable decreases in health care utilization in the year following screening, which suggests that there are therapeutic benefits to bringing ACEs to light and fostering discussion.²
3. Remain ever compassionate in your interactions with all patients, knowing that many have significant childhood scars.

Twenty years ago, the American Journal of Preventive Medicine published Felitti and colleagues’ seminal publication on the relationship between adverse childhood experiences (ACEs) and poor mental and physical health.¹ It is astonishing that mainstream medicine is only now taking this finding seriously under the current banner of “trauma informed care.” Better late than never.

In this issue of JFP, Stillerman provides a cogent summary of the research on diagnosis and treatment of ACEs performed over the past 20 years. There are good data supporting the effectiveness of identifying and treating ACEs to lessen the adverse health outcomes that can result. More important, however, is taking a public health approach to preventing the adverse health effects of ACEs by staging community interventions and providing support to new mothers and families.

Research strongly supports a causal relationship between ACEs and a host of mental and physical ailments. Felitti found that adults with 4 or more ACEs compared with none had a 4- to 12-fold increased health risk for alcoholism, drug abuse, depression, and suicide attempt. ACEs also increased the risk of ischemic heart disease, cancer, chronic lung disease, skeletal fractures, and liver disease.¹

The research strongly supports a causal relationship between adverse childhood experiences and a host of mental and physical ailments.

There is need for further research on screening for, and treating, ACEs. A large randomized trial using one of the practical brief screeners would help us learn more about the impact that screening can have on the mental and physical health of those affected. Does the identification and empathetic acknowledgement of the traumatic events lead to improved health? If it does not, what type of treatment is most effective?

Continue to: Pending further research...

Pending further research, here are 3 steps that family physicians can take today:

1. Be aware of the strength of the relationship between ACEs and health problems.
2. Begin screening adults and children for ACEs using one of the simple, validated screening tools described by Stillerman. In a large follow-up study, screening along with discussion of the results with the patient’s physician led to remarkable decreases in health care utilization in the year following screening, which suggests that there are therapeutic benefits to bringing ACEs to light and fostering discussion.²
3. Remain ever compassionate in your interactions with all patients, knowing that many have significant childhood scars.

Twenty years ago, the American Journal of Preventive Medicine published Felitti and colleagues’ seminal publication on the relationship between adverse childhood experiences (ACEs) and poor mental and physical health.¹ It is astonishing that mainstream medicine is only now taking this finding seriously under the current banner of “trauma informed care.” Better late than never.

In this issue of JFP, Stillerman provides a cogent summary of the research on diagnosis and treatment of ACEs performed over the past 20 years. There are good data supporting the effectiveness of identifying and treating ACEs to lessen the adverse health outcomes that can result. More important, however, is taking a public health approach to preventing the adverse health effects of ACEs by staging community interventions and providing support to new mothers and families.

Research strongly supports a causal relationship between ACEs and a host of mental and physical ailments. Felitti found that adults with 4 or more ACEs compared with none had a 4- to 12-fold increased health risk for alcoholism, drug abuse, depression, and suicide attempt. ACEs also increased the risk of ischemic heart disease, cancer, chronic lung disease, skeletal fractures, and liver disease.¹

The research strongly supports a causal relationship between adverse childhood experiences and a host of mental and physical ailments.

There is need for further research on screening for, and treating, ACEs. A large randomized trial using one of the practical brief screeners would help us learn more about the impact that screening can have on the mental and physical health of those affected. Does the identification and empathetic acknowledgement of the traumatic events lead to improved health? If it does not, what type of treatment is most effective?

Continue to: Pending further research...

Pending further research, here are 3 steps that family physicians can take today:

1. Be aware of the strength of the relationship between ACEs and health problems.
2. Begin screening adults and children for ACEs using one of the simple, validated screening tools described by Stillerman. In a large follow-up study, screening along with discussion of the results with the patient’s physician led to remarkable decreases in health care utilization in the year following screening, which suggests that there are therapeutic benefits to bringing ACEs to light and fostering discussion.²
3. Remain ever compassionate in your interactions with all patients, knowing that many have significant childhood scars.

The rising prevalence of obesity, widespread community violence, and the opioid epidemic are urgent health crises that we have, so far, failed to solve. Physicians must therefore ask: Are we employing the right framework to effectively understand and address these complex problems?

Careful review of the literature reveals that these problems and many others begin with, and are profoundly affected by, childhood adversity. Compounding this, studies over the past 20 years that have focused on abuse and neglect without including community, structural, and historical adversity demonstrate that our definitions of adversity and trauma have been too narrow. The prevalence and diversity of factors affecting development and health is much greater than our medical model anticipates.^1,2

CASE

Eileen W, a 55-year-old married, self-employed woman with a 20-year history of autoimmune thyroiditis, longstanding insomnia, and anxiety presents with intense episodes of terror related to public speaking, which are compromising her work performance. Her history is significant for tobacco and alcohol use beginning in early adolescence and continuing into young adulthood, as well as 2 unplanned pregnancies in her 20s. Additional adversities included the murder of her maternal aunt while Ms. W was in utero, resulting in her parents having fostered 2 young cousins; bullying; and the premature death of a special-needs sibling.

What treatment strategies might have been undertaken to manage consequences of the adversities of Ms. W’s childhood—both on her own initiative and as interventions by her health care providers?

IMAGE: © ALICIA BUELOW

Our medical model must be updated to be effective

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day—a reality incompletely addressed by our conventional theories and practices.^1,3 Consequently, updating our medical model to incorporate research that confirms the critical and widespread impact of childhood experience on health and illness is an essential task for family medicine.

Core values of family medicine integrate biological, clinical, and behavioral sciences. They include comprehensive and compassionate care that is provided within the context of family and community across the lifespan.^4,5 Family medicine is therefore the ideal specialty to lead a movement that will translate scientific evidence of the effects of childhood adversity on health into training, delivery of care, and research—transforming clinical practice and patient health across the lifespan.

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day.

This article describes the dramatic impact of childhood adversity on health and well-being and calls on family physicians to play a crucial role in preventing, mitigating, and treating the consequences of childhood adversity, an important root cause of disease.

Continue to: Childhood adversity makes us sick

 

 

Childhood adversity makes us sick

The first paper about the landmark Adverse Childhood Experiences (ACE) Study, published 20 years ago, is 1 of more than 90 on this topic.³ This study explored the relationship of physical, emotional, and social health in adulthood and self-reported childhood adversity, and comprised 10 categories of abuse, neglect, and household distress between birth and 18 years of age. One of the largest epidemiological studies of its kind, the ACE Study surveyed more than 17,000 mostly white, middle-aged, educated, and insured participants. Study researchers developed an “ACE Score”—the total number of ACEs faced by a person before her (his) 18th birthday—and found that 64% of respondents endorsed 1 or more ACEs; 27% reported 3 or more ACEs; and 5% experienced 6 or more.

The ACE Study revealed a dose–response relationship between ACEs and more than 40 health-compromising behaviors, negative health conditions, and poor social outcomes. Examples include cardiac, autoimmune disease, obesity, intravenous drug abuse, depression and anxiety, adolescent pregnancy, and worker absenteeism. Tragically, an ACE score of ≥6 conferred a significant risk for premature death.¹

ACE data have been collected in diverse populations in 32 states and many countries through the Behavioral Risk Factor Surveillance Survey conducted by the Centers for Disease Control and Prevention³; the Child & Adolescent Health Measurement Initiative’s National Survey of Children’s Health⁶; and The World Health Organization’s ACE International Questionnaire⁷—underscoring the pervasiveness of childhood adversity. Evaluation of ACEs in special populations, such as people experiencing homelessness,⁸ incarcerated youth,⁹ people struggling with addiction,¹⁰ and even health care workers,¹¹ uncovers notably higher rates of ACEs in these populations than in the general population.

Is childhood adversity a true cause of bad outcomes?

Or is the relationship between the 2 entities merely an association? To help answer this question, researchers evaluated the ACE Study using Bradford Hill criteria—9 epidemiological principles employed to infer causation. Their findings strongly support the hypothesis that not only are ACEs associated with myriad negative outcomes, they are their root cause¹² and therefore a powerful determinant of our most pressing and expensive health and social problems.Nevertheless, strategies to prevent and address childhood adversity, which are critical to meeting national health goals of successful prevention and treatment of myriad conditions, are absent from the paradigm and practice of most physicians.

Childhood adversity is at the root of our most pressing physical, psychological, and social health problems.

The body of research about the health impact of additional adverse experiences is growing to include community violence, poverty, longstanding discrimination,² and other experiences that we describe as social determinants of health. Furthermore, social determinants of health, or adverse community experiences, appear to maintain a dose–response relationship with health and social outcomes.^{2 ,13} Along with adverse collective historical experiences (historical trauma),¹⁴ these community experiences are forcing further re-examination of existing paradigms of health.

Continue to: The biological pathway from experience to illness

 

 

The biological pathway from experience to illness

Neuroscience supports the epidemiology of ACEs.¹² The brain develops from the bottom up, in a use-dependent fashion, contingent on genetic potential and, most importantly, on our experiences, which also influence genetic expression. Although present across the lifespan, the brain’s capacity to change—neuroplasticity—is most robust from the prenatal period until about 3 years of age.¹⁵ The autonomic nervous system receives information from the body about our internal world and from sensory organs about our external environment and sends it to the brain for processing and interpretation, resulting in micro- and macro-adaptations in structure and function, both within the brain and in the rest of the body.¹⁶

Neuroscience demonstrates that adverse experiences, in the context of insufficient protective factors and depending on their timing, severity, and frequency, cause overactivation or prolonged activation, or both, of the stress response system, thus derailing optimal growth and development of the brain and disrupting healthy signaling in all body systems. The dysregulated stress response drives inflammation and subsequent chronic disease (FIGURE^17,18), and may influence genetic expression in this, and future, generations.^12,14,19 Using neuroimaging and assessment of biomarkers, researchers can see the harm caused by inadequately buffered adversity on overall anatomy and physiology. Protective factors such as a safe environment and positive relationships provide hope that normal biological responses to adverse circumstances can be prevented or reversed, leading to clinical, cognitive, and functional improvement¹¹ (TABLE 1^20-22).

Evidence-based primary prevention of childhood adversity succeeds

Primary prevention of childhood adversity offers significant benefits across the lifespan and, likely, into the next generation. It ensures that every infant has at least 1 nurturing, attuned caregiver with whom to develop a secure attachment relationship that is essential for optimal growth and development of brain and body.

Primary prevention is most effective when it focuses on supporting caregivers during the perinatal and early childhood periods of their families, before children’s brains are fully organized. Primary prevention involves evidence-based program implementation; collaboration among multiple sectors, including early childhood education, child welfare, criminal justice, business, faith, and health care; and, ultimately, policy change. It incorporates individual, family, and community-based strategies to meet basic needs, ensure safety, fortify a sense of love and belonging in families, and support parents in developing optimal parenting skills. This allows caregivers to devote attention to their children, thus strengthening attunement and attachment, reducing toxic stress, and building protective factors and resilience. Evidence-based and -informed prevention programs include the Nurse–Family Partnership (NFP), Positive Parenting Program (Triple P), and the Family-Centered Medical Home.

NFP. Randomized controlled trials of the NFP, a perinatal home visiting program for low-income, first-time pregnant women and their offspring, showed a reduction in the incidence of domestic violence, child maltreatment, and maternal smoking, with improvement in maternal financial stability, cognitive and socioemotional outcomes, and rates of substance abuse and incarceration in children and/or youth.²³

Continue to: Triple P

Triple P. A randomized controlled trial of Triple P, an evidence-based, multilevel, population-based preventive intervention system that was designed to support parents and enhance parenting practices for families with at least 1 child (birth to 12 years old), demonstrated a statistically significant reduction in substantiated child maltreatment cases, out-of-home placements, and emergency room visits and hospitalizations for childhood injuries that were the result of child maltreatment.²⁴

The Family-Centered Medical Home, a primary care strategy to reduce premature and low-birth-weight deliveries, used Medicaid dollars for services not traditionally considered “medical” to address all physical and emotional needs of mothers and families as part of the medical relationship. This program eliminated premature delivery and low birth weight,²⁵ both considered evidence of in utero toxic stress.²⁶

Screening can be brief: In some cases, a single question

The prevalence and impact of childhood adversity, along with the opportunity for significant health improvements and savings, inspires providers to explore screening. Existing screening programs have consistent goals^27,28:

• identify unique experiences shaping our patients’ health
• reframe “What’s wrong with you?” as “What happened to you?” “What’s right with you?” and “What matters to you?”
• facilitate health education and neuro-education, particularly meaning-making and self-regulation
• prevent and mitigate the sequelae of exposure to ACEs
• promote health in this and subsequent generations.

The ACE Study screened patients in the context of a comprehensive periodic health assessment. Study participants completed an at-home questionnaire and reviewed it with their physician.¹ The Urban ACE Survey added important community stressors such as neighborhood violence, bullying, and food insecurity to the original ACE questionnaire.²

Primary care tool. Wade developed a short, 2-question ACE pre-screener for primary care²⁹ and is exploring screening for childhood adversity in pediatric practice, as are primary care clinicians around the country.

Continue to: Single-question screener

Single-question screener. A Chicago internist interviewed more than 500 patients using a single-question screener that asked whether growing up was “mostly okay or pretty difficult.” This tool accurately confirmed childhood adversity in patients with complex chronic illness, prevented re-traumatization by allowing patients control over disclosure, and opened the door to collaborative healing work over time.³⁰

The Hague Protocol, now mandated in the Netherlands for health and justice professionals, focuses its efforts upstream by offering early detection of children at risk for adverse experiences. The protocol requires asking adults who present with intimate partner violence, suicidality, psychiatric disturbance, or severe substance abuse whether they care for children in any capacity. Those who are so identified are referred to a center at which support services are offered.³¹

Toxic stress impairs and sensitizes the stress response system, causes neuroinflammation and systemic inflammation, and leads to chronic illness, disability, and early death.

Uncertainty about the utility of existing tools. Many screening tools appear to be promising in terms of identification of the risk for, or actual, childhood adversity, patient and provider satisfaction, and their “fit” in the clinical workflow. Even so, no best practice guidelines exist in primary care to steer screening efforts. Questions remain about^27-29:

• broad implementation of a specific tool
• how, when, and where screening should take place
• whether to screen adults, parents, or children—or all 3
• how best to use the content and pacing of screening questions to promote self-regulation and prevent re-traumatization
• best strategies for training and supporting health care workers around screening activities
• how to optimally manage a positive screen.

How best to approach treatment

Treatment includes trauma-informed care, an organizational transformation process (described in TABLE 2³²; in “The lexicon of childhood adversity: Concepts and tools for care”^33-45; and in the subsection, “Lessons from neuroscience”), and individual treatment strategies. The Substance Abuse and Mental Health Services Administration (SAMHSA) of the US Department of Health and Human Services is advocating for implementation of trauma-informed approaches in health systems.

Continue to: The lexicon of childhood adversity...

Continue to: Trauma-informed care is a model...

Trauma-informed care is a model intended to promote healing and reduce the risk for re-traumatization of patients by staff—significant concerns in clinical settings, where the dynamics of loss of power, control, and safety that are inherent in traumatic experience can be replicated.⁴⁶ To operationalize trauma-informed care more formally, the Center for Health Care Strategies, Inc., and the National Council for Behavioral Health are developing recommendations for 1) standardized screening and assessment tools, evidence-based clinical interventions, implementation processes, and relevant and replicable outcome measures, and 2) policy changes to improve patient and staff engagement, enhance health outcomes, and reduce avoidable care and excess costs.^47,48

Asking patients whether growing up was “mostly okay or pretty difficult” accurately confirmed childhood adversity in patients with complex chronic illness.

Lessons from neuroscience guide effective treatment.¹⁶ Treatment begins with bottom-up strategies that are focused on decreasing suboptimal excitatory input from the survival brainstem to create safety, connect patients to resources to meet basic needs, teach self-regulation skills, and improve relational health in and outside of the office. Later-stage top-down methods, such as education and other cognitive activities, focus on strengthening the regulatory capacity of the thinking cortex.¹⁶ In many ways, treatment mirrors prevention: It emphasizes first helping patients feel safe and loved.

In a follow-up to the ACE Study, 100,000 patients had a primary care visit in which their practitioner reviewed the ACE questionnaire with them; said “I see that you have________. Tell me how that has affected you later in your life” for every “Yes” response; and listened to the answers without passing judgment. This simple intervention profoundly decreased health resource utilization by these patients during the following year: a reduction of 35% in office visits, 11% in emergency room visits, and 3% in hospitalizations.¹

The neurosequential model of therapeutics assesses neurodevelopment in the context of childhood adversity and relational health to evaluate consequences of childhood adversity and direct treatment. Adopted domestically and internationally, this model has had statistically significant success facilitating improvement in patients’ physical, emotional, and social health status.^16,49

Successful strategies for childhood adversity emphasize parenting education programs, trauma-informed organizational practices, and neuromodulatory treatments.

Trauma-specific treatment modalities such as trauma-focused cognitive behavioral therapy and eye-movement desensitization and reprocessing (EMDR),⁵⁰ a trauma-specific treatment effective in resolving painful childhood memories, are evidence-based treatments that reduce trauma-related symptoms; evidence is also emerging about the efficacy of yoga⁵¹ and neurofeedback.⁵² These therapies have been best studied as treatment for posttraumatic stress disorder and other mental health disorders and also hold promise for addressing physical and social consequences of adversity. They present a low risk for harm, appear to be cost-effective, and improve outcomes.

Continue to: Best regimens involve a multifaceted approach that combines...

Best regimens involve a multifaceted approach that combines health-system resources with referral to other community practitioners and agencies. An excellent example is a current collaboration between health systems and affordable housing programs to reduce and, ultimately, eliminate chronic homelessness. Positive outcomes of this collaboration include both improved health and life satisfaction for participants and cost savings to the health system.⁵³

CASE

Beginning in adulthood, Ms. W began long-term psychotherapy and had a therapeutic trial of antidepressants, without significant improvement. None of her medical or mental-health providers educated her about the connection between childhood adversity and illness to help her make sense of her health history and autoimmune disease, or to guide treatment. She learned from a friend about the relationship between childhood adversity and poor health and self-administered the ACE questionnaire, scoring 5 points out of a possible 10.

Ms. W enjoyed loving relationships with her mother, sisters, and friends. She had long-standing personal practices of individual and group physical activity, journaling, and spending time in nature.

Evidence is emerging about the efficacy of yoga and neurofeedback for reducing trauma-related symptoms.

About 10 years ago, Ms. W committed to regular yoga practice and later saw a functional medicine provider, who focused on nutrition and restorative sleep. She noticed improvement in all signs and symptoms; however, the terror of public speaking remained. Through friends, she found a practitioner who offered EMDR. Over the past 2 years, her terror has resolved and general anxiety and insomnia have continued to improve; she is now able to speak with fluency and comfort in any arena.

Addressing childhood adversity: Our “natural domain”

Experiences, positive and negative, shape our psychology and biology; they are powerful determinants of health—or illness. Prevention of, and response to, childhood adversity demand a systems approach to the whole person in context—the natural domain of family medicine.

Continue to: Although clinical translation is still unfolding...

Although clinical translation is still unfolding, the risks of implementing promising prevention and treatment strategies are low, the stakes are high, and the potential benefits are vast. Therefore, we as family physicians can—must—learn and incorporate the science of childhood adversity, neurobiology, and life course into our training, research, and clinical paradigm and practice; we can do that by embedding this framework throughout our training and continuing education in formal didactics, case discussions, hands-on skill-building, scientific investigation, and patient care.

We must make our offices and hospitals trauma-informed; connect patients with resources to meet basic needs and with home-visiting and parent education programs; educate patients about the impact of protective and adverse factors on health; provide and practice self-regulation training in our offices or by referral; and advocate for equity.

Using these strategies, family physicians will play a crucial role in the prevention, mitigation, and treatment of the root cause of disease and society’s deepest individual and collective suffering.

CORRESPONDENCE
Audrey Stillerman, MD, ABFM, ABIHM, ABOIM, Office of Community Engagement and Neighborhood Health Partnerships, 808 South Wolcott Street, Room 809, Chicago, IL 60612; [email protected].

ACKNOWLEDGMENT
Patricia Rush, MD, MBA, and Adrienne Williams, PhD, reviewed the manuscript of this article.

The rising prevalence of obesity, widespread community violence, and the opioid epidemic are urgent health crises that we have, so far, failed to solve. Physicians must therefore ask: Are we employing the right framework to effectively understand and address these complex problems?

Careful review of the literature reveals that these problems and many others begin with, and are profoundly affected by, childhood adversity. Compounding this, studies over the past 20 years that have focused on abuse and neglect without including community, structural, and historical adversity demonstrate that our definitions of adversity and trauma have been too narrow. The prevalence and diversity of factors affecting development and health is much greater than our medical model anticipates.^1,2

CASE

Eileen W, a 55-year-old married, self-employed woman with a 20-year history of autoimmune thyroiditis, longstanding insomnia, and anxiety presents with intense episodes of terror related to public speaking, which are compromising her work performance. Her history is significant for tobacco and alcohol use beginning in early adolescence and continuing into young adulthood, as well as 2 unplanned pregnancies in her 20s. Additional adversities included the murder of her maternal aunt while Ms. W was in utero, resulting in her parents having fostered 2 young cousins; bullying; and the premature death of a special-needs sibling.

What treatment strategies might have been undertaken to manage consequences of the adversities of Ms. W’s childhood—both on her own initiative and as interventions by her health care providers?

IMAGE: © ALICIA BUELOW

Our medical model must be updated to be effective

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day—a reality incompletely addressed by our conventional theories and practices.^1,3 Consequently, updating our medical model to incorporate research that confirms the critical and widespread impact of childhood experience on health and illness is an essential task for family medicine.

Core values of family medicine integrate biological, clinical, and behavioral sciences. They include comprehensive and compassionate care that is provided within the context of family and community across the lifespan.^4,5 Family medicine is therefore the ideal specialty to lead a movement that will translate scientific evidence of the effects of childhood adversity on health into training, delivery of care, and research—transforming clinical practice and patient health across the lifespan.

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day.

This article describes the dramatic impact of childhood adversity on health and well-being and calls on family physicians to play a crucial role in preventing, mitigating, and treating the consequences of childhood adversity, an important root cause of disease.

Continue to: Childhood adversity makes us sick

 

 

Childhood adversity makes us sick

The first paper about the landmark Adverse Childhood Experiences (ACE) Study, published 20 years ago, is 1 of more than 90 on this topic.³ This study explored the relationship of physical, emotional, and social health in adulthood and self-reported childhood adversity, and comprised 10 categories of abuse, neglect, and household distress between birth and 18 years of age. One of the largest epidemiological studies of its kind, the ACE Study surveyed more than 17,000 mostly white, middle-aged, educated, and insured participants. Study researchers developed an “ACE Score”—the total number of ACEs faced by a person before her (his) 18th birthday—and found that 64% of respondents endorsed 1 or more ACEs; 27% reported 3 or more ACEs; and 5% experienced 6 or more.

The ACE Study revealed a dose–response relationship between ACEs and more than 40 health-compromising behaviors, negative health conditions, and poor social outcomes. Examples include cardiac, autoimmune disease, obesity, intravenous drug abuse, depression and anxiety, adolescent pregnancy, and worker absenteeism. Tragically, an ACE score of ≥6 conferred a significant risk for premature death.¹

ACE data have been collected in diverse populations in 32 states and many countries through the Behavioral Risk Factor Surveillance Survey conducted by the Centers for Disease Control and Prevention³; the Child & Adolescent Health Measurement Initiative’s National Survey of Children’s Health⁶; and The World Health Organization’s ACE International Questionnaire⁷—underscoring the pervasiveness of childhood adversity. Evaluation of ACEs in special populations, such as people experiencing homelessness,⁸ incarcerated youth,⁹ people struggling with addiction,¹⁰ and even health care workers,¹¹ uncovers notably higher rates of ACEs in these populations than in the general population.

Is childhood adversity a true cause of bad outcomes?

Or is the relationship between the 2 entities merely an association? To help answer this question, researchers evaluated the ACE Study using Bradford Hill criteria—9 epidemiological principles employed to infer causation. Their findings strongly support the hypothesis that not only are ACEs associated with myriad negative outcomes, they are their root cause¹² and therefore a powerful determinant of our most pressing and expensive health and social problems.Nevertheless, strategies to prevent and address childhood adversity, which are critical to meeting national health goals of successful prevention and treatment of myriad conditions, are absent from the paradigm and practice of most physicians.

Childhood adversity is at the root of our most pressing physical, psychological, and social health problems.

The body of research about the health impact of additional adverse experiences is growing to include community violence, poverty, longstanding discrimination,² and other experiences that we describe as social determinants of health. Furthermore, social determinants of health, or adverse community experiences, appear to maintain a dose–response relationship with health and social outcomes.^{2 ,13} Along with adverse collective historical experiences (historical trauma),¹⁴ these community experiences are forcing further re-examination of existing paradigms of health.

Continue to: The biological pathway from experience to illness

 

 

The biological pathway from experience to illness

Neuroscience supports the epidemiology of ACEs.¹² The brain develops from the bottom up, in a use-dependent fashion, contingent on genetic potential and, most importantly, on our experiences, which also influence genetic expression. Although present across the lifespan, the brain’s capacity to change—neuroplasticity—is most robust from the prenatal period until about 3 years of age.¹⁵ The autonomic nervous system receives information from the body about our internal world and from sensory organs about our external environment and sends it to the brain for processing and interpretation, resulting in micro- and macro-adaptations in structure and function, both within the brain and in the rest of the body.¹⁶

Neuroscience demonstrates that adverse experiences, in the context of insufficient protective factors and depending on their timing, severity, and frequency, cause overactivation or prolonged activation, or both, of the stress response system, thus derailing optimal growth and development of the brain and disrupting healthy signaling in all body systems. The dysregulated stress response drives inflammation and subsequent chronic disease (FIGURE^17,18), and may influence genetic expression in this, and future, generations.^12,14,19 Using neuroimaging and assessment of biomarkers, researchers can see the harm caused by inadequately buffered adversity on overall anatomy and physiology. Protective factors such as a safe environment and positive relationships provide hope that normal biological responses to adverse circumstances can be prevented or reversed, leading to clinical, cognitive, and functional improvement¹¹ (TABLE 1^20-22).

Evidence-based primary prevention of childhood adversity succeeds

Primary prevention of childhood adversity offers significant benefits across the lifespan and, likely, into the next generation. It ensures that every infant has at least 1 nurturing, attuned caregiver with whom to develop a secure attachment relationship that is essential for optimal growth and development of brain and body.

Primary prevention is most effective when it focuses on supporting caregivers during the perinatal and early childhood periods of their families, before children’s brains are fully organized. Primary prevention involves evidence-based program implementation; collaboration among multiple sectors, including early childhood education, child welfare, criminal justice, business, faith, and health care; and, ultimately, policy change. It incorporates individual, family, and community-based strategies to meet basic needs, ensure safety, fortify a sense of love and belonging in families, and support parents in developing optimal parenting skills. This allows caregivers to devote attention to their children, thus strengthening attunement and attachment, reducing toxic stress, and building protective factors and resilience. Evidence-based and -informed prevention programs include the Nurse–Family Partnership (NFP), Positive Parenting Program (Triple P), and the Family-Centered Medical Home.

NFP. Randomized controlled trials of the NFP, a perinatal home visiting program for low-income, first-time pregnant women and their offspring, showed a reduction in the incidence of domestic violence, child maltreatment, and maternal smoking, with improvement in maternal financial stability, cognitive and socioemotional outcomes, and rates of substance abuse and incarceration in children and/or youth.²³

Continue to: Triple P

Triple P. A randomized controlled trial of Triple P, an evidence-based, multilevel, population-based preventive intervention system that was designed to support parents and enhance parenting practices for families with at least 1 child (birth to 12 years old), demonstrated a statistically significant reduction in substantiated child maltreatment cases, out-of-home placements, and emergency room visits and hospitalizations for childhood injuries that were the result of child maltreatment.²⁴

The Family-Centered Medical Home, a primary care strategy to reduce premature and low-birth-weight deliveries, used Medicaid dollars for services not traditionally considered “medical” to address all physical and emotional needs of mothers and families as part of the medical relationship. This program eliminated premature delivery and low birth weight,²⁵ both considered evidence of in utero toxic stress.²⁶

Screening can be brief: In some cases, a single question

The prevalence and impact of childhood adversity, along with the opportunity for significant health improvements and savings, inspires providers to explore screening. Existing screening programs have consistent goals^27,28:

• identify unique experiences shaping our patients’ health
• reframe “What’s wrong with you?” as “What happened to you?” “What’s right with you?” and “What matters to you?”
• facilitate health education and neuro-education, particularly meaning-making and self-regulation
• prevent and mitigate the sequelae of exposure to ACEs
• promote health in this and subsequent generations.

The ACE Study screened patients in the context of a comprehensive periodic health assessment. Study participants completed an at-home questionnaire and reviewed it with their physician.¹ The Urban ACE Survey added important community stressors such as neighborhood violence, bullying, and food insecurity to the original ACE questionnaire.²

Primary care tool. Wade developed a short, 2-question ACE pre-screener for primary care²⁹ and is exploring screening for childhood adversity in pediatric practice, as are primary care clinicians around the country.

Continue to: Single-question screener

Single-question screener. A Chicago internist interviewed more than 500 patients using a single-question screener that asked whether growing up was “mostly okay or pretty difficult.” This tool accurately confirmed childhood adversity in patients with complex chronic illness, prevented re-traumatization by allowing patients control over disclosure, and opened the door to collaborative healing work over time.³⁰

The Hague Protocol, now mandated in the Netherlands for health and justice professionals, focuses its efforts upstream by offering early detection of children at risk for adverse experiences. The protocol requires asking adults who present with intimate partner violence, suicidality, psychiatric disturbance, or severe substance abuse whether they care for children in any capacity. Those who are so identified are referred to a center at which support services are offered.³¹

Toxic stress impairs and sensitizes the stress response system, causes neuroinflammation and systemic inflammation, and leads to chronic illness, disability, and early death.

Uncertainty about the utility of existing tools. Many screening tools appear to be promising in terms of identification of the risk for, or actual, childhood adversity, patient and provider satisfaction, and their “fit” in the clinical workflow. Even so, no best practice guidelines exist in primary care to steer screening efforts. Questions remain about^27-29:

• broad implementation of a specific tool
• how, when, and where screening should take place
• whether to screen adults, parents, or children—or all 3
• how best to use the content and pacing of screening questions to promote self-regulation and prevent re-traumatization
• best strategies for training and supporting health care workers around screening activities
• how to optimally manage a positive screen.

How best to approach treatment

Treatment includes trauma-informed care, an organizational transformation process (described in TABLE 2³²; in “The lexicon of childhood adversity: Concepts and tools for care”^33-45; and in the subsection, “Lessons from neuroscience”), and individual treatment strategies. The Substance Abuse and Mental Health Services Administration (SAMHSA) of the US Department of Health and Human Services is advocating for implementation of trauma-informed approaches in health systems.

Continue to: The lexicon of childhood adversity...

Continue to: Trauma-informed care is a model...

Trauma-informed care is a model intended to promote healing and reduce the risk for re-traumatization of patients by staff—significant concerns in clinical settings, where the dynamics of loss of power, control, and safety that are inherent in traumatic experience can be replicated.⁴⁶ To operationalize trauma-informed care more formally, the Center for Health Care Strategies, Inc., and the National Council for Behavioral Health are developing recommendations for 1) standardized screening and assessment tools, evidence-based clinical interventions, implementation processes, and relevant and replicable outcome measures, and 2) policy changes to improve patient and staff engagement, enhance health outcomes, and reduce avoidable care and excess costs.^47,48

Asking patients whether growing up was “mostly okay or pretty difficult” accurately confirmed childhood adversity in patients with complex chronic illness.

Lessons from neuroscience guide effective treatment.¹⁶ Treatment begins with bottom-up strategies that are focused on decreasing suboptimal excitatory input from the survival brainstem to create safety, connect patients to resources to meet basic needs, teach self-regulation skills, and improve relational health in and outside of the office. Later-stage top-down methods, such as education and other cognitive activities, focus on strengthening the regulatory capacity of the thinking cortex.¹⁶ In many ways, treatment mirrors prevention: It emphasizes first helping patients feel safe and loved.

In a follow-up to the ACE Study, 100,000 patients had a primary care visit in which their practitioner reviewed the ACE questionnaire with them; said “I see that you have________. Tell me how that has affected you later in your life” for every “Yes” response; and listened to the answers without passing judgment. This simple intervention profoundly decreased health resource utilization by these patients during the following year: a reduction of 35% in office visits, 11% in emergency room visits, and 3% in hospitalizations.¹

The neurosequential model of therapeutics assesses neurodevelopment in the context of childhood adversity and relational health to evaluate consequences of childhood adversity and direct treatment. Adopted domestically and internationally, this model has had statistically significant success facilitating improvement in patients’ physical, emotional, and social health status.^16,49

Successful strategies for childhood adversity emphasize parenting education programs, trauma-informed organizational practices, and neuromodulatory treatments.

Trauma-specific treatment modalities such as trauma-focused cognitive behavioral therapy and eye-movement desensitization and reprocessing (EMDR),⁵⁰ a trauma-specific treatment effective in resolving painful childhood memories, are evidence-based treatments that reduce trauma-related symptoms; evidence is also emerging about the efficacy of yoga⁵¹ and neurofeedback.⁵² These therapies have been best studied as treatment for posttraumatic stress disorder and other mental health disorders and also hold promise for addressing physical and social consequences of adversity. They present a low risk for harm, appear to be cost-effective, and improve outcomes.

Continue to: Best regimens involve a multifaceted approach that combines...

Best regimens involve a multifaceted approach that combines health-system resources with referral to other community practitioners and agencies. An excellent example is a current collaboration between health systems and affordable housing programs to reduce and, ultimately, eliminate chronic homelessness. Positive outcomes of this collaboration include both improved health and life satisfaction for participants and cost savings to the health system.⁵³

CASE

Beginning in adulthood, Ms. W began long-term psychotherapy and had a therapeutic trial of antidepressants, without significant improvement. None of her medical or mental-health providers educated her about the connection between childhood adversity and illness to help her make sense of her health history and autoimmune disease, or to guide treatment. She learned from a friend about the relationship between childhood adversity and poor health and self-administered the ACE questionnaire, scoring 5 points out of a possible 10.

Ms. W enjoyed loving relationships with her mother, sisters, and friends. She had long-standing personal practices of individual and group physical activity, journaling, and spending time in nature.

Evidence is emerging about the efficacy of yoga and neurofeedback for reducing trauma-related symptoms.

About 10 years ago, Ms. W committed to regular yoga practice and later saw a functional medicine provider, who focused on nutrition and restorative sleep. She noticed improvement in all signs and symptoms; however, the terror of public speaking remained. Through friends, she found a practitioner who offered EMDR. Over the past 2 years, her terror has resolved and general anxiety and insomnia have continued to improve; she is now able to speak with fluency and comfort in any arena.

Addressing childhood adversity: Our “natural domain”

Experiences, positive and negative, shape our psychology and biology; they are powerful determinants of health—or illness. Prevention of, and response to, childhood adversity demand a systems approach to the whole person in context—the natural domain of family medicine.

Continue to: Although clinical translation is still unfolding...

Although clinical translation is still unfolding, the risks of implementing promising prevention and treatment strategies are low, the stakes are high, and the potential benefits are vast. Therefore, we as family physicians can—must—learn and incorporate the science of childhood adversity, neurobiology, and life course into our training, research, and clinical paradigm and practice; we can do that by embedding this framework throughout our training and continuing education in formal didactics, case discussions, hands-on skill-building, scientific investigation, and patient care.

We must make our offices and hospitals trauma-informed; connect patients with resources to meet basic needs and with home-visiting and parent education programs; educate patients about the impact of protective and adverse factors on health; provide and practice self-regulation training in our offices or by referral; and advocate for equity.

Using these strategies, family physicians will play a crucial role in the prevention, mitigation, and treatment of the root cause of disease and society’s deepest individual and collective suffering.

CORRESPONDENCE
Audrey Stillerman, MD, ABFM, ABIHM, ABOIM, Office of Community Engagement and Neighborhood Health Partnerships, 808 South Wolcott Street, Room 809, Chicago, IL 60612; [email protected].

ACKNOWLEDGMENT
Patricia Rush, MD, MBA, and Adrienne Williams, PhD, reviewed the manuscript of this article.

The rising prevalence of obesity, widespread community violence, and the opioid epidemic are urgent health crises that we have, so far, failed to solve. Physicians must therefore ask: Are we employing the right framework to effectively understand and address these complex problems?

Careful review of the literature reveals that these problems and many others begin with, and are profoundly affected by, childhood adversity. Compounding this, studies over the past 20 years that have focused on abuse and neglect without including community, structural, and historical adversity demonstrate that our definitions of adversity and trauma have been too narrow. The prevalence and diversity of factors affecting development and health is much greater than our medical model anticipates.^1,2

CASE

Eileen W, a 55-year-old married, self-employed woman with a 20-year history of autoimmune thyroiditis, longstanding insomnia, and anxiety presents with intense episodes of terror related to public speaking, which are compromising her work performance. Her history is significant for tobacco and alcohol use beginning in early adolescence and continuing into young adulthood, as well as 2 unplanned pregnancies in her 20s. Additional adversities included the murder of her maternal aunt while Ms. W was in utero, resulting in her parents having fostered 2 young cousins; bullying; and the premature death of a special-needs sibling.

What treatment strategies might have been undertaken to manage consequences of the adversities of Ms. W’s childhood—both on her own initiative and as interventions by her health care providers?

IMAGE: © ALICIA BUELOW

Our medical model must be updated to be effective

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day—a reality incompletely addressed by our conventional theories and practices.^1,3 Consequently, updating our medical model to incorporate research that confirms the critical and widespread impact of childhood experience on health and illness is an essential task for family medicine.

Core values of family medicine integrate biological, clinical, and behavioral sciences. They include comprehensive and compassionate care that is provided within the context of family and community across the lifespan.^4,5 Family medicine is therefore the ideal specialty to lead a movement that will translate scientific evidence of the effects of childhood adversity on health into training, delivery of care, and research—transforming clinical practice and patient health across the lifespan.

Because at least 60% of Americans have had 1 or more experiences of childhood adversity, family physicians care for affected patients every day.

This article describes the dramatic impact of childhood adversity on health and well-being and calls on family physicians to play a crucial role in preventing, mitigating, and treating the consequences of childhood adversity, an important root cause of disease.

Continue to: Childhood adversity makes us sick

 

 

Childhood adversity makes us sick

The first paper about the landmark Adverse Childhood Experiences (ACE) Study, published 20 years ago, is 1 of more than 90 on this topic.³ This study explored the relationship of physical, emotional, and social health in adulthood and self-reported childhood adversity, and comprised 10 categories of abuse, neglect, and household distress between birth and 18 years of age. One of the largest epidemiological studies of its kind, the ACE Study surveyed more than 17,000 mostly white, middle-aged, educated, and insured participants. Study researchers developed an “ACE Score”—the total number of ACEs faced by a person before her (his) 18th birthday—and found that 64% of respondents endorsed 1 or more ACEs; 27% reported 3 or more ACEs; and 5% experienced 6 or more.

The ACE Study revealed a dose–response relationship between ACEs and more than 40 health-compromising behaviors, negative health conditions, and poor social outcomes. Examples include cardiac, autoimmune disease, obesity, intravenous drug abuse, depression and anxiety, adolescent pregnancy, and worker absenteeism. Tragically, an ACE score of ≥6 conferred a significant risk for premature death.¹

ACE data have been collected in diverse populations in 32 states and many countries through the Behavioral Risk Factor Surveillance Survey conducted by the Centers for Disease Control and Prevention³; the Child & Adolescent Health Measurement Initiative’s National Survey of Children’s Health⁶; and The World Health Organization’s ACE International Questionnaire⁷—underscoring the pervasiveness of childhood adversity. Evaluation of ACEs in special populations, such as people experiencing homelessness,⁸ incarcerated youth,⁹ people struggling with addiction,¹⁰ and even health care workers,¹¹ uncovers notably higher rates of ACEs in these populations than in the general population.

Is childhood adversity a true cause of bad outcomes?

Or is the relationship between the 2 entities merely an association? To help answer this question, researchers evaluated the ACE Study using Bradford Hill criteria—9 epidemiological principles employed to infer causation. Their findings strongly support the hypothesis that not only are ACEs associated with myriad negative outcomes, they are their root cause¹² and therefore a powerful determinant of our most pressing and expensive health and social problems.Nevertheless, strategies to prevent and address childhood adversity, which are critical to meeting national health goals of successful prevention and treatment of myriad conditions, are absent from the paradigm and practice of most physicians.

Childhood adversity is at the root of our most pressing physical, psychological, and social health problems.

The body of research about the health impact of additional adverse experiences is growing to include community violence, poverty, longstanding discrimination,² and other experiences that we describe as social determinants of health. Furthermore, social determinants of health, or adverse community experiences, appear to maintain a dose–response relationship with health and social outcomes.^{2 ,13} Along with adverse collective historical experiences (historical trauma),¹⁴ these community experiences are forcing further re-examination of existing paradigms of health.

Continue to: The biological pathway from experience to illness

 

 

The biological pathway from experience to illness

Neuroscience supports the epidemiology of ACEs.¹² The brain develops from the bottom up, in a use-dependent fashion, contingent on genetic potential and, most importantly, on our experiences, which also influence genetic expression. Although present across the lifespan, the brain’s capacity to change—neuroplasticity—is most robust from the prenatal period until about 3 years of age.¹⁵ The autonomic nervous system receives information from the body about our internal world and from sensory organs about our external environment and sends it to the brain for processing and interpretation, resulting in micro- and macro-adaptations in structure and function, both within the brain and in the rest of the body.¹⁶

Neuroscience demonstrates that adverse experiences, in the context of insufficient protective factors and depending on their timing, severity, and frequency, cause overactivation or prolonged activation, or both, of the stress response system, thus derailing optimal growth and development of the brain and disrupting healthy signaling in all body systems. The dysregulated stress response drives inflammation and subsequent chronic disease (FIGURE^17,18), and may influence genetic expression in this, and future, generations.^12,14,19 Using neuroimaging and assessment of biomarkers, researchers can see the harm caused by inadequately buffered adversity on overall anatomy and physiology. Protective factors such as a safe environment and positive relationships provide hope that normal biological responses to adverse circumstances can be prevented or reversed, leading to clinical, cognitive, and functional improvement¹¹ (TABLE 1^20-22).

Evidence-based primary prevention of childhood adversity succeeds

Primary prevention of childhood adversity offers significant benefits across the lifespan and, likely, into the next generation. It ensures that every infant has at least 1 nurturing, attuned caregiver with whom to develop a secure attachment relationship that is essential for optimal growth and development of brain and body.

Primary prevention is most effective when it focuses on supporting caregivers during the perinatal and early childhood periods of their families, before children’s brains are fully organized. Primary prevention involves evidence-based program implementation; collaboration among multiple sectors, including early childhood education, child welfare, criminal justice, business, faith, and health care; and, ultimately, policy change. It incorporates individual, family, and community-based strategies to meet basic needs, ensure safety, fortify a sense of love and belonging in families, and support parents in developing optimal parenting skills. This allows caregivers to devote attention to their children, thus strengthening attunement and attachment, reducing toxic stress, and building protective factors and resilience. Evidence-based and -informed prevention programs include the Nurse–Family Partnership (NFP), Positive Parenting Program (Triple P), and the Family-Centered Medical Home.

NFP. Randomized controlled trials of the NFP, a perinatal home visiting program for low-income, first-time pregnant women and their offspring, showed a reduction in the incidence of domestic violence, child maltreatment, and maternal smoking, with improvement in maternal financial stability, cognitive and socioemotional outcomes, and rates of substance abuse and incarceration in children and/or youth.²³

Continue to: Triple P

Triple P. A randomized controlled trial of Triple P, an evidence-based, multilevel, population-based preventive intervention system that was designed to support parents and enhance parenting practices for families with at least 1 child (birth to 12 years old), demonstrated a statistically significant reduction in substantiated child maltreatment cases, out-of-home placements, and emergency room visits and hospitalizations for childhood injuries that were the result of child maltreatment.²⁴

The Family-Centered Medical Home, a primary care strategy to reduce premature and low-birth-weight deliveries, used Medicaid dollars for services not traditionally considered “medical” to address all physical and emotional needs of mothers and families as part of the medical relationship. This program eliminated premature delivery and low birth weight,²⁵ both considered evidence of in utero toxic stress.²⁶

Screening can be brief: In some cases, a single question

The prevalence and impact of childhood adversity, along with the opportunity for significant health improvements and savings, inspires providers to explore screening. Existing screening programs have consistent goals^27,28:

• identify unique experiences shaping our patients’ health
• reframe “What’s wrong with you?” as “What happened to you?” “What’s right with you?” and “What matters to you?”
• facilitate health education and neuro-education, particularly meaning-making and self-regulation
• prevent and mitigate the sequelae of exposure to ACEs
• promote health in this and subsequent generations.

The ACE Study screened patients in the context of a comprehensive periodic health assessment. Study participants completed an at-home questionnaire and reviewed it with their physician.¹ The Urban ACE Survey added important community stressors such as neighborhood violence, bullying, and food insecurity to the original ACE questionnaire.²

Primary care tool. Wade developed a short, 2-question ACE pre-screener for primary care²⁹ and is exploring screening for childhood adversity in pediatric practice, as are primary care clinicians around the country.

Continue to: Single-question screener

Single-question screener. A Chicago internist interviewed more than 500 patients using a single-question screener that asked whether growing up was “mostly okay or pretty difficult.” This tool accurately confirmed childhood adversity in patients with complex chronic illness, prevented re-traumatization by allowing patients control over disclosure, and opened the door to collaborative healing work over time.³⁰

The Hague Protocol, now mandated in the Netherlands for health and justice professionals, focuses its efforts upstream by offering early detection of children at risk for adverse experiences. The protocol requires asking adults who present with intimate partner violence, suicidality, psychiatric disturbance, or severe substance abuse whether they care for children in any capacity. Those who are so identified are referred to a center at which support services are offered.³¹

Toxic stress impairs and sensitizes the stress response system, causes neuroinflammation and systemic inflammation, and leads to chronic illness, disability, and early death.

Uncertainty about the utility of existing tools. Many screening tools appear to be promising in terms of identification of the risk for, or actual, childhood adversity, patient and provider satisfaction, and their “fit” in the clinical workflow. Even so, no best practice guidelines exist in primary care to steer screening efforts. Questions remain about^27-29:

• broad implementation of a specific tool
• how, when, and where screening should take place
• whether to screen adults, parents, or children—or all 3
• how best to use the content and pacing of screening questions to promote self-regulation and prevent re-traumatization
• best strategies for training and supporting health care workers around screening activities
• how to optimally manage a positive screen.

How best to approach treatment

Treatment includes trauma-informed care, an organizational transformation process (described in TABLE 2³²; in “The lexicon of childhood adversity: Concepts and tools for care”^33-45; and in the subsection, “Lessons from neuroscience”), and individual treatment strategies. The Substance Abuse and Mental Health Services Administration (SAMHSA) of the US Department of Health and Human Services is advocating for implementation of trauma-informed approaches in health systems.

Continue to: The lexicon of childhood adversity...

Continue to: Trauma-informed care is a model...

Trauma-informed care is a model intended to promote healing and reduce the risk for re-traumatization of patients by staff—significant concerns in clinical settings, where the dynamics of loss of power, control, and safety that are inherent in traumatic experience can be replicated.⁴⁶ To operationalize trauma-informed care more formally, the Center for Health Care Strategies, Inc., and the National Council for Behavioral Health are developing recommendations for 1) standardized screening and assessment tools, evidence-based clinical interventions, implementation processes, and relevant and replicable outcome measures, and 2) policy changes to improve patient and staff engagement, enhance health outcomes, and reduce avoidable care and excess costs.^47,48

Asking patients whether growing up was “mostly okay or pretty difficult” accurately confirmed childhood adversity in patients with complex chronic illness.

Lessons from neuroscience guide effective treatment.¹⁶ Treatment begins with bottom-up strategies that are focused on decreasing suboptimal excitatory input from the survival brainstem to create safety, connect patients to resources to meet basic needs, teach self-regulation skills, and improve relational health in and outside of the office. Later-stage top-down methods, such as education and other cognitive activities, focus on strengthening the regulatory capacity of the thinking cortex.¹⁶ In many ways, treatment mirrors prevention: It emphasizes first helping patients feel safe and loved.

In a follow-up to the ACE Study, 100,000 patients had a primary care visit in which their practitioner reviewed the ACE questionnaire with them; said “I see that you have________. Tell me how that has affected you later in your life” for every “Yes” response; and listened to the answers without passing judgment. This simple intervention profoundly decreased health resource utilization by these patients during the following year: a reduction of 35% in office visits, 11% in emergency room visits, and 3% in hospitalizations.¹

The neurosequential model of therapeutics assesses neurodevelopment in the context of childhood adversity and relational health to evaluate consequences of childhood adversity and direct treatment. Adopted domestically and internationally, this model has had statistically significant success facilitating improvement in patients’ physical, emotional, and social health status.^16,49

Successful strategies for childhood adversity emphasize parenting education programs, trauma-informed organizational practices, and neuromodulatory treatments.

Trauma-specific treatment modalities such as trauma-focused cognitive behavioral therapy and eye-movement desensitization and reprocessing (EMDR),⁵⁰ a trauma-specific treatment effective in resolving painful childhood memories, are evidence-based treatments that reduce trauma-related symptoms; evidence is also emerging about the efficacy of yoga⁵¹ and neurofeedback.⁵² These therapies have been best studied as treatment for posttraumatic stress disorder and other mental health disorders and also hold promise for addressing physical and social consequences of adversity. They present a low risk for harm, appear to be cost-effective, and improve outcomes.

Continue to: Best regimens involve a multifaceted approach that combines...

Best regimens involve a multifaceted approach that combines health-system resources with referral to other community practitioners and agencies. An excellent example is a current collaboration between health systems and affordable housing programs to reduce and, ultimately, eliminate chronic homelessness. Positive outcomes of this collaboration include both improved health and life satisfaction for participants and cost savings to the health system.⁵³

CASE

Beginning in adulthood, Ms. W began long-term psychotherapy and had a therapeutic trial of antidepressants, without significant improvement. None of her medical or mental-health providers educated her about the connection between childhood adversity and illness to help her make sense of her health history and autoimmune disease, or to guide treatment. She learned from a friend about the relationship between childhood adversity and poor health and self-administered the ACE questionnaire, scoring 5 points out of a possible 10.

Ms. W enjoyed loving relationships with her mother, sisters, and friends. She had long-standing personal practices of individual and group physical activity, journaling, and spending time in nature.

Evidence is emerging about the efficacy of yoga and neurofeedback for reducing trauma-related symptoms.

About 10 years ago, Ms. W committed to regular yoga practice and later saw a functional medicine provider, who focused on nutrition and restorative sleep. She noticed improvement in all signs and symptoms; however, the terror of public speaking remained. Through friends, she found a practitioner who offered EMDR. Over the past 2 years, her terror has resolved and general anxiety and insomnia have continued to improve; she is now able to speak with fluency and comfort in any arena.

Addressing childhood adversity: Our “natural domain”

Experiences, positive and negative, shape our psychology and biology; they are powerful determinants of health—or illness. Prevention of, and response to, childhood adversity demand a systems approach to the whole person in context—the natural domain of family medicine.

Continue to: Although clinical translation is still unfolding...

Although clinical translation is still unfolding, the risks of implementing promising prevention and treatment strategies are low, the stakes are high, and the potential benefits are vast. Therefore, we as family physicians can—must—learn and incorporate the science of childhood adversity, neurobiology, and life course into our training, research, and clinical paradigm and practice; we can do that by embedding this framework throughout our training and continuing education in formal didactics, case discussions, hands-on skill-building, scientific investigation, and patient care.

We must make our offices and hospitals trauma-informed; connect patients with resources to meet basic needs and with home-visiting and parent education programs; educate patients about the impact of protective and adverse factors on health; provide and practice self-regulation training in our offices or by referral; and advocate for equity.

Using these strategies, family physicians will play a crucial role in the prevention, mitigation, and treatment of the root cause of disease and society’s deepest individual and collective suffering.

CORRESPONDENCE
Audrey Stillerman, MD, ABFM, ABIHM, ABOIM, Office of Community Engagement and Neighborhood Health Partnerships, 808 South Wolcott Street, Room 809, Chicago, IL 60612; [email protected].

ACKNOWLEDGMENT
Patricia Rush, MD, MBA, and Adrienne Williams, PhD, reviewed the manuscript of this article.

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Short-term NSAIDs appear safe for high-risk patients

To take the posttest, go to: https://bit.ly/2PgXKGx
Expires October 8, 2019

2. Chronic liver disease raises death risk in pneumonia patients

To take the posttest, go to: https://bit.ly/2NPSXXA
Expires October 8, 2019

3. Half of outpatient antibiotics prescribed with no infectious disease code

To take the posttest, go to: https://bit.ly/2pWEWxU
Expires October 6, 2019

4. Secondary fractures in older men spike soon after first, but exercise may help

To take the posttest, go to: https://bit.ly/2OCNl8A
Expires October 3, 2019

5. Consider ART for younger endometriosis patients

To take the posttest, go to: https://bit.ly/2NO1Sc4
Expires October 5, 2019

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Short-term NSAIDs appear safe for high-risk patients

To take the posttest, go to: https://bit.ly/2PgXKGx
Expires October 8, 2019

2. Chronic liver disease raises death risk in pneumonia patients

To take the posttest, go to: https://bit.ly/2NPSXXA
Expires October 8, 2019

3. Half of outpatient antibiotics prescribed with no infectious disease code

To take the posttest, go to: https://bit.ly/2pWEWxU
Expires October 6, 2019

4. Secondary fractures in older men spike soon after first, but exercise may help

To take the posttest, go to: https://bit.ly/2OCNl8A
Expires October 3, 2019

5. Consider ART for younger endometriosis patients

To take the posttest, go to: https://bit.ly/2NO1Sc4
Expires October 5, 2019

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Short-term NSAIDs appear safe for high-risk patients

To take the posttest, go to: https://bit.ly/2PgXKGx
Expires October 8, 2019

2. Chronic liver disease raises death risk in pneumonia patients

To take the posttest, go to: https://bit.ly/2NPSXXA
Expires October 8, 2019

3. Half of outpatient antibiotics prescribed with no infectious disease code

To take the posttest, go to: https://bit.ly/2pWEWxU
Expires October 6, 2019

4. Secondary fractures in older men spike soon after first, but exercise may help

To take the posttest, go to: https://bit.ly/2OCNl8A
Expires October 3, 2019

5. Consider ART for younger endometriosis patients

To take the posttest, go to: https://bit.ly/2NO1Sc4
Expires October 5, 2019

Resources

US Preventive Services Task Force. Final recommendation statement: Cardiovascular disease risk: screening with electrocardiography.
https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/cardiovascular-disease-risk-screening-with-electrocardiography. Published June 2018. Accessed October 23, 2018.

US Preventive Services Task Force. Final recommendation statement: Atrial fibrillation: screening with electrocardiography.
https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/atrial-fibrillation-screening-with-electrocardiography. Published August 2018. Accessed October 23, 2018.

Resources

US Preventive Services Task Force. Final recommendation statement: Cardiovascular disease risk: screening with electrocardiography.
https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/cardiovascular-disease-risk-screening-with-electrocardiography. Published June 2018. Accessed October 23, 2018.

US Preventive Services Task Force. Final recommendation statement: Atrial fibrillation: screening with electrocardiography.
https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/atrial-fibrillation-screening-with-electrocardiography. Published August 2018. Accessed October 23, 2018.

Resources

US Preventive Services Task Force. Final recommendation statement: Cardiovascular disease risk: screening with electrocardiography.
https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/cardiovascular-disease-risk-screening-with-electrocardiography. Published June 2018. Accessed October 23, 2018.

US Preventive Services Task Force. Final recommendation statement: Atrial fibrillation: screening with electrocardiography.
https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/atrial-fibrillation-screening-with-electrocardiography. Published August 2018. Accessed October 23, 2018.

From Wayne State University, Detroit, MI (Dr. Gibson-Scipio), and the University of Texas Rio Grande Valley, Edinburg, TX (Dr. Krouse).

Abstract

• Objective: To review the literature on barriers to asthma self-management among African American adolescents.
• Methods: Review of the literature.
• Results: Asthma self-management barriers experienced by African American adolescents are often related to developmental needs, lack of knowledge, and personal perspectives and experiences. Adolescents find managing their symptoms and adhering to prescriptive therapies a burden and desire to be more like healthy peers. As they struggle to identify with peers, they may engage in risky behaviors such as ignoring symptoms and delaying treatment, thus leading to poorer asthma control and health outcomes. African American adolescents struggle with perceptions of racial biases from health care providers and teachers that interfere with self-management behaviors. They also describe the influence of culturally based practices learned from caregivers that contribute to their misconceptions and inadequate skills in effectively managing their asthma.
• Conclusion: Researchers should seek to develop interventions to address the unique contextual and culturally based needs of African American adolescents that support the development of effective asthma self-management behaviors. This may include making use of family members (especially mothers) and extended support for self-management during this period of rapid growth and transition. Health care providers should consider a team-based approach to the adolescent patient. Such an approach should be grounded in recommendations from national guidelines that suggest a patient-centered approach to care that includes a partnership between the patient and the provider to address unique barriers to effective self-management.

Keywords: youth; caregiver; drug-therapy; self-efficacy; disease-management; patient-centered care.

Effective asthma self-management by urban African American adolescents is a critical aspect of care that should be addressed with vigilance due to the persistent disparities in disease prevalence, morbidity, and mortality compared to Caucasians.^1-3 The overarching goal of asthma self-management is to achieve symptom control, maintain normal activity levels, and minimize future risk of exacerbations and medication side effects.^4,5 Best practices for asthma self-management begin with a partnership between health care providers and clients (including parent/caregiver). This relationship should help affected individuals gain asthma control based on knowledge of their disease and treatment options, confidence and skills in trigger avoidance, medication administration, and management of acute exacerbations.^4,5

Among youth aged 18 years and younger, African Americans have the highest asthma prevalence rates of all racial and ethnic groups, and between 2001 and 2009 asthma prevalence rates rose by 50% among African American youth.⁶ As of 2015, prevalence rates for asthma among African American youth were 13.4%, as compared to 7.4% for white youth.⁷ African American youth have been found to have more frequent asthma exacerbations and related school absences than white youth.⁸ Furthermore, African American youth younger than 18 years are more likely to be admitted to the hospital for asthma and are 10 times more likely to die from asthma compared to non-Hispanic white children.⁶

Urban African American adolescents with asthma are particularly vulnerable to poor asthma self-management due to the complexity of the disease in this population.³ African American youth must deal with multiple adverse environmental conditions, lack of knowledge or disbelief concerning effective disease self-management strategies, variable access and quality of care, and the psychosocial dynamics of being young while having a chronic disease.^2,3,9-11 It is important to understand and address barriers to successful asthma self-management during adolescence, as behaviors developed during this stage of life often persist into adulthood.⁹ In this article, we review the literature on barriers to asthma self-management among African American adolescents and offer suggestions on clinical strategies for improving self-management in this vulnerable population.

 

 

Methods

The initial search strategy was developed in collaboration with an experienced librarian. Keywords, MeSH terms, and potential databases were identified. Keywords included urban, African American, adolescent, asthma, self-management, and barriers. These terms were expanded based on search results and a review of abstracts that fit the intent of our review. The search was limited to U.S. studies published between 2005 and 2017. Excluded from the search were conference abstracts, doctoral dissertations, master’s theses, meta-analyses, systematic reviews, and studies conducted outside of the United States. Additional articles for the review were identified during the review process from the reference lists of the publications.

Abstracts were reviewed for articles that reported a study population inclusive of African American adolescents with asthma and that were related to self-management. Studies that used qualitative and other descriptive methods and cohort and randomized control trials were reviewed. Due to the limited number of articles found that exclusively focused on African Americans, the authors set a threshold for African American participants at 40% or greater for inclusion in this review.

Full papers were retrieved that met the inclusion criteria for a full review. Each author initially independently reviewed a selected number of papers and abstracted the study purpose, sample, study design, results, conclusions, and limitations. Subsequently, both authors reviewed in tandem and then discussed each selected manuscript to assure the appropriateness for inclusion. The subject matter was considered the priority for inclusion in the review. Study methods, sample size, and noted limitations were categorized but were not considered as a basis for exclusion. Thematic analysis was used to identify common themes across studies.

 

 

Results

We identified 23 papers that met our criteria (Table). Five common themes were found that related to barriers in disease self-management for African American adolescents: (a) knowledge and skills, (b) beliefs and attitudes, (c) personal/emotional factors, (d) caregivers, and (e) schools.

 

 

Knowledge and Skills

Adequate knowledge of the elements of asthma self-management is critical for achieving control of this condition. Asthma knowledge includes a basic understanding of the disease process and treatment strategies, an awareness of early signs and symptoms of worsening asthma, and an understanding of how to manage environmental triggers.^4,5 Sin and colleagues conducted one of the earlier studies to examine the influence of asthma knowledge on asthma self-management in African American adolescents and found a significant positive association between knowledge and asthma self-management behaviors.¹²

Adherence to an asthma medication, especially inhaled corticosteroids (ICS), is one of the cornerstones to successful self-management of asthma.^13,14 Consistent use of ICS therapy to control asthma symptoms and disease progression is often suboptimal in African American adolescents and tends to worsen as they age;¹⁵ studies have found lower adherence levels were more prominent in older African American adolescents and males.^13,16 In a recent study of adolescents with persistent asthma who were prescribed daily ICS, youth with greater ICS knowledge as assessed using a standardized instrument demonstrated significantly higher adherence rates.¹³ Proper technique in the use of an inhaler is also important in medication administration. Asthma ICS medication delivery devices vary significantly and require different techniques for medication administration. However, inhaler device skills have been found to be very inadequate in high-risk African American adolescents.¹⁷ Thus, knowledge related to ICS therapy and proper skills in the use of inhaler devices is an important aspect of asthma self-management that have been found to be inadequate in African American Adolescents.

Interventions and programs geared to improving education may lead to improved self-management. Multisystemic Therapy-Health Care (MST-HC) is a tailored home-based intervention that includes knowledge and skill-building components. In a study of African American youth with poorly controlled asthma, the program was found to improve illness management.¹⁸ In addition, adolescents who complete formal asthma education programs demonstrate significantly higher scores in self-management than those youth who do not participate in these programs.^13,19 Unfortunately, few African American teens report participation in an asthma education program.¹⁹ In a study of a motivational interviewing intervention to improve controller medication adherence for African American adolescents,¹⁴ youth reported gaining more knowledge about their asthma medications and were significantly more motivated to take their controller medications after participating in the intervention; however, while adherence to controller medications was greater than baseline, it was not significantly different.¹⁴ This study demonstrated the value of asthma education and the feasibility of a motivational intervention to support controller medication adherence. However, this study also demonstrated the complexity of medication adherence in that neither knowledge or motivation led to significant changes in medication adherence among African American adolescents.

Low health literacy can also act as a barrier to asthma self-management. Health literacy requires skills and knowledge that enable an individual to communicate, process, and understand basic health information that informs health decisions.²⁰ Health literacy was found to be associated with indicators of poor disease self-management among urban African American adolescents in grades 9 through 12.²¹ In this study, health literacy was established using questions about confidence in filling out medical forms, self-reported problems with learning about the youth’s medical condition, and the need for assistance in reading hospital materials. Adolescents with poor health literacy scores were more likely to reside in a household with the following characteristics: mother with less than a high school education, Medicaid health insurance, family members with a body mass index exceeding the 85th percentile, and lack of rescue medication. Poor health literacy was most common among younger adolescents (ie, ninth graders). Some youth with poor health literacy also reported more emergency department visits, hospitalizations, and lower overall quality of life.²¹

Beliefs and Attitudes

Beliefs and attitudes towards taking asthma medications can act as barriers to adherence in the adolescent. African American adolescents often report the belief that ICS are not helpful or necessary.^16,22-25 These beliefs have been correlated with a lack of understanding of the inflammatory mechanisms of asthma, reports of asthma attacks despite use of controller medications, fear of addiction to medications, and a belief that nontraditional interventions (eg, exercise) will work better to get rid of asthma or abate symptoms.^16-19,22-24 African American adolescents also report beliefs that asthma will go away or get better as they age, and they are willing to forgo the use of controller medications based on these beliefs.²⁴

African American adolescents often engage in asthma self-management independent of caregivers. These youth describe asthma self-management activities an annoyance and of low priority in part due to competing tasks and negative interactions with caregivers.²⁵ During early adolescence asthma self-management is often suboptimal, and as youth age they become less observant regarding their asthma and are less likely to seek help.²⁶ Adolescents’ beliefs and low prioritization of asthma self-management may contribute to forgetfulness and loss of inhalers, which are common reasons reported for poor adherence to ICS.^16,23-26 Further, the role of caregivers during this period has often been overlooked. Caregivers of African American adolescents have been found to be stressed and overwhelmed with personal responsibilities and neighborhood conditions, leaving them little time to attend to the asthma self-management behavior of youth. Due to these contextual factors, interactions with chronically ill youth may be strained, resulting in negative interactions with youth related to asthma self-management. However, in an intervention study that used multisystemic therapy (an approach that targets the affected individual, family, and community), improvement in positive parenting behaviors related to asthma self-management contributed to improved ICS adherence by adolescents.²⁷

Adolescents can perceive traditional asthma self-management as conflicting with their own personal and/or cultural beliefs. They may seek options beyond the use of medicine and have voiced preferences for behaviors that they believe will “strengthen their lungs” more naturally.²⁴ An appreciation of how youth might use complementary/alternative medicine (CAM) as an adjunctive therapy or in place of evidence-based asthma care is important to understanding the potential effect on morbidity and mortality. Behaviors and beliefs about the use of CAM have not been well studied among urban African American adolescents with asthma. Only one study was found that assessed the use of CAM among a primarily urban African American adolescent population. In that study, 71% of the population reported using some form of CAM during the past 30 days.²⁸ Prayer and relaxation were the most frequently used strategies in the management of asthma symptoms. Perceived efficacy of relaxation and prayer among teens who engaged in this form of CAM was 87% and 85%, respectively. Other CAM strategies included yoga, meditation, guided imagery, and biofeedback. When adolescents were asked if they shared their use of CAM in asthma management with a health care provider, most reported sharing the use of yoga and dietary changes but were least likely to share their use of prayer and guided imagery.²⁸

Personal/Emotional Factors

African American adolescents have reported asthma as a limiting factor in terms of both physical and social activities. They perceive asthma as a burden to themselves and others (eg, peers, family, coaches).^9,25 The burden of asthma is further exemplified in the emotional response to the symptoms of the disease and the self-management responsibilities. The need to prevent and respond to asthma symptoms is associated with being embarrassed, frustrated, angry, annoyed, worried, lonely, and isolated.^9,11,25 Negative coping strategies by youth in response to psychosocial experiences include decisions to disregard or give minimal attention to asthma symptoms and to delay or not take prescribed medications. Students report ignoring asthma symptom management while engaging in physical activities to maintain a sense of normalcy among peers and as a way of dealing with perceptions by coaches or teachers that they are weak or in need of being protected.^24,25

Negative thoughts and experiences can result in depressive disorders and poor quality of life. Depression is a common finding among urban youth with asthma.^29,30 Youth diagnosed with asthma who have comorbid depression may benefit from interventions to improve self-management. In a secondary analysis from a Web-based asthma management intervention targeting African American adolescents, depression was found to have a modifying effect on the emotional domain of quality of life for youth in the intervention arm of the study. This finding indicates that participants who were depressed and who reported low levels of emotional quality of life benefited from the Web-based interventions that targeted self-management.³¹

Caregivers

Caregivers (especially moms) are a common source of support for the development and implementation of asthma self-management behaviors in adolescents.³² Caregivers sometimes hold beliefs similar to those of youth and believe the urban environment can act as a barrier to asthma management.^9,25,32 They describe the complexity of asthma treatment plans, a lack of understanding of the disease process, and insensitivity of health care providers to their expressed needs along with the providers’ limited cultural awareness in the development of self-management plans.^9,22,33 Caregivers describe how family finances, insurance gaps, access to care, and their own familial/cultural beliefs influence their decisions and ability to support their child’s asthma management.³³ When faced with the cost of care they report instances of having to decide between necessities such as food and housing or co-pays for medications and office visits.^22,33 They also report concerns about visits with multiple providers due to an inability to access their primary care provider, which can lead to delays in their child being diagnosed with asthma.²²

Caregivers report a need to include culturally based practices, past experiences, and personal beliefs into the adolescents’ asthma management plan.^22,32,33 In a small interview-based study of caregivers residing in 3 New Jersey public housing communities, caregivers reported preferring “familial” methods of controlling asthma (eg, restriction of activities; use of showers, steam, vaporizers, and nebulizers) over evidence-based recommendations. Many caregivers were confused or lacked knowledge about asthma action plans.³³ Caregivers have also been found to lack adequate or accurate knowledge related to asthma medications and factors that improved or worsened asthma. While caregivers report a desire to help educate their teens by passing on what they know, their lack of adequate asthma knowledge may hamper their efforts and potentially worsen the teens’ asthma self-management.³²

While African American caregivers often describe themselves as hypervigilant concerning their child’s asthma, they may report different information than their adolescent when both are questioned about asthma symptom experiences and functional status.³⁴ Factors increasing the level of congruence between caregiver and teen asthma symptom reports were found to be related to the adolescents’ age and asthma disease classification. Symptom questionnaire responses of older teens and those with mild intermittent asthma were more likely to be similar to caregiver reports. The researchers concluded that clinicians and researchers may obtain reliable asthma symptom and functional status reports by asking the adolescent directly.³⁴

Schools

Caregivers and adolescents describe schools as a threat to self-management and the overall health of youth with asthma.^9,32 They perceive that a lack of knowledge by staff, teachers, and coaches contributes to inattentiveness or disbelief in the credibility of reported asthma symptoms by youth.^11,23 These misperceptions and the lack of attentiveness by adults in the school may pose safety and health issues for African American youth.^9,25,33,34 For example, adolescents report pressure from teacher, coaches, and peers in school settings to partake in sports and/or gym classes. Youth want to identify with healthy peers and thus often choose not to take asthma medications during such activities or opt to continue participating while being compromised by airway obstruction. Of great concern were reports by caregivers and teens of not being allowed to call a parent for support or retrieve their medications when needed for asthma symptoms.³²

Future Research and Practice Implications

In this review, we identified 5 common themes around barriers to asthma self-management for African American adolescents (knowledge and skills, beliefs and attitudes, personal/emotional factors, caregivers, and schools). Caregivers, especially mothers, play a pivotal role in the development of effective asthma self-management behaviors. Depsite good intentions, there is evidence of caregivers passing on ineffective experiential and culturally based beliefs and practices to their adolescents that can negatively influence self-care behaviors.^13,28,38 Studies are needed to further investigate these findings among caregivers as their beliefs and practices for asthma self-management have been found to coexist among adolescents. Studies that investigate how to incorporate caregiver asthma knowledge, cultural beliefs and behaviors in developing self-management interventions have the potential to positively influence asthma outcomes among African American adolescents.²⁷ The unique cultural beliefs, contextual environmental, and social disparities faced by African American caregivers should not be neglected.

African American adolescents, like adolescents in other racial or ethnic groups, desire to be autonomous in their asthma self-management. However, as adolescents age their adherence behaviors often decline. This may suggest a need for a longer transition period to self-management that extends into emerging adulthood (18-25 years). While youth want to feel supported, there appears to be a fine line between receiving needed support and what youth describe as “nagging” behaviors by adults. Additional investigations into how asthma responsibilities are transitioned from the parent to youth and how best to support the development and maintenance of related behaviors and skills are warranted. In addition, teens described problems related to communicating with health care providers, noting a lack of clarity in explanations received about how to manage their asthma. Some teens believed the communication challenges were based on beliefs and biases held by providers that African American youth had limited capacities for self-management.⁹ There is a need to better understand interactions among African American adolescents, parents, and clinicians so that communication and transitioning asthma care to the youth will produce optimal health outcomes.

According to asthma guidelines, the patient-provider relationship is essential to effective asthma self-management.^4,5 However, there is little mention in the literature of team-based care. Clinicians such as physicians, physician assistants, and nurse practitioners provide direct care to adolescents in terms of disease management and the overall effectiveness of treatment plans. African American youth demonstrate a need for asthma education that is comprehensive and that is contextualized to their daily lives. A team-based approach to care that includes social workers and community health workers may help to extend the reach of clinicians. Follow-up times with families and youth between office visits can be used to support adolescents to develop asthma self-management and allow them a safe space to describe frustrations and other emotions that contribute to their desire to be disease-free.

Summary

Asthma is a chronic disease that is often more severe and difficult to manage in African American adolescents. While African American adolescents describe developmental needs like those of other youth, cultural beliefs and contextual experiences influence their self-care management in unique ways. Opportunities exist to better understand the needs of African American adolescents and to help them successfully gain the knowledge, skills, and behaviors needed to effectively engage in self-management of their asthma.

Corresponding author: Wanda Gibson-Scipio, PhD, FNP-BC, FAANP, 5557 Cass Ave., 346 Cohn Building, Detroit, MI 48324; [email protected].

Financial disclosures: None.

From Wayne State University, Detroit, MI (Dr. Gibson-Scipio), and the University of Texas Rio Grande Valley, Edinburg, TX (Dr. Krouse).

Abstract

• Objective: To review the literature on barriers to asthma self-management among African American adolescents.
• Methods: Review of the literature.
• Results: Asthma self-management barriers experienced by African American adolescents are often related to developmental needs, lack of knowledge, and personal perspectives and experiences. Adolescents find managing their symptoms and adhering to prescriptive therapies a burden and desire to be more like healthy peers. As they struggle to identify with peers, they may engage in risky behaviors such as ignoring symptoms and delaying treatment, thus leading to poorer asthma control and health outcomes. African American adolescents struggle with perceptions of racial biases from health care providers and teachers that interfere with self-management behaviors. They also describe the influence of culturally based practices learned from caregivers that contribute to their misconceptions and inadequate skills in effectively managing their asthma.
• Conclusion: Researchers should seek to develop interventions to address the unique contextual and culturally based needs of African American adolescents that support the development of effective asthma self-management behaviors. This may include making use of family members (especially mothers) and extended support for self-management during this period of rapid growth and transition. Health care providers should consider a team-based approach to the adolescent patient. Such an approach should be grounded in recommendations from national guidelines that suggest a patient-centered approach to care that includes a partnership between the patient and the provider to address unique barriers to effective self-management.

Keywords: youth; caregiver; drug-therapy; self-efficacy; disease-management; patient-centered care.

Effective asthma self-management by urban African American adolescents is a critical aspect of care that should be addressed with vigilance due to the persistent disparities in disease prevalence, morbidity, and mortality compared to Caucasians.^1-3 The overarching goal of asthma self-management is to achieve symptom control, maintain normal activity levels, and minimize future risk of exacerbations and medication side effects.^4,5 Best practices for asthma self-management begin with a partnership between health care providers and clients (including parent/caregiver). This relationship should help affected individuals gain asthma control based on knowledge of their disease and treatment options, confidence and skills in trigger avoidance, medication administration, and management of acute exacerbations.^4,5

Among youth aged 18 years and younger, African Americans have the highest asthma prevalence rates of all racial and ethnic groups, and between 2001 and 2009 asthma prevalence rates rose by 50% among African American youth.⁶ As of 2015, prevalence rates for asthma among African American youth were 13.4%, as compared to 7.4% for white youth.⁷ African American youth have been found to have more frequent asthma exacerbations and related school absences than white youth.⁸ Furthermore, African American youth younger than 18 years are more likely to be admitted to the hospital for asthma and are 10 times more likely to die from asthma compared to non-Hispanic white children.⁶

Urban African American adolescents with asthma are particularly vulnerable to poor asthma self-management due to the complexity of the disease in this population.³ African American youth must deal with multiple adverse environmental conditions, lack of knowledge or disbelief concerning effective disease self-management strategies, variable access and quality of care, and the psychosocial dynamics of being young while having a chronic disease.^2,3,9-11 It is important to understand and address barriers to successful asthma self-management during adolescence, as behaviors developed during this stage of life often persist into adulthood.⁹ In this article, we review the literature on barriers to asthma self-management among African American adolescents and offer suggestions on clinical strategies for improving self-management in this vulnerable population.

 

 

Methods

The initial search strategy was developed in collaboration with an experienced librarian. Keywords, MeSH terms, and potential databases were identified. Keywords included urban, African American, adolescent, asthma, self-management, and barriers. These terms were expanded based on search results and a review of abstracts that fit the intent of our review. The search was limited to U.S. studies published between 2005 and 2017. Excluded from the search were conference abstracts, doctoral dissertations, master’s theses, meta-analyses, systematic reviews, and studies conducted outside of the United States. Additional articles for the review were identified during the review process from the reference lists of the publications.

Abstracts were reviewed for articles that reported a study population inclusive of African American adolescents with asthma and that were related to self-management. Studies that used qualitative and other descriptive methods and cohort and randomized control trials were reviewed. Due to the limited number of articles found that exclusively focused on African Americans, the authors set a threshold for African American participants at 40% or greater for inclusion in this review.

Full papers were retrieved that met the inclusion criteria for a full review. Each author initially independently reviewed a selected number of papers and abstracted the study purpose, sample, study design, results, conclusions, and limitations. Subsequently, both authors reviewed in tandem and then discussed each selected manuscript to assure the appropriateness for inclusion. The subject matter was considered the priority for inclusion in the review. Study methods, sample size, and noted limitations were categorized but were not considered as a basis for exclusion. Thematic analysis was used to identify common themes across studies.

 

 

Results

We identified 23 papers that met our criteria (Table). Five common themes were found that related to barriers in disease self-management for African American adolescents: (a) knowledge and skills, (b) beliefs and attitudes, (c) personal/emotional factors, (d) caregivers, and (e) schools.

 

 

Knowledge and Skills

Adequate knowledge of the elements of asthma self-management is critical for achieving control of this condition. Asthma knowledge includes a basic understanding of the disease process and treatment strategies, an awareness of early signs and symptoms of worsening asthma, and an understanding of how to manage environmental triggers.^4,5 Sin and colleagues conducted one of the earlier studies to examine the influence of asthma knowledge on asthma self-management in African American adolescents and found a significant positive association between knowledge and asthma self-management behaviors.¹²

Adherence to an asthma medication, especially inhaled corticosteroids (ICS), is one of the cornerstones to successful self-management of asthma.^13,14 Consistent use of ICS therapy to control asthma symptoms and disease progression is often suboptimal in African American adolescents and tends to worsen as they age;¹⁵ studies have found lower adherence levels were more prominent in older African American adolescents and males.^13,16 In a recent study of adolescents with persistent asthma who were prescribed daily ICS, youth with greater ICS knowledge as assessed using a standardized instrument demonstrated significantly higher adherence rates.¹³ Proper technique in the use of an inhaler is also important in medication administration. Asthma ICS medication delivery devices vary significantly and require different techniques for medication administration. However, inhaler device skills have been found to be very inadequate in high-risk African American adolescents.¹⁷ Thus, knowledge related to ICS therapy and proper skills in the use of inhaler devices is an important aspect of asthma self-management that have been found to be inadequate in African American Adolescents.

Interventions and programs geared to improving education may lead to improved self-management. Multisystemic Therapy-Health Care (MST-HC) is a tailored home-based intervention that includes knowledge and skill-building components. In a study of African American youth with poorly controlled asthma, the program was found to improve illness management.¹⁸ In addition, adolescents who complete formal asthma education programs demonstrate significantly higher scores in self-management than those youth who do not participate in these programs.^13,19 Unfortunately, few African American teens report participation in an asthma education program.¹⁹ In a study of a motivational interviewing intervention to improve controller medication adherence for African American adolescents,¹⁴ youth reported gaining more knowledge about their asthma medications and were significantly more motivated to take their controller medications after participating in the intervention; however, while adherence to controller medications was greater than baseline, it was not significantly different.¹⁴ This study demonstrated the value of asthma education and the feasibility of a motivational intervention to support controller medication adherence. However, this study also demonstrated the complexity of medication adherence in that neither knowledge or motivation led to significant changes in medication adherence among African American adolescents.

Low health literacy can also act as a barrier to asthma self-management. Health literacy requires skills and knowledge that enable an individual to communicate, process, and understand basic health information that informs health decisions.²⁰ Health literacy was found to be associated with indicators of poor disease self-management among urban African American adolescents in grades 9 through 12.²¹ In this study, health literacy was established using questions about confidence in filling out medical forms, self-reported problems with learning about the youth’s medical condition, and the need for assistance in reading hospital materials. Adolescents with poor health literacy scores were more likely to reside in a household with the following characteristics: mother with less than a high school education, Medicaid health insurance, family members with a body mass index exceeding the 85th percentile, and lack of rescue medication. Poor health literacy was most common among younger adolescents (ie, ninth graders). Some youth with poor health literacy also reported more emergency department visits, hospitalizations, and lower overall quality of life.²¹

Beliefs and Attitudes

Beliefs and attitudes towards taking asthma medications can act as barriers to adherence in the adolescent. African American adolescents often report the belief that ICS are not helpful or necessary.^16,22-25 These beliefs have been correlated with a lack of understanding of the inflammatory mechanisms of asthma, reports of asthma attacks despite use of controller medications, fear of addiction to medications, and a belief that nontraditional interventions (eg, exercise) will work better to get rid of asthma or abate symptoms.^16-19,22-24 African American adolescents also report beliefs that asthma will go away or get better as they age, and they are willing to forgo the use of controller medications based on these beliefs.²⁴

African American adolescents often engage in asthma self-management independent of caregivers. These youth describe asthma self-management activities an annoyance and of low priority in part due to competing tasks and negative interactions with caregivers.²⁵ During early adolescence asthma self-management is often suboptimal, and as youth age they become less observant regarding their asthma and are less likely to seek help.²⁶ Adolescents’ beliefs and low prioritization of asthma self-management may contribute to forgetfulness and loss of inhalers, which are common reasons reported for poor adherence to ICS.^16,23-26 Further, the role of caregivers during this period has often been overlooked. Caregivers of African American adolescents have been found to be stressed and overwhelmed with personal responsibilities and neighborhood conditions, leaving them little time to attend to the asthma self-management behavior of youth. Due to these contextual factors, interactions with chronically ill youth may be strained, resulting in negative interactions with youth related to asthma self-management. However, in an intervention study that used multisystemic therapy (an approach that targets the affected individual, family, and community), improvement in positive parenting behaviors related to asthma self-management contributed to improved ICS adherence by adolescents.²⁷

Adolescents can perceive traditional asthma self-management as conflicting with their own personal and/or cultural beliefs. They may seek options beyond the use of medicine and have voiced preferences for behaviors that they believe will “strengthen their lungs” more naturally.²⁴ An appreciation of how youth might use complementary/alternative medicine (CAM) as an adjunctive therapy or in place of evidence-based asthma care is important to understanding the potential effect on morbidity and mortality. Behaviors and beliefs about the use of CAM have not been well studied among urban African American adolescents with asthma. Only one study was found that assessed the use of CAM among a primarily urban African American adolescent population. In that study, 71% of the population reported using some form of CAM during the past 30 days.²⁸ Prayer and relaxation were the most frequently used strategies in the management of asthma symptoms. Perceived efficacy of relaxation and prayer among teens who engaged in this form of CAM was 87% and 85%, respectively. Other CAM strategies included yoga, meditation, guided imagery, and biofeedback. When adolescents were asked if they shared their use of CAM in asthma management with a health care provider, most reported sharing the use of yoga and dietary changes but were least likely to share their use of prayer and guided imagery.²⁸

Personal/Emotional Factors

African American adolescents have reported asthma as a limiting factor in terms of both physical and social activities. They perceive asthma as a burden to themselves and others (eg, peers, family, coaches).^9,25 The burden of asthma is further exemplified in the emotional response to the symptoms of the disease and the self-management responsibilities. The need to prevent and respond to asthma symptoms is associated with being embarrassed, frustrated, angry, annoyed, worried, lonely, and isolated.^9,11,25 Negative coping strategies by youth in response to psychosocial experiences include decisions to disregard or give minimal attention to asthma symptoms and to delay or not take prescribed medications. Students report ignoring asthma symptom management while engaging in physical activities to maintain a sense of normalcy among peers and as a way of dealing with perceptions by coaches or teachers that they are weak or in need of being protected.^24,25

Negative thoughts and experiences can result in depressive disorders and poor quality of life. Depression is a common finding among urban youth with asthma.^29,30 Youth diagnosed with asthma who have comorbid depression may benefit from interventions to improve self-management. In a secondary analysis from a Web-based asthma management intervention targeting African American adolescents, depression was found to have a modifying effect on the emotional domain of quality of life for youth in the intervention arm of the study. This finding indicates that participants who were depressed and who reported low levels of emotional quality of life benefited from the Web-based interventions that targeted self-management.³¹

Caregivers

Caregivers (especially moms) are a common source of support for the development and implementation of asthma self-management behaviors in adolescents.³² Caregivers sometimes hold beliefs similar to those of youth and believe the urban environment can act as a barrier to asthma management.^9,25,32 They describe the complexity of asthma treatment plans, a lack of understanding of the disease process, and insensitivity of health care providers to their expressed needs along with the providers’ limited cultural awareness in the development of self-management plans.^9,22,33 Caregivers describe how family finances, insurance gaps, access to care, and their own familial/cultural beliefs influence their decisions and ability to support their child’s asthma management.³³ When faced with the cost of care they report instances of having to decide between necessities such as food and housing or co-pays for medications and office visits.^22,33 They also report concerns about visits with multiple providers due to an inability to access their primary care provider, which can lead to delays in their child being diagnosed with asthma.²²

Caregivers report a need to include culturally based practices, past experiences, and personal beliefs into the adolescents’ asthma management plan.^22,32,33 In a small interview-based study of caregivers residing in 3 New Jersey public housing communities, caregivers reported preferring “familial” methods of controlling asthma (eg, restriction of activities; use of showers, steam, vaporizers, and nebulizers) over evidence-based recommendations. Many caregivers were confused or lacked knowledge about asthma action plans.³³ Caregivers have also been found to lack adequate or accurate knowledge related to asthma medications and factors that improved or worsened asthma. While caregivers report a desire to help educate their teens by passing on what they know, their lack of adequate asthma knowledge may hamper their efforts and potentially worsen the teens’ asthma self-management.³²

While African American caregivers often describe themselves as hypervigilant concerning their child’s asthma, they may report different information than their adolescent when both are questioned about asthma symptom experiences and functional status.³⁴ Factors increasing the level of congruence between caregiver and teen asthma symptom reports were found to be related to the adolescents’ age and asthma disease classification. Symptom questionnaire responses of older teens and those with mild intermittent asthma were more likely to be similar to caregiver reports. The researchers concluded that clinicians and researchers may obtain reliable asthma symptom and functional status reports by asking the adolescent directly.³⁴

Schools

Caregivers and adolescents describe schools as a threat to self-management and the overall health of youth with asthma.^9,32 They perceive that a lack of knowledge by staff, teachers, and coaches contributes to inattentiveness or disbelief in the credibility of reported asthma symptoms by youth.^11,23 These misperceptions and the lack of attentiveness by adults in the school may pose safety and health issues for African American youth.^9,25,33,34 For example, adolescents report pressure from teacher, coaches, and peers in school settings to partake in sports and/or gym classes. Youth want to identify with healthy peers and thus often choose not to take asthma medications during such activities or opt to continue participating while being compromised by airway obstruction. Of great concern were reports by caregivers and teens of not being allowed to call a parent for support or retrieve their medications when needed for asthma symptoms.³²

Future Research and Practice Implications

In this review, we identified 5 common themes around barriers to asthma self-management for African American adolescents (knowledge and skills, beliefs and attitudes, personal/emotional factors, caregivers, and schools). Caregivers, especially mothers, play a pivotal role in the development of effective asthma self-management behaviors. Depsite good intentions, there is evidence of caregivers passing on ineffective experiential and culturally based beliefs and practices to their adolescents that can negatively influence self-care behaviors.^13,28,38 Studies are needed to further investigate these findings among caregivers as their beliefs and practices for asthma self-management have been found to coexist among adolescents. Studies that investigate how to incorporate caregiver asthma knowledge, cultural beliefs and behaviors in developing self-management interventions have the potential to positively influence asthma outcomes among African American adolescents.²⁷ The unique cultural beliefs, contextual environmental, and social disparities faced by African American caregivers should not be neglected.

African American adolescents, like adolescents in other racial or ethnic groups, desire to be autonomous in their asthma self-management. However, as adolescents age their adherence behaviors often decline. This may suggest a need for a longer transition period to self-management that extends into emerging adulthood (18-25 years). While youth want to feel supported, there appears to be a fine line between receiving needed support and what youth describe as “nagging” behaviors by adults. Additional investigations into how asthma responsibilities are transitioned from the parent to youth and how best to support the development and maintenance of related behaviors and skills are warranted. In addition, teens described problems related to communicating with health care providers, noting a lack of clarity in explanations received about how to manage their asthma. Some teens believed the communication challenges were based on beliefs and biases held by providers that African American youth had limited capacities for self-management.⁹ There is a need to better understand interactions among African American adolescents, parents, and clinicians so that communication and transitioning asthma care to the youth will produce optimal health outcomes.

According to asthma guidelines, the patient-provider relationship is essential to effective asthma self-management.^4,5 However, there is little mention in the literature of team-based care. Clinicians such as physicians, physician assistants, and nurse practitioners provide direct care to adolescents in terms of disease management and the overall effectiveness of treatment plans. African American youth demonstrate a need for asthma education that is comprehensive and that is contextualized to their daily lives. A team-based approach to care that includes social workers and community health workers may help to extend the reach of clinicians. Follow-up times with families and youth between office visits can be used to support adolescents to develop asthma self-management and allow them a safe space to describe frustrations and other emotions that contribute to their desire to be disease-free.

Summary

Asthma is a chronic disease that is often more severe and difficult to manage in African American adolescents. While African American adolescents describe developmental needs like those of other youth, cultural beliefs and contextual experiences influence their self-care management in unique ways. Opportunities exist to better understand the needs of African American adolescents and to help them successfully gain the knowledge, skills, and behaviors needed to effectively engage in self-management of their asthma.

Corresponding author: Wanda Gibson-Scipio, PhD, FNP-BC, FAANP, 5557 Cass Ave., 346 Cohn Building, Detroit, MI 48324; [email protected].

Financial disclosures: None.

From Wayne State University, Detroit, MI (Dr. Gibson-Scipio), and the University of Texas Rio Grande Valley, Edinburg, TX (Dr. Krouse).

Abstract

• Objective: To review the literature on barriers to asthma self-management among African American adolescents.
• Methods: Review of the literature.
• Results: Asthma self-management barriers experienced by African American adolescents are often related to developmental needs, lack of knowledge, and personal perspectives and experiences. Adolescents find managing their symptoms and adhering to prescriptive therapies a burden and desire to be more like healthy peers. As they struggle to identify with peers, they may engage in risky behaviors such as ignoring symptoms and delaying treatment, thus leading to poorer asthma control and health outcomes. African American adolescents struggle with perceptions of racial biases from health care providers and teachers that interfere with self-management behaviors. They also describe the influence of culturally based practices learned from caregivers that contribute to their misconceptions and inadequate skills in effectively managing their asthma.
• Conclusion: Researchers should seek to develop interventions to address the unique contextual and culturally based needs of African American adolescents that support the development of effective asthma self-management behaviors. This may include making use of family members (especially mothers) and extended support for self-management during this period of rapid growth and transition. Health care providers should consider a team-based approach to the adolescent patient. Such an approach should be grounded in recommendations from national guidelines that suggest a patient-centered approach to care that includes a partnership between the patient and the provider to address unique barriers to effective self-management.

Keywords: youth; caregiver; drug-therapy; self-efficacy; disease-management; patient-centered care.

Effective asthma self-management by urban African American adolescents is a critical aspect of care that should be addressed with vigilance due to the persistent disparities in disease prevalence, morbidity, and mortality compared to Caucasians.^1-3 The overarching goal of asthma self-management is to achieve symptom control, maintain normal activity levels, and minimize future risk of exacerbations and medication side effects.^4,5 Best practices for asthma self-management begin with a partnership between health care providers and clients (including parent/caregiver). This relationship should help affected individuals gain asthma control based on knowledge of their disease and treatment options, confidence and skills in trigger avoidance, medication administration, and management of acute exacerbations.^4,5

Among youth aged 18 years and younger, African Americans have the highest asthma prevalence rates of all racial and ethnic groups, and between 2001 and 2009 asthma prevalence rates rose by 50% among African American youth.⁶ As of 2015, prevalence rates for asthma among African American youth were 13.4%, as compared to 7.4% for white youth.⁷ African American youth have been found to have more frequent asthma exacerbations and related school absences than white youth.⁸ Furthermore, African American youth younger than 18 years are more likely to be admitted to the hospital for asthma and are 10 times more likely to die from asthma compared to non-Hispanic white children.⁶

Urban African American adolescents with asthma are particularly vulnerable to poor asthma self-management due to the complexity of the disease in this population.³ African American youth must deal with multiple adverse environmental conditions, lack of knowledge or disbelief concerning effective disease self-management strategies, variable access and quality of care, and the psychosocial dynamics of being young while having a chronic disease.^2,3,9-11 It is important to understand and address barriers to successful asthma self-management during adolescence, as behaviors developed during this stage of life often persist into adulthood.⁹ In this article, we review the literature on barriers to asthma self-management among African American adolescents and offer suggestions on clinical strategies for improving self-management in this vulnerable population.

 

 

Methods

The initial search strategy was developed in collaboration with an experienced librarian. Keywords, MeSH terms, and potential databases were identified. Keywords included urban, African American, adolescent, asthma, self-management, and barriers. These terms were expanded based on search results and a review of abstracts that fit the intent of our review. The search was limited to U.S. studies published between 2005 and 2017. Excluded from the search were conference abstracts, doctoral dissertations, master’s theses, meta-analyses, systematic reviews, and studies conducted outside of the United States. Additional articles for the review were identified during the review process from the reference lists of the publications.

Abstracts were reviewed for articles that reported a study population inclusive of African American adolescents with asthma and that were related to self-management. Studies that used qualitative and other descriptive methods and cohort and randomized control trials were reviewed. Due to the limited number of articles found that exclusively focused on African Americans, the authors set a threshold for African American participants at 40% or greater for inclusion in this review.

Full papers were retrieved that met the inclusion criteria for a full review. Each author initially independently reviewed a selected number of papers and abstracted the study purpose, sample, study design, results, conclusions, and limitations. Subsequently, both authors reviewed in tandem and then discussed each selected manuscript to assure the appropriateness for inclusion. The subject matter was considered the priority for inclusion in the review. Study methods, sample size, and noted limitations were categorized but were not considered as a basis for exclusion. Thematic analysis was used to identify common themes across studies.

 

 

Results

We identified 23 papers that met our criteria (Table). Five common themes were found that related to barriers in disease self-management for African American adolescents: (a) knowledge and skills, (b) beliefs and attitudes, (c) personal/emotional factors, (d) caregivers, and (e) schools.

 

 

Knowledge and Skills

Adequate knowledge of the elements of asthma self-management is critical for achieving control of this condition. Asthma knowledge includes a basic understanding of the disease process and treatment strategies, an awareness of early signs and symptoms of worsening asthma, and an understanding of how to manage environmental triggers.^4,5 Sin and colleagues conducted one of the earlier studies to examine the influence of asthma knowledge on asthma self-management in African American adolescents and found a significant positive association between knowledge and asthma self-management behaviors.¹²

Adherence to an asthma medication, especially inhaled corticosteroids (ICS), is one of the cornerstones to successful self-management of asthma.^13,14 Consistent use of ICS therapy to control asthma symptoms and disease progression is often suboptimal in African American adolescents and tends to worsen as they age;¹⁵ studies have found lower adherence levels were more prominent in older African American adolescents and males.^13,16 In a recent study of adolescents with persistent asthma who were prescribed daily ICS, youth with greater ICS knowledge as assessed using a standardized instrument demonstrated significantly higher adherence rates.¹³ Proper technique in the use of an inhaler is also important in medication administration. Asthma ICS medication delivery devices vary significantly and require different techniques for medication administration. However, inhaler device skills have been found to be very inadequate in high-risk African American adolescents.¹⁷ Thus, knowledge related to ICS therapy and proper skills in the use of inhaler devices is an important aspect of asthma self-management that have been found to be inadequate in African American Adolescents.

Interventions and programs geared to improving education may lead to improved self-management. Multisystemic Therapy-Health Care (MST-HC) is a tailored home-based intervention that includes knowledge and skill-building components. In a study of African American youth with poorly controlled asthma, the program was found to improve illness management.¹⁸ In addition, adolescents who complete formal asthma education programs demonstrate significantly higher scores in self-management than those youth who do not participate in these programs.^13,19 Unfortunately, few African American teens report participation in an asthma education program.¹⁹ In a study of a motivational interviewing intervention to improve controller medication adherence for African American adolescents,¹⁴ youth reported gaining more knowledge about their asthma medications and were significantly more motivated to take their controller medications after participating in the intervention; however, while adherence to controller medications was greater than baseline, it was not significantly different.¹⁴ This study demonstrated the value of asthma education and the feasibility of a motivational intervention to support controller medication adherence. However, this study also demonstrated the complexity of medication adherence in that neither knowledge or motivation led to significant changes in medication adherence among African American adolescents.

Low health literacy can also act as a barrier to asthma self-management. Health literacy requires skills and knowledge that enable an individual to communicate, process, and understand basic health information that informs health decisions.²⁰ Health literacy was found to be associated with indicators of poor disease self-management among urban African American adolescents in grades 9 through 12.²¹ In this study, health literacy was established using questions about confidence in filling out medical forms, self-reported problems with learning about the youth’s medical condition, and the need for assistance in reading hospital materials. Adolescents with poor health literacy scores were more likely to reside in a household with the following characteristics: mother with less than a high school education, Medicaid health insurance, family members with a body mass index exceeding the 85th percentile, and lack of rescue medication. Poor health literacy was most common among younger adolescents (ie, ninth graders). Some youth with poor health literacy also reported more emergency department visits, hospitalizations, and lower overall quality of life.²¹

Beliefs and Attitudes

Beliefs and attitudes towards taking asthma medications can act as barriers to adherence in the adolescent. African American adolescents often report the belief that ICS are not helpful or necessary.^16,22-25 These beliefs have been correlated with a lack of understanding of the inflammatory mechanisms of asthma, reports of asthma attacks despite use of controller medications, fear of addiction to medications, and a belief that nontraditional interventions (eg, exercise) will work better to get rid of asthma or abate symptoms.^16-19,22-24 African American adolescents also report beliefs that asthma will go away or get better as they age, and they are willing to forgo the use of controller medications based on these beliefs.²⁴

African American adolescents often engage in asthma self-management independent of caregivers. These youth describe asthma self-management activities an annoyance and of low priority in part due to competing tasks and negative interactions with caregivers.²⁵ During early adolescence asthma self-management is often suboptimal, and as youth age they become less observant regarding their asthma and are less likely to seek help.²⁶ Adolescents’ beliefs and low prioritization of asthma self-management may contribute to forgetfulness and loss of inhalers, which are common reasons reported for poor adherence to ICS.^16,23-26 Further, the role of caregivers during this period has often been overlooked. Caregivers of African American adolescents have been found to be stressed and overwhelmed with personal responsibilities and neighborhood conditions, leaving them little time to attend to the asthma self-management behavior of youth. Due to these contextual factors, interactions with chronically ill youth may be strained, resulting in negative interactions with youth related to asthma self-management. However, in an intervention study that used multisystemic therapy (an approach that targets the affected individual, family, and community), improvement in positive parenting behaviors related to asthma self-management contributed to improved ICS adherence by adolescents.²⁷

Adolescents can perceive traditional asthma self-management as conflicting with their own personal and/or cultural beliefs. They may seek options beyond the use of medicine and have voiced preferences for behaviors that they believe will “strengthen their lungs” more naturally.²⁴ An appreciation of how youth might use complementary/alternative medicine (CAM) as an adjunctive therapy or in place of evidence-based asthma care is important to understanding the potential effect on morbidity and mortality. Behaviors and beliefs about the use of CAM have not been well studied among urban African American adolescents with asthma. Only one study was found that assessed the use of CAM among a primarily urban African American adolescent population. In that study, 71% of the population reported using some form of CAM during the past 30 days.²⁸ Prayer and relaxation were the most frequently used strategies in the management of asthma symptoms. Perceived efficacy of relaxation and prayer among teens who engaged in this form of CAM was 87% and 85%, respectively. Other CAM strategies included yoga, meditation, guided imagery, and biofeedback. When adolescents were asked if they shared their use of CAM in asthma management with a health care provider, most reported sharing the use of yoga and dietary changes but were least likely to share their use of prayer and guided imagery.²⁸

Personal/Emotional Factors

African American adolescents have reported asthma as a limiting factor in terms of both physical and social activities. They perceive asthma as a burden to themselves and others (eg, peers, family, coaches).^9,25 The burden of asthma is further exemplified in the emotional response to the symptoms of the disease and the self-management responsibilities. The need to prevent and respond to asthma symptoms is associated with being embarrassed, frustrated, angry, annoyed, worried, lonely, and isolated.^9,11,25 Negative coping strategies by youth in response to psychosocial experiences include decisions to disregard or give minimal attention to asthma symptoms and to delay or not take prescribed medications. Students report ignoring asthma symptom management while engaging in physical activities to maintain a sense of normalcy among peers and as a way of dealing with perceptions by coaches or teachers that they are weak or in need of being protected.^24,25

Negative thoughts and experiences can result in depressive disorders and poor quality of life. Depression is a common finding among urban youth with asthma.^29,30 Youth diagnosed with asthma who have comorbid depression may benefit from interventions to improve self-management. In a secondary analysis from a Web-based asthma management intervention targeting African American adolescents, depression was found to have a modifying effect on the emotional domain of quality of life for youth in the intervention arm of the study. This finding indicates that participants who were depressed and who reported low levels of emotional quality of life benefited from the Web-based interventions that targeted self-management.³¹

Caregivers

Caregivers (especially moms) are a common source of support for the development and implementation of asthma self-management behaviors in adolescents.³² Caregivers sometimes hold beliefs similar to those of youth and believe the urban environment can act as a barrier to asthma management.^9,25,32 They describe the complexity of asthma treatment plans, a lack of understanding of the disease process, and insensitivity of health care providers to their expressed needs along with the providers’ limited cultural awareness in the development of self-management plans.^9,22,33 Caregivers describe how family finances, insurance gaps, access to care, and their own familial/cultural beliefs influence their decisions and ability to support their child’s asthma management.³³ When faced with the cost of care they report instances of having to decide between necessities such as food and housing or co-pays for medications and office visits.^22,33 They also report concerns about visits with multiple providers due to an inability to access their primary care provider, which can lead to delays in their child being diagnosed with asthma.²²

Caregivers report a need to include culturally based practices, past experiences, and personal beliefs into the adolescents’ asthma management plan.^22,32,33 In a small interview-based study of caregivers residing in 3 New Jersey public housing communities, caregivers reported preferring “familial” methods of controlling asthma (eg, restriction of activities; use of showers, steam, vaporizers, and nebulizers) over evidence-based recommendations. Many caregivers were confused or lacked knowledge about asthma action plans.³³ Caregivers have also been found to lack adequate or accurate knowledge related to asthma medications and factors that improved or worsened asthma. While caregivers report a desire to help educate their teens by passing on what they know, their lack of adequate asthma knowledge may hamper their efforts and potentially worsen the teens’ asthma self-management.³²

While African American caregivers often describe themselves as hypervigilant concerning their child’s asthma, they may report different information than their adolescent when both are questioned about asthma symptom experiences and functional status.³⁴ Factors increasing the level of congruence between caregiver and teen asthma symptom reports were found to be related to the adolescents’ age and asthma disease classification. Symptom questionnaire responses of older teens and those with mild intermittent asthma were more likely to be similar to caregiver reports. The researchers concluded that clinicians and researchers may obtain reliable asthma symptom and functional status reports by asking the adolescent directly.³⁴

Schools

Caregivers and adolescents describe schools as a threat to self-management and the overall health of youth with asthma.^9,32 They perceive that a lack of knowledge by staff, teachers, and coaches contributes to inattentiveness or disbelief in the credibility of reported asthma symptoms by youth.^11,23 These misperceptions and the lack of attentiveness by adults in the school may pose safety and health issues for African American youth.^9,25,33,34 For example, adolescents report pressure from teacher, coaches, and peers in school settings to partake in sports and/or gym classes. Youth want to identify with healthy peers and thus often choose not to take asthma medications during such activities or opt to continue participating while being compromised by airway obstruction. Of great concern were reports by caregivers and teens of not being allowed to call a parent for support or retrieve their medications when needed for asthma symptoms.³²

Future Research and Practice Implications

In this review, we identified 5 common themes around barriers to asthma self-management for African American adolescents (knowledge and skills, beliefs and attitudes, personal/emotional factors, caregivers, and schools). Caregivers, especially mothers, play a pivotal role in the development of effective asthma self-management behaviors. Depsite good intentions, there is evidence of caregivers passing on ineffective experiential and culturally based beliefs and practices to their adolescents that can negatively influence self-care behaviors.^13,28,38 Studies are needed to further investigate these findings among caregivers as their beliefs and practices for asthma self-management have been found to coexist among adolescents. Studies that investigate how to incorporate caregiver asthma knowledge, cultural beliefs and behaviors in developing self-management interventions have the potential to positively influence asthma outcomes among African American adolescents.²⁷ The unique cultural beliefs, contextual environmental, and social disparities faced by African American caregivers should not be neglected.

African American adolescents, like adolescents in other racial or ethnic groups, desire to be autonomous in their asthma self-management. However, as adolescents age their adherence behaviors often decline. This may suggest a need for a longer transition period to self-management that extends into emerging adulthood (18-25 years). While youth want to feel supported, there appears to be a fine line between receiving needed support and what youth describe as “nagging” behaviors by adults. Additional investigations into how asthma responsibilities are transitioned from the parent to youth and how best to support the development and maintenance of related behaviors and skills are warranted. In addition, teens described problems related to communicating with health care providers, noting a lack of clarity in explanations received about how to manage their asthma. Some teens believed the communication challenges were based on beliefs and biases held by providers that African American youth had limited capacities for self-management.⁹ There is a need to better understand interactions among African American adolescents, parents, and clinicians so that communication and transitioning asthma care to the youth will produce optimal health outcomes.

According to asthma guidelines, the patient-provider relationship is essential to effective asthma self-management.^4,5 However, there is little mention in the literature of team-based care. Clinicians such as physicians, physician assistants, and nurse practitioners provide direct care to adolescents in terms of disease management and the overall effectiveness of treatment plans. African American youth demonstrate a need for asthma education that is comprehensive and that is contextualized to their daily lives. A team-based approach to care that includes social workers and community health workers may help to extend the reach of clinicians. Follow-up times with families and youth between office visits can be used to support adolescents to develop asthma self-management and allow them a safe space to describe frustrations and other emotions that contribute to their desire to be disease-free.

Summary

Asthma is a chronic disease that is often more severe and difficult to manage in African American adolescents. While African American adolescents describe developmental needs like those of other youth, cultural beliefs and contextual experiences influence their self-care management in unique ways. Opportunities exist to better understand the needs of African American adolescents and to help them successfully gain the knowledge, skills, and behaviors needed to effectively engage in self-management of their asthma.

Corresponding author: Wanda Gibson-Scipio, PhD, FNP-BC, FAANP, 5557 Cass Ave., 346 Cohn Building, Detroit, MI 48324; [email protected].

Financial disclosures: None.

From the University of Arizona College of Medicine, Tucson, AZ (Dr. Beatty), and the Baylor College of Medicine, Houston, TX (Dr. Mohajer).

Abstract

• Objective: To review management issues regarding health care–associated urinary tract infections (UTIs) commonly encountered by practicing clinicians.
• Methods: Review of the literature.
• Results: Because urinary catheter (UC) placement plays a major role in the development of catheter-associated UTIs (CA-UTI), clinicians should be aware of the appropriate and inappropriate uses of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key to preventing CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. Percutaneous nephrostomy and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected. Candiduria rarely leads to symptoms unless it is related to an ascending process. Proper urine collection is crucial in determining whether contamination, colonization, or infection is present. Fluconazole is recommended in most cases of Candida UTI, while intravenous amphotericin B is recommended for fluconazole-resistant Candida species.
• Conclusion: Continued use of evidence-based strategies for preventing and managing health care–associated UTI should lead to further improvements in patient outcomes and overall decreased rates of infection.

Keywords: bacteriuria; catheter-associated UTI; catheterization; percutaneous nephrostomy; candiduria.

Health care–associated urinary tract infections (UTIs) are estimated to be the most common adverse infectious event in U.S. hospitals, occurring in 1 of 10 admitted patients.^1-3 Approximately 32% of all health care–associated infections are UTIs.¹ Furthermore, urinary catheters (UCs) are associated with 8% to 21% of health care–associated infections that occur in the intensive care unit.⁴ The most important predisposing factor for nosocomial UTI is urinary catheterization.⁵ Genitourinary manipulation and/or implementation also play a major role in the development of nosocomial UTIs.

In 2008, the U.S. Centers for Medicare & Medicaid Services instituted a new policy that reduced reimbursement rates for hospitalizations linked to health care–associated infections.⁶ Indwelling UCs are among the most overused health care devices in the hospital setting. They are placed in an estimated 15% to 25% of all hospitalized patients,^7,8 and are often inserted in the emergency department (ED) without a physician order or appropriate indication.⁹ Intermittent straight catheterization, male or female condom catheterization, and/or placement of an indwelling UC are the most common causes of catheter-associated asymptomatic bacteriuria (CA-ASB) and catheter-associated UTIs (CA-UTI).⁵ Prevention and management of CA-ASB and CA-UTI can be challenging and require an evidence-based approach. Furthermore, guidelines for the management of UTIs in the setting of active percutaneous nephrostomy (PCN) drainage and/or ureteral stenting are not established.⁵ This may leave clinicians with little mainstream data to aid in management decisions.

In 2009 the Centers for Disease Control and Prevention provided a guideline for the appropriate and inappropriate use of indwelling UCs to help promote their proper use.¹⁰ In the time since the guideline’s initiatives were instituted around the United States, published data have shown some improvement in the use of UCs,^11,12 but other recent reports indicate that rates of UC use have remained unchanged.¹³ This review discusses management issues regarding health care–associated UTIs that are commonly encountered by practicing clinicians, with a focus on current guidelines and evidence.

Catheter-Associated UTI

CA-UTI is defined as the presence of signs or symptoms of UTI with no other explainable infectious source along with ≥ 1000 colony-forming units (cfu) of ≥ 1 bacterial species per milliliter in a urine specimen from a catheter that has been changed within 48 hours of collection of the urine specimen.⁵ Signs and symptoms of CA-UTI include, but are not limited to: new-onset or worsening fever, chills, altered sensorium from baseline, lethargy, malaise, flank pain, pelvic pain, costovertebral angle tenderness, and acute hematuria.⁵ New-onset “foul-smelling” (odorous)urine and “cloudy” urine are neither sensitive nor specific when assessing for CA-UTI, and do not have significant clinical relevance when found alone.^14,15 Patients who have removed or exchanged the UC during this event and then experience dysuria, increased frequency, urgency, or suprapubic pain are likely having symptoms of CA-UTI.⁵

What is the recommended method for collecting urine samples when CA-UTI is suspected?

In a patient with an indwelling catheter that has been in place for more than 2 weeks at the onset of a suspected CA-UTI, the catheter should be replaced (if still indicated) or removed to accelerate resolution of symptoms and to reduce the risk of subsequent catheter-associated bacteriuria and CA-UTI. The urine culture should be acquired from the freshly placed UC.⁵

When should a patient be empirically treated?

A patient presenting with evidence of sepsis should be empirically treated with antimicrobials. Empiric coverage should be based on risk factors for multidrug-resistant organisms and data pertaining to local antimicrobial resistance patterns. A urine specimen for urinalysis and possible culture should be sent prior to administering empiric antibiotics (if possible) in a symptomatic patient.⁵

What bacteria are commonly associated with CA-UTI?

The bacteria most commonly associated with CA-UTI are found in or around the gastrointestinal and genitourinary tracts and also are part of the normal skin flora. The introduction and/or facilitated ascension of these microorganisms is believed to occur during UC insertion.^16,17 Two-thirds of all isolated uropathogens in those with indwelling UCs are extraluminally acquired (via ascension along the catheter-urethral mucosa interface), and one-third are believed to be intraluminally acquired.¹⁸

The most commonly isolated bacteria in CA-UTI are Enterobacteriaceae, which include Escherichia coli (most common), Klebsiella species (K. oxytoca, K. pneumoniae), Serratia species (S. marcescens), Citrobacter species (C. koseri), Enterobacter species (E. cloacae), and Proteus species; non-Enterobacteriaceae such as Pseudomonas species; and gram-positive cocci, which include coagulase-negative staphylococci (S. saprophyticus), Staphylococcus aureus, group B streptococci, and Enterococcus species (E. faecalis, E. faecium).^19-21 Coagulase-negative staphylococci and Enterococcus species can lead to CA-UTI but are usually avirulent and more commonly isolated from asymptomatic individuals.¹⁹ Also, coagulase-negative staphylococci such as S. epidermidis and S. lugdunensis are usually the manifestation of contamination during the collection process and their presence should prompt a repeat sample collection under sterile techniques. Monomicrobial infection is usually seen in those with short-term catheter use and CA-UTI. In contrast, polymicrobial infection is more common in those with long-term indwelling UCs and CA-UTI.¹⁹ Providencia stuartii, Proteus mirabilis, S. aureus, and Morganella morganii have all been associated with CA-UTI in those with long-term indwelling UCs.

Growth of S. aureus in the urine should prompt further investigation with blood cultures to explore the possibility of hematogenous dissemination to the urinary tract. Organisms leading to bacteremia due to CA-UTI are most commonly gram-negative bacilli (E. coli, Klebsiella species, Pseudomonas aeruginosa) and E. faecalis.²¹

What is the difference between CA-ASB and CA-UTI?

CA-ASB is defined as the presence of ≥ 1 bacteria species growing on urine culture at ≥ 100,000 cfu/mL in a patient with a history of urinary catheterization and/or indwelling UC who lacks signs or symptoms of UTI. In a man with a condom catheter, CA-ASB is defined using the same criteria, but the urine sample is collected after a fresh condom catheter is applied.⁵ The difference between CA-ASB and CA-UTI is simply the presence or absence of signs and symptoms related to UTI. Currently, there is no standard definition for significant bacteriuria in a catheterized patient.⁵ Pyuria found on urinalysis is indicative of genitourinary inflammation and can be present in both CA-ASB and CA-UTI. The absence, presence, and/or degree of pyuria in catheterized patients does not accurately differentiate between CA-ASB and CA-UTI.^5,22,23 On the other hand, the absence of pyuria in a symptomatic catheterized patient suggests an etiology other than CA-UTI.⁵

How can CA-UTI be prevented in patients with a short-term indwelling urinary catheter?

If a short-term UC is essential, the most important approach to preventing CA-UTI is limiting the duration of time it will be used. Strategies such as computer-based order entry and care maps with automated discontinuation of UCs have been shown to decrease catheter usage.¹⁹ Using closed-systems for UC collection with ports in the distal catheter for needle aspiration of urine has also been shown to decrease the incidence of CA-UTI.⁵ Securing the UC to avoid urethral trauma, aseptic techniques for insertion and repositioning, and placement of the tubing and collection bag below the level of the bladder to prevent reflux will likely also prevent CA-UTI, but these strategies have not been evaluated thoroughly.¹⁹

When should you screen for and treat CA-ASB?

The 2009 Infectious Diseases Society of America (IDSA) guidelines recommend that the only patients who should be screened and treated for CA-ASB are pregnant women and those who will undergo a potentially traumatic urologic procedure for which mucosal breaching may occur, causing bleeding. Routinely screening or treating patients for CA-ASB in not recommended in any other group of patients and will lead to unnecessary antibiotic use and antibiotic resistance.⁵

UTI Associated with Percutaneous Nephrostomy and Ureteral Stenting

Similar systemic symptoms of infection (fever, rigors, malaise, shock) are present in patients with and without percutaneous nephrostomy (PCN) and/or ureteral stent placement. Dysuria is not commonly present in those with PCN. The first signs of CA-UTI may be decreased urine output and pericatheter leakage due to an obstructive process resulting from the encrustation.^24-27 The most common complaint among patients with either acute or chronic ureteral stenting is discomfort, which has been described as “urinary symptoms” and “body pain.”²⁸ This discomfort can be related to ureteral hyperperistalsis after placement of the stent and is usually self-limiting. Ureteral stent migration, usually at the distal end, can also lead to discomfort, but is easily rectified with cystoscopy.²⁵ Body pain and/or urinary symptoms in the setting of ureteral stenting are not indicative of infection alone.

What is urinary catheter and/or ureteral stent encrustation?

Encrustation is the formation of a conditioning film that develops on the surface of the UC or ureteral stent. The exact mechanism is not well understood, but it is believed to involve electrostatic interactions of urinary proteins that stimulate binding onto the stent or UC surface.²⁵ Encrustation increases exponentially with the dwell time. Among patients with ureteral stents placed due to urolithiasis, encrustation occurred in 9.2% of stents removed prior to 6 weeks, 47.5% of stents removed at 6 weeks, and 76.3% of stents removed at 12 weeks.²⁶ Encrustation is most common at the proximal and distal ends (pigtails) of the ureteral stent and usually spares or presents last within the lumen.²⁹ Attempts have been made to prevent ureteral stent encrustation through the development of biodegradable, drug-eluting, and tissue-engineered substrates. These developments are promising, but currently there is limited observational data from large randomized trials to suggest that these new modalities decrease rates of encrustation.²⁵ Encrustation is highly associated with certain microorganisms, especially those that create biofilms.³⁰ Urease-producing bacteria, most commonly P. mirabilis, play a role in encrustation formation.³¹ Bacteria most commonly associated with encrustation include Proteus species (P. mirabilis is most common), P. aeruginosa, K. pneumoniae, Providencia species (P. stuartii is most common), and M. morganii.

Does ureteral stent bacterial colonization correlate with UTI?

Ureteral stent colonization with bacteria increases with dwell time and is found in 40% to 98.5% of stents placed.^32-35 If UTI is suspected in a patient with an active indwelling ureteral stent, a sample of urine should be cultured while the stent is in place.²⁵ Typically, genitourinary and normal skin flora pathogens are found when the ureteral stent is cultured. The top 3 organisms cultured from ureteral stents are S. aureus, P. aeruginosa, and E. faecalis.³⁴ Urine culture usually does not correlate with stent culture results, which has brought up the debate of how bacterial colonization occurs. It has been postulated that colonization is actually a manifestation of contamination during the insertion procedure, but this has yet to be validated.²⁵ In patients with symptoms of UTI in the setting of an indwelling ureteral stent, a positive culture has low sensitivity, with estimates between 21% and 40%.³⁵ Therefore, a negative urine culture does not rule out UTI alone in a symptomatic patient. Multiple studies have suggested that colonization of the ureteral stent does not correlate strongly with developing a UTI.^25,32-34

How can UTI be prevented in those receiving PCN or ureteral stent placement?

Antibiotic prophylaxis has been recommended to prevent UTI in patients who will undergo PCN or ureteral stent placement. The American Urological Association recommends empiric treatment even in the absence of signs and symptoms of UTI,³⁶ but substantial evidence is lacking that this approach prevents infection.³⁷ Ciprofloxacin or trimethoprim/sulfamethoxazole has been recommended by some for empiric coverage for enteric gram-negative bacilli and enterococcus in those undergoing genitourinary manipulation or instrumentation.^32,38 Most patients who develop CA-UTI and pyelonephritis do so within the first 2 to 6 weeks after placement.^37,39 Bacteriuria, candiduria, and/or pyuria are present in all patients approximately within 9 weeks even when sterile urine is confirmed prior to PCN placement.³⁹ Data on the effectiveness of antibiotic prophylaxis to prevent CA-UTI in those with PCN or ureteral stenting is limited. Currently, there are no recommendations from the IDSA on how to prevent infection in these situations.⁵ Early or frequent stent removal or exchanges has been proven to reduce UTI in those with ureteral stenting.³³ Patients with diabetes mellitus and chronic renal failure are at high-risk for UTI when ureteral stents are in place. This population should undergo close monitoring for UTI development and may warrant more frequent stent exchanges.^27,40

What is the treatment of CA-UTI associated with PCN and/or ureteral stenting?

The IDSA guidelines do not apply to patients with PCN and/or ureteral stenting.⁵ There is no treatment protocol for UTI related to these processes. Generally speaking, they are considered “complicated UTI” by most experts. Broad-spectrum, empiric antibiotic administration along with prompt removal of the PCN and/or ureteral stent is the gold standard of therapy.²⁷ The recommended duration of targeted antibiotic therapy is generally between 5 and 14 days.¹⁹ Most clinicians will treat this complicated UTI for at least 10 to 14 days. Antibiotic administration should be continued even after removal of the catheter and/or stent to complete the full course. Repeat urinalysis and culture is not indicated at the end of therapy if the patient is clinically improving or has remission of symptoms.

What is the exchange rate for those who require chronic PCN and/or ureteral stent use?

On average a PCN or ureteral stent should be exchanged every 2 to 3 months in patients who require chronic usage.^24,27 Some patients with persistent complications may require more frequent exchanges (< 10 weeks).²⁷ Encrustation and bacterial colonization become more prevalent the longer the devices are in place. This process is estimated to begin within the first 2 weeks after placement.^27,33,34 A “forgotten stent” is one that has been left in place after the patient is lost to follow-up. This unfortunate event can lead to massive encrustation, UTI, stent fracturing, and complete ureteral obstruction.²⁴ As noted, patients with diabetes mellitus, chronic renal failure, and frequent UTI may warrant more frequent exchanges, but this should be determined on a case-by-case basis.

 

 

Catheter-Associated UTI in Patients with Spinal Cord Injury

Spinal cord injury (SCI) at any level can cause neurogenic bladder. This process ultimately leads to urinary stasis and colonization of the bladder with bacteria. According to the IDSA, the acceptable indications for UC insertion are: clinically significant urinary retention (if medical therapy is not effective), urinary incontinence, accurate urine output monitoring required, and patient is unable and/or unwilling to collect urine (Table 1).⁵ Recently, further guidelines were published regarding appropriate and inappropriate indwelling UC placement in hospitalized medical patients (Table 2 and Table 3), expanding upon the earlier acceptable criteria provided by the IDSA.⁴¹ According to the IDSA and Ann Arbor Criteria for Appropriate Urinary Catheter Use, patients with SCI and subsequent neurogenic bladder without obstruction where intermittent bladder straight catheterization for the drainage of urine is not feasible will likely need an indwelling UC.⁴¹ SCI patients often experience decubitus ulcers, and an indwelling UC can be used if needed to help with wound healing if other urinary management alternatives have been attempted. Other such situations in which an indwelling UC can used before attempting alternative approaches would be in a patient who is actively dying and is pursuing comfort care and/or hospice.⁴¹

Which indwelling UCs should be used in patients with SCI?

Efforts to reduce the likelihood of infection in patients with SCI have led to several advances in the design and manufacturing of UCs. UCs are made of either latex, plastic, silicone, or polytetrafluoroethylene (Teflon). None of these substrates is free of complications, but of them latex UCs have been studied the most in regards to their associated complications. Aside from being allergenic in nature, latex UCs have an increased propensity to allow bacteria to adhere to their surface due to microscopic planes of unevenness.⁴² Silicone UCs are less frequently associated with infection but are more rigid, leading to increased discomfort.^43,44 Hydrophilic and silver-hydrogel coatings are innovative methods that have been developed to increase comfort and reduce the likelihood of infection. Hydrophilic-coated UCs are associated with reduced microbial adherence, decreased encrustation, and better patient satisfaction.^45,46 In SCI patients, these UCs have demonstrated lower complication rates, including UTI; fewer episodes of post-, intra-, and inter-catheterization bleeding; and decreased rates of antibiotic-resistant bacteria.^45,46 Silver-hydrogel-coated UCs are less well studied but have also demonstrated reduced UTI rates in SCI patients; however, their efficacy over the long term has yet to be determined. Antibiotic-impregnated UCs are not currently recommended for either short- or long-term indwelling UC use.⁵

How can CA-UTI be prevented in a patient who will require a long-term indwelling catheter?

At this time, the data is insufficient to make a recommendation on routine UC exchange (eg, every 2 to 4 weeks) in patients who require long-term indwelling urethral or suprapubic catheters in an attempt to reduce the risk of CA-ASB or CA-UTI. This is also true for those who experience even repeated early catheter blockage from encrustation.⁵ Thus, the rate at which these exchanges occur can be controversial, but typically around every 4 weeks is a common approach. Some would argue that if the patient has repeated CA-UTI, an exchange rate of every 2 weeks might be needed, but data is currently lacking to support this practice.⁵ If intermittent urinary catheterization is feasible, it should be done at least every 6 hours and before bedtime. In general, when the volume of urine in the bladder reaches approximately 400 mL, the patient should undergo bladder catheterization to prevent stasis and infection.⁴⁷ A closed drainage system is recommended in all patients who require long-term indwelling UC use.^48,49 Placement of the collection bag above the catheter or above the level of the bladder and a breach in the closed drainage system have been shown to result in higher rates of catheter-associated bacteriuria.^48,50 Proper hand hygiene and sterile and/or clean techniques should be used when placing or exchanging a UC. However, in one study there was no difference in bacteremia or UTIs when using sterile versus clean techniques.⁵¹

Asymptomatic bacteriuria should not be treated in patients with long-term indwelling UCs, and prophylactic antibiotics have led to the emergence of resistance.⁵² At this time it is not clear whether prophylactic weekly oral cyclic antibiotic administration can effectively reduce the frequency of CA-UTI in patients with SCI and chronic indwelling UC use.

What are the signs and symptoms of CA-UTI in a patient with SCI?

Subjective and objective findings may be limited when a patient with SCI presents with CA-UTI. These patients often lack the usual symptoms of UTI (dysuria, suprapubic discomfort, urgency, increased frequency) and pyelonephritis (flank pain, costovertebral angle tenderness). Caregivers and health care providers should be aware that nonspecific symptoms such as foul-smelling urine, pyuria, increased residual volume of urine in the bladder, change in voiding habits, worsening detrusor spasticity, and aggravation of autonomic dysreflexia can be the only initial presenting symptoms.⁵³

 

 

What is the duration of therapy for CA-UTI in SCI, and how can antibiotic stewardship principles be applied in this patient population?

Antibiotic therapy is indicated for a duration of 7 days if there is prompt resolution of symptoms, or for a total of 10 to 14 days if the response is delayed, regardless of whether the patient remains with a UC.⁵ Antibiotic stewardship is very important to reduce the risk for developing drug resistance in this high-risk population. Methods such as prescriber education practices, institution protocols, guideline implementation, auditing and feedback, restriction and reauthorization practices, computer-assisted programs, de-escalation or streamlining, and antibiotic cycling or dosage optimization have all been shown to assist in antibiotic stewardship in UTIs.⁵⁴

Candida UTI

What is the initial evaluation for a patient with candiduria?

The workup for candiduria hinges on determining whether the candiduria likely represents contamination, colonization, or infection; certain predisposing risk factors are associated with Candida UTI (Table 4).^55-57 The most important aspect to candiduria is the patient’s clinical status and comorbid conditions.⁵⁸ Among funguria, Candida species are the most common and represent 95% of organisms isolated on urine cultures (Table 5).⁵⁹ Candiduria is usually present in those with significant comorbidities and rarely is associated with healthy individuals.^59,60 Candiduria is increasing in prevalence among hospitalized patients, representing 22% to 40% of all nosocomial UTIs.^59,60 Markers in the urine (leukocyte esterase, colony count of culture growth, presence or absence of Candida casts and pseudohyphae) cannot alone differentiate colonization from infection.⁵⁵ When candiduria is discovered in a patient with symptoms related to UTI in the setting of predisposing risk factors, it should be considered a real infection until proven otherwise.

In a situation where an asymptomatic patient without an indwelling UC has Candida species isolated from a urine culture, a repeat culture (clean-catch midstream sample) should be performed to assess for a likely contaminated collection.⁵⁵ If the patient has an indwelling UC then it should be exchanged and urine collected from the fresh catheter.⁶¹ When candiduria is found in healthy asymptomatic adults, it is most commonly associated with poor collection techniques or postcollection contamination.⁵⁹ If candiduria persists in an asymptomatic patient, the patient should be assessed for predisposing factors. This includes checking hemoglobin A1C for developing diabetes and renal ultrasound looking for urolithiasis, renal abscess, hydronephrosis, and fungus ball. Postvoid residual urinary retention should also be ruled out with bladder ultrasound. Treatment of predisposing factors can lead to resolution of candiduria without antifungal treatment, and a urine culture should be repeated (1 to 2 weeks later).⁶¹ Asymptomatic patients lacking any predisposing factors can be observed with repeat urine cultures in 1 to 3 months.⁶¹

Candiduria may actually represent candidemia in those patients who have a predisposing risk factor for disseminated candidiasis. These risk factors include central venous catheters, administration of total parental nutrition, antibiotic use (especially broad spectrum), critical illness, recent surgical intervention (especially intra-abdominal), acute renal failure, nasogastric tube use, and active gastric acid suppression (ie, proton pump inhibitors).^62,63 The hematogenous spread of Candida can lead to the detection of candiduria in 46% to 80% of persons who are experiencing candidemia.⁵⁹ If the patient is at risk for candidemia, then blood fungal cultures should be drawn. It is not unreasonable to also order a serum-D-glucan assay if suspicions are high. A thorough skin assessment should be completed and ophthalmology consulted for a detailed eye exam in the event that the patient has candidemia. Candiduria is highly prevalent among those who are candidemic, but overall candidemia is encountered in less than 5% of patients in most intensive care units.⁵⁹ Thus, most patients with candiduria do not have disseminated candidiasis.

Candiduria rarely leads to symptoms of UTI,⁵⁸ unless the pathogenesis is related to an ascending process.⁵⁶ Symptoms of Candida UTI are no different from those experienced from a bacterial etiology. Some patients may complain of pneumaturia and/or endorse seeing particulate matter in their urine.⁵⁵ Patients showing signs of sepsis (fever, chills, flank pain) should be investigated for possible Candida pyelonephritis in the setting of candiduria.⁶⁴

When should asymptomatic candiduria be treated?

In adult patients with asymptomatic candiduria, there are 2 situations in which antifungal therapy is recommended. A patient undergoing a traumatic urologic procedure would be treated to avoid the risk for candidemia caused by the procedure. Also, in neutropenic patients empiric antifungal therapy should be administered because there is a high likelihood that this candiduria may actually represent hematogenous spread from candidemia.^61,65

What is the treatment for symptomatic Candida cystitis?

Empiric treatment with oral fluconazole 200 to 400 mg daily for a total of 2 weeks is recommended in patients with persisting candiduria and symptoms of cystitis.⁶⁵ Identifying the species is a crucial step in the treatment of Candida UTI. Several species (C. glabrata, C. krusei) are known to be resistant to fluconazole. Species identification and antifungal sensitivities should be done and therapy directed after obtaining these results.⁵⁵

What is the recommended treatment for Candida pyelonephritis?

Treatment for pyelonephritis caused by fluconazole-susceptible Candida species is oral fluconazole 200 to 400 mg (3-6 mg/kg) for a total of 2 weeks.⁶⁵ A fluconazole-resistant organism should be suspected when a non-albicans Candida species is isolated, such as C. krusei or C. glabrata. In this circumstance, in vitro antifungal susceptibility testing should be done. Echinocandins are not a good option in this situation because they do not reach adequate urine concentration and treatment failure is well documented.^66-68 Amphotericin B deoxycholate (AmB) 0.3 to 0.6 mg/kg daily for 1 to 7 days, with or without oral flucytosine (25 mg/kg) 4 times daily, is recommended by the IDSA for the treatment of fluconazole-resistant isolates of C. glabrata and C. krusei.⁶⁵ Further imaging with ultrasound, CT, or magnetic resonance should be done to rule out urinary tract obstruction and/or “fungus ball” formation. Emphysematous pyelonephritis and necrosis can occur and usually require nephrectomy. Perinephric abscess will need drainage, which can be accomplished through interventional radiological techniques.⁵⁵

If a “fungus ball” is suspected in the kidney, how does the management change in a patient with Candida pyelonephritis?

A fungus ball must be treated with both antifungals and surgical intervention. Antifungal therapy should be continued during the surgical removal process to avoid fungemia. Interventional radiology should be consulted and is usually the best option for removal. Fungus ball(s) can and often do cause urinary obstruction. Temporary nephrostomy tube placement may be warranted in these situations to relieve the obstruction.^55,65 AmB can be infused through the nephrostomy tube to increase local concentrations. This route of administration is not known to be nephrotoxic.⁵⁵ Fluconazole infusion through a nephrostomy tube has also been used in the successful treatment of a fungus ball.⁶⁹

Summary

Health care–associated UTIs are the most common nosocomial infection in the United States. UC placement and genitourinary manipulation or instrumentation play a major role in the development of CA-UTI. Clinicians should be aware of the appropriate and inappropriate use of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key in prevention of CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. A multidisciplinary approach is essential when managing chronic indwelling UCs in SCI. PCN and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected.

Candiduria is an emerging nosocomial source of UTI but rarely leads to symptoms unless related to an ascending process. Proper urine collection is crucial in determining whether you are dealing with contamination, colonization, or infection. If candiduria persists in an asymptomatic individual, then further investigations should be done in regards to possible predisposing risks factors. Fluconazole is recommended for treatment of most patients with Candida UTI, while intravenous AmB is the treatment of choice for fluconazole-resistant Candida species. As we continue to take an evidence-based approach to the prevention and management of health care-associated UTI, we will likely see continued improvement in patient outcomes and overall decreased rates of infection.

Corresponding author: Norman Beatty, MD, 1501 N. Campbell Ave., Tucson, AZ 85724; [email protected].

Financial disclosures: None.

From the University of Arizona College of Medicine, Tucson, AZ (Dr. Beatty), and the Baylor College of Medicine, Houston, TX (Dr. Mohajer).

Abstract

• Objective: To review management issues regarding health care–associated urinary tract infections (UTIs) commonly encountered by practicing clinicians.
• Methods: Review of the literature.
• Results: Because urinary catheter (UC) placement plays a major role in the development of catheter-associated UTIs (CA-UTI), clinicians should be aware of the appropriate and inappropriate uses of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key to preventing CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. Percutaneous nephrostomy and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected. Candiduria rarely leads to symptoms unless it is related to an ascending process. Proper urine collection is crucial in determining whether contamination, colonization, or infection is present. Fluconazole is recommended in most cases of Candida UTI, while intravenous amphotericin B is recommended for fluconazole-resistant Candida species.
• Conclusion: Continued use of evidence-based strategies for preventing and managing health care–associated UTI should lead to further improvements in patient outcomes and overall decreased rates of infection.

Keywords: bacteriuria; catheter-associated UTI; catheterization; percutaneous nephrostomy; candiduria.

Health care–associated urinary tract infections (UTIs) are estimated to be the most common adverse infectious event in U.S. hospitals, occurring in 1 of 10 admitted patients.^1-3 Approximately 32% of all health care–associated infections are UTIs.¹ Furthermore, urinary catheters (UCs) are associated with 8% to 21% of health care–associated infections that occur in the intensive care unit.⁴ The most important predisposing factor for nosocomial UTI is urinary catheterization.⁵ Genitourinary manipulation and/or implementation also play a major role in the development of nosocomial UTIs.

In 2008, the U.S. Centers for Medicare & Medicaid Services instituted a new policy that reduced reimbursement rates for hospitalizations linked to health care–associated infections.⁶ Indwelling UCs are among the most overused health care devices in the hospital setting. They are placed in an estimated 15% to 25% of all hospitalized patients,^7,8 and are often inserted in the emergency department (ED) without a physician order or appropriate indication.⁹ Intermittent straight catheterization, male or female condom catheterization, and/or placement of an indwelling UC are the most common causes of catheter-associated asymptomatic bacteriuria (CA-ASB) and catheter-associated UTIs (CA-UTI).⁵ Prevention and management of CA-ASB and CA-UTI can be challenging and require an evidence-based approach. Furthermore, guidelines for the management of UTIs in the setting of active percutaneous nephrostomy (PCN) drainage and/or ureteral stenting are not established.⁵ This may leave clinicians with little mainstream data to aid in management decisions.

In 2009 the Centers for Disease Control and Prevention provided a guideline for the appropriate and inappropriate use of indwelling UCs to help promote their proper use.¹⁰ In the time since the guideline’s initiatives were instituted around the United States, published data have shown some improvement in the use of UCs,^11,12 but other recent reports indicate that rates of UC use have remained unchanged.¹³ This review discusses management issues regarding health care–associated UTIs that are commonly encountered by practicing clinicians, with a focus on current guidelines and evidence.

Catheter-Associated UTI

CA-UTI is defined as the presence of signs or symptoms of UTI with no other explainable infectious source along with ≥ 1000 colony-forming units (cfu) of ≥ 1 bacterial species per milliliter in a urine specimen from a catheter that has been changed within 48 hours of collection of the urine specimen.⁵ Signs and symptoms of CA-UTI include, but are not limited to: new-onset or worsening fever, chills, altered sensorium from baseline, lethargy, malaise, flank pain, pelvic pain, costovertebral angle tenderness, and acute hematuria.⁵ New-onset “foul-smelling” (odorous)urine and “cloudy” urine are neither sensitive nor specific when assessing for CA-UTI, and do not have significant clinical relevance when found alone.^14,15 Patients who have removed or exchanged the UC during this event and then experience dysuria, increased frequency, urgency, or suprapubic pain are likely having symptoms of CA-UTI.⁵

What is the recommended method for collecting urine samples when CA-UTI is suspected?

In a patient with an indwelling catheter that has been in place for more than 2 weeks at the onset of a suspected CA-UTI, the catheter should be replaced (if still indicated) or removed to accelerate resolution of symptoms and to reduce the risk of subsequent catheter-associated bacteriuria and CA-UTI. The urine culture should be acquired from the freshly placed UC.⁵

When should a patient be empirically treated?

A patient presenting with evidence of sepsis should be empirically treated with antimicrobials. Empiric coverage should be based on risk factors for multidrug-resistant organisms and data pertaining to local antimicrobial resistance patterns. A urine specimen for urinalysis and possible culture should be sent prior to administering empiric antibiotics (if possible) in a symptomatic patient.⁵

What bacteria are commonly associated with CA-UTI?

The bacteria most commonly associated with CA-UTI are found in or around the gastrointestinal and genitourinary tracts and also are part of the normal skin flora. The introduction and/or facilitated ascension of these microorganisms is believed to occur during UC insertion.^16,17 Two-thirds of all isolated uropathogens in those with indwelling UCs are extraluminally acquired (via ascension along the catheter-urethral mucosa interface), and one-third are believed to be intraluminally acquired.¹⁸

The most commonly isolated bacteria in CA-UTI are Enterobacteriaceae, which include Escherichia coli (most common), Klebsiella species (K. oxytoca, K. pneumoniae), Serratia species (S. marcescens), Citrobacter species (C. koseri), Enterobacter species (E. cloacae), and Proteus species; non-Enterobacteriaceae such as Pseudomonas species; and gram-positive cocci, which include coagulase-negative staphylococci (S. saprophyticus), Staphylococcus aureus, group B streptococci, and Enterococcus species (E. faecalis, E. faecium).^19-21 Coagulase-negative staphylococci and Enterococcus species can lead to CA-UTI but are usually avirulent and more commonly isolated from asymptomatic individuals.¹⁹ Also, coagulase-negative staphylococci such as S. epidermidis and S. lugdunensis are usually the manifestation of contamination during the collection process and their presence should prompt a repeat sample collection under sterile techniques. Monomicrobial infection is usually seen in those with short-term catheter use and CA-UTI. In contrast, polymicrobial infection is more common in those with long-term indwelling UCs and CA-UTI.¹⁹ Providencia stuartii, Proteus mirabilis, S. aureus, and Morganella morganii have all been associated with CA-UTI in those with long-term indwelling UCs.

Growth of S. aureus in the urine should prompt further investigation with blood cultures to explore the possibility of hematogenous dissemination to the urinary tract. Organisms leading to bacteremia due to CA-UTI are most commonly gram-negative bacilli (E. coli, Klebsiella species, Pseudomonas aeruginosa) and E. faecalis.²¹

What is the difference between CA-ASB and CA-UTI?

CA-ASB is defined as the presence of ≥ 1 bacteria species growing on urine culture at ≥ 100,000 cfu/mL in a patient with a history of urinary catheterization and/or indwelling UC who lacks signs or symptoms of UTI. In a man with a condom catheter, CA-ASB is defined using the same criteria, but the urine sample is collected after a fresh condom catheter is applied.⁵ The difference between CA-ASB and CA-UTI is simply the presence or absence of signs and symptoms related to UTI. Currently, there is no standard definition for significant bacteriuria in a catheterized patient.⁵ Pyuria found on urinalysis is indicative of genitourinary inflammation and can be present in both CA-ASB and CA-UTI. The absence, presence, and/or degree of pyuria in catheterized patients does not accurately differentiate between CA-ASB and CA-UTI.^5,22,23 On the other hand, the absence of pyuria in a symptomatic catheterized patient suggests an etiology other than CA-UTI.⁵

How can CA-UTI be prevented in patients with a short-term indwelling urinary catheter?

If a short-term UC is essential, the most important approach to preventing CA-UTI is limiting the duration of time it will be used. Strategies such as computer-based order entry and care maps with automated discontinuation of UCs have been shown to decrease catheter usage.¹⁹ Using closed-systems for UC collection with ports in the distal catheter for needle aspiration of urine has also been shown to decrease the incidence of CA-UTI.⁵ Securing the UC to avoid urethral trauma, aseptic techniques for insertion and repositioning, and placement of the tubing and collection bag below the level of the bladder to prevent reflux will likely also prevent CA-UTI, but these strategies have not been evaluated thoroughly.¹⁹

When should you screen for and treat CA-ASB?

The 2009 Infectious Diseases Society of America (IDSA) guidelines recommend that the only patients who should be screened and treated for CA-ASB are pregnant women and those who will undergo a potentially traumatic urologic procedure for which mucosal breaching may occur, causing bleeding. Routinely screening or treating patients for CA-ASB in not recommended in any other group of patients and will lead to unnecessary antibiotic use and antibiotic resistance.⁵

UTI Associated with Percutaneous Nephrostomy and Ureteral Stenting

Similar systemic symptoms of infection (fever, rigors, malaise, shock) are present in patients with and without percutaneous nephrostomy (PCN) and/or ureteral stent placement. Dysuria is not commonly present in those with PCN. The first signs of CA-UTI may be decreased urine output and pericatheter leakage due to an obstructive process resulting from the encrustation.^24-27 The most common complaint among patients with either acute or chronic ureteral stenting is discomfort, which has been described as “urinary symptoms” and “body pain.”²⁸ This discomfort can be related to ureteral hyperperistalsis after placement of the stent and is usually self-limiting. Ureteral stent migration, usually at the distal end, can also lead to discomfort, but is easily rectified with cystoscopy.²⁵ Body pain and/or urinary symptoms in the setting of ureteral stenting are not indicative of infection alone.

What is urinary catheter and/or ureteral stent encrustation?

Encrustation is the formation of a conditioning film that develops on the surface of the UC or ureteral stent. The exact mechanism is not well understood, but it is believed to involve electrostatic interactions of urinary proteins that stimulate binding onto the stent or UC surface.²⁵ Encrustation increases exponentially with the dwell time. Among patients with ureteral stents placed due to urolithiasis, encrustation occurred in 9.2% of stents removed prior to 6 weeks, 47.5% of stents removed at 6 weeks, and 76.3% of stents removed at 12 weeks.²⁶ Encrustation is most common at the proximal and distal ends (pigtails) of the ureteral stent and usually spares or presents last within the lumen.²⁹ Attempts have been made to prevent ureteral stent encrustation through the development of biodegradable, drug-eluting, and tissue-engineered substrates. These developments are promising, but currently there is limited observational data from large randomized trials to suggest that these new modalities decrease rates of encrustation.²⁵ Encrustation is highly associated with certain microorganisms, especially those that create biofilms.³⁰ Urease-producing bacteria, most commonly P. mirabilis, play a role in encrustation formation.³¹ Bacteria most commonly associated with encrustation include Proteus species (P. mirabilis is most common), P. aeruginosa, K. pneumoniae, Providencia species (P. stuartii is most common), and M. morganii.

Does ureteral stent bacterial colonization correlate with UTI?

Ureteral stent colonization with bacteria increases with dwell time and is found in 40% to 98.5% of stents placed.^32-35 If UTI is suspected in a patient with an active indwelling ureteral stent, a sample of urine should be cultured while the stent is in place.²⁵ Typically, genitourinary and normal skin flora pathogens are found when the ureteral stent is cultured. The top 3 organisms cultured from ureteral stents are S. aureus, P. aeruginosa, and E. faecalis.³⁴ Urine culture usually does not correlate with stent culture results, which has brought up the debate of how bacterial colonization occurs. It has been postulated that colonization is actually a manifestation of contamination during the insertion procedure, but this has yet to be validated.²⁵ In patients with symptoms of UTI in the setting of an indwelling ureteral stent, a positive culture has low sensitivity, with estimates between 21% and 40%.³⁵ Therefore, a negative urine culture does not rule out UTI alone in a symptomatic patient. Multiple studies have suggested that colonization of the ureteral stent does not correlate strongly with developing a UTI.^25,32-34

How can UTI be prevented in those receiving PCN or ureteral stent placement?

Antibiotic prophylaxis has been recommended to prevent UTI in patients who will undergo PCN or ureteral stent placement. The American Urological Association recommends empiric treatment even in the absence of signs and symptoms of UTI,³⁶ but substantial evidence is lacking that this approach prevents infection.³⁷ Ciprofloxacin or trimethoprim/sulfamethoxazole has been recommended by some for empiric coverage for enteric gram-negative bacilli and enterococcus in those undergoing genitourinary manipulation or instrumentation.^32,38 Most patients who develop CA-UTI and pyelonephritis do so within the first 2 to 6 weeks after placement.^37,39 Bacteriuria, candiduria, and/or pyuria are present in all patients approximately within 9 weeks even when sterile urine is confirmed prior to PCN placement.³⁹ Data on the effectiveness of antibiotic prophylaxis to prevent CA-UTI in those with PCN or ureteral stenting is limited. Currently, there are no recommendations from the IDSA on how to prevent infection in these situations.⁵ Early or frequent stent removal or exchanges has been proven to reduce UTI in those with ureteral stenting.³³ Patients with diabetes mellitus and chronic renal failure are at high-risk for UTI when ureteral stents are in place. This population should undergo close monitoring for UTI development and may warrant more frequent stent exchanges.^27,40

What is the treatment of CA-UTI associated with PCN and/or ureteral stenting?

The IDSA guidelines do not apply to patients with PCN and/or ureteral stenting.⁵ There is no treatment protocol for UTI related to these processes. Generally speaking, they are considered “complicated UTI” by most experts. Broad-spectrum, empiric antibiotic administration along with prompt removal of the PCN and/or ureteral stent is the gold standard of therapy.²⁷ The recommended duration of targeted antibiotic therapy is generally between 5 and 14 days.¹⁹ Most clinicians will treat this complicated UTI for at least 10 to 14 days. Antibiotic administration should be continued even after removal of the catheter and/or stent to complete the full course. Repeat urinalysis and culture is not indicated at the end of therapy if the patient is clinically improving or has remission of symptoms.

What is the exchange rate for those who require chronic PCN and/or ureteral stent use?

On average a PCN or ureteral stent should be exchanged every 2 to 3 months in patients who require chronic usage.^24,27 Some patients with persistent complications may require more frequent exchanges (< 10 weeks).²⁷ Encrustation and bacterial colonization become more prevalent the longer the devices are in place. This process is estimated to begin within the first 2 weeks after placement.^27,33,34 A “forgotten stent” is one that has been left in place after the patient is lost to follow-up. This unfortunate event can lead to massive encrustation, UTI, stent fracturing, and complete ureteral obstruction.²⁴ As noted, patients with diabetes mellitus, chronic renal failure, and frequent UTI may warrant more frequent exchanges, but this should be determined on a case-by-case basis.

 

 

Catheter-Associated UTI in Patients with Spinal Cord Injury

Spinal cord injury (SCI) at any level can cause neurogenic bladder. This process ultimately leads to urinary stasis and colonization of the bladder with bacteria. According to the IDSA, the acceptable indications for UC insertion are: clinically significant urinary retention (if medical therapy is not effective), urinary incontinence, accurate urine output monitoring required, and patient is unable and/or unwilling to collect urine (Table 1).⁵ Recently, further guidelines were published regarding appropriate and inappropriate indwelling UC placement in hospitalized medical patients (Table 2 and Table 3), expanding upon the earlier acceptable criteria provided by the IDSA.⁴¹ According to the IDSA and Ann Arbor Criteria for Appropriate Urinary Catheter Use, patients with SCI and subsequent neurogenic bladder without obstruction where intermittent bladder straight catheterization for the drainage of urine is not feasible will likely need an indwelling UC.⁴¹ SCI patients often experience decubitus ulcers, and an indwelling UC can be used if needed to help with wound healing if other urinary management alternatives have been attempted. Other such situations in which an indwelling UC can used before attempting alternative approaches would be in a patient who is actively dying and is pursuing comfort care and/or hospice.⁴¹

Which indwelling UCs should be used in patients with SCI?

Efforts to reduce the likelihood of infection in patients with SCI have led to several advances in the design and manufacturing of UCs. UCs are made of either latex, plastic, silicone, or polytetrafluoroethylene (Teflon). None of these substrates is free of complications, but of them latex UCs have been studied the most in regards to their associated complications. Aside from being allergenic in nature, latex UCs have an increased propensity to allow bacteria to adhere to their surface due to microscopic planes of unevenness.⁴² Silicone UCs are less frequently associated with infection but are more rigid, leading to increased discomfort.^43,44 Hydrophilic and silver-hydrogel coatings are innovative methods that have been developed to increase comfort and reduce the likelihood of infection. Hydrophilic-coated UCs are associated with reduced microbial adherence, decreased encrustation, and better patient satisfaction.^45,46 In SCI patients, these UCs have demonstrated lower complication rates, including UTI; fewer episodes of post-, intra-, and inter-catheterization bleeding; and decreased rates of antibiotic-resistant bacteria.^45,46 Silver-hydrogel-coated UCs are less well studied but have also demonstrated reduced UTI rates in SCI patients; however, their efficacy over the long term has yet to be determined. Antibiotic-impregnated UCs are not currently recommended for either short- or long-term indwelling UC use.⁵

How can CA-UTI be prevented in a patient who will require a long-term indwelling catheter?

At this time, the data is insufficient to make a recommendation on routine UC exchange (eg, every 2 to 4 weeks) in patients who require long-term indwelling urethral or suprapubic catheters in an attempt to reduce the risk of CA-ASB or CA-UTI. This is also true for those who experience even repeated early catheter blockage from encrustation.⁵ Thus, the rate at which these exchanges occur can be controversial, but typically around every 4 weeks is a common approach. Some would argue that if the patient has repeated CA-UTI, an exchange rate of every 2 weeks might be needed, but data is currently lacking to support this practice.⁵ If intermittent urinary catheterization is feasible, it should be done at least every 6 hours and before bedtime. In general, when the volume of urine in the bladder reaches approximately 400 mL, the patient should undergo bladder catheterization to prevent stasis and infection.⁴⁷ A closed drainage system is recommended in all patients who require long-term indwelling UC use.^48,49 Placement of the collection bag above the catheter or above the level of the bladder and a breach in the closed drainage system have been shown to result in higher rates of catheter-associated bacteriuria.^48,50 Proper hand hygiene and sterile and/or clean techniques should be used when placing or exchanging a UC. However, in one study there was no difference in bacteremia or UTIs when using sterile versus clean techniques.⁵¹

Asymptomatic bacteriuria should not be treated in patients with long-term indwelling UCs, and prophylactic antibiotics have led to the emergence of resistance.⁵² At this time it is not clear whether prophylactic weekly oral cyclic antibiotic administration can effectively reduce the frequency of CA-UTI in patients with SCI and chronic indwelling UC use.

What are the signs and symptoms of CA-UTI in a patient with SCI?

Subjective and objective findings may be limited when a patient with SCI presents with CA-UTI. These patients often lack the usual symptoms of UTI (dysuria, suprapubic discomfort, urgency, increased frequency) and pyelonephritis (flank pain, costovertebral angle tenderness). Caregivers and health care providers should be aware that nonspecific symptoms such as foul-smelling urine, pyuria, increased residual volume of urine in the bladder, change in voiding habits, worsening detrusor spasticity, and aggravation of autonomic dysreflexia can be the only initial presenting symptoms.⁵³

 

 

What is the duration of therapy for CA-UTI in SCI, and how can antibiotic stewardship principles be applied in this patient population?

Antibiotic therapy is indicated for a duration of 7 days if there is prompt resolution of symptoms, or for a total of 10 to 14 days if the response is delayed, regardless of whether the patient remains with a UC.⁵ Antibiotic stewardship is very important to reduce the risk for developing drug resistance in this high-risk population. Methods such as prescriber education practices, institution protocols, guideline implementation, auditing and feedback, restriction and reauthorization practices, computer-assisted programs, de-escalation or streamlining, and antibiotic cycling or dosage optimization have all been shown to assist in antibiotic stewardship in UTIs.⁵⁴

Candida UTI

What is the initial evaluation for a patient with candiduria?

The workup for candiduria hinges on determining whether the candiduria likely represents contamination, colonization, or infection; certain predisposing risk factors are associated with Candida UTI (Table 4).^55-57 The most important aspect to candiduria is the patient’s clinical status and comorbid conditions.⁵⁸ Among funguria, Candida species are the most common and represent 95% of organisms isolated on urine cultures (Table 5).⁵⁹ Candiduria is usually present in those with significant comorbidities and rarely is associated with healthy individuals.^59,60 Candiduria is increasing in prevalence among hospitalized patients, representing 22% to 40% of all nosocomial UTIs.^59,60 Markers in the urine (leukocyte esterase, colony count of culture growth, presence or absence of Candida casts and pseudohyphae) cannot alone differentiate colonization from infection.⁵⁵ When candiduria is discovered in a patient with symptoms related to UTI in the setting of predisposing risk factors, it should be considered a real infection until proven otherwise.

In a situation where an asymptomatic patient without an indwelling UC has Candida species isolated from a urine culture, a repeat culture (clean-catch midstream sample) should be performed to assess for a likely contaminated collection.⁵⁵ If the patient has an indwelling UC then it should be exchanged and urine collected from the fresh catheter.⁶¹ When candiduria is found in healthy asymptomatic adults, it is most commonly associated with poor collection techniques or postcollection contamination.⁵⁹ If candiduria persists in an asymptomatic patient, the patient should be assessed for predisposing factors. This includes checking hemoglobin A1C for developing diabetes and renal ultrasound looking for urolithiasis, renal abscess, hydronephrosis, and fungus ball. Postvoid residual urinary retention should also be ruled out with bladder ultrasound. Treatment of predisposing factors can lead to resolution of candiduria without antifungal treatment, and a urine culture should be repeated (1 to 2 weeks later).⁶¹ Asymptomatic patients lacking any predisposing factors can be observed with repeat urine cultures in 1 to 3 months.⁶¹

Candiduria may actually represent candidemia in those patients who have a predisposing risk factor for disseminated candidiasis. These risk factors include central venous catheters, administration of total parental nutrition, antibiotic use (especially broad spectrum), critical illness, recent surgical intervention (especially intra-abdominal), acute renal failure, nasogastric tube use, and active gastric acid suppression (ie, proton pump inhibitors).^62,63 The hematogenous spread of Candida can lead to the detection of candiduria in 46% to 80% of persons who are experiencing candidemia.⁵⁹ If the patient is at risk for candidemia, then blood fungal cultures should be drawn. It is not unreasonable to also order a serum-D-glucan assay if suspicions are high. A thorough skin assessment should be completed and ophthalmology consulted for a detailed eye exam in the event that the patient has candidemia. Candiduria is highly prevalent among those who are candidemic, but overall candidemia is encountered in less than 5% of patients in most intensive care units.⁵⁹ Thus, most patients with candiduria do not have disseminated candidiasis.

Candiduria rarely leads to symptoms of UTI,⁵⁸ unless the pathogenesis is related to an ascending process.⁵⁶ Symptoms of Candida UTI are no different from those experienced from a bacterial etiology. Some patients may complain of pneumaturia and/or endorse seeing particulate matter in their urine.⁵⁵ Patients showing signs of sepsis (fever, chills, flank pain) should be investigated for possible Candida pyelonephritis in the setting of candiduria.⁶⁴

When should asymptomatic candiduria be treated?

In adult patients with asymptomatic candiduria, there are 2 situations in which antifungal therapy is recommended. A patient undergoing a traumatic urologic procedure would be treated to avoid the risk for candidemia caused by the procedure. Also, in neutropenic patients empiric antifungal therapy should be administered because there is a high likelihood that this candiduria may actually represent hematogenous spread from candidemia.^61,65

What is the treatment for symptomatic Candida cystitis?

Empiric treatment with oral fluconazole 200 to 400 mg daily for a total of 2 weeks is recommended in patients with persisting candiduria and symptoms of cystitis.⁶⁵ Identifying the species is a crucial step in the treatment of Candida UTI. Several species (C. glabrata, C. krusei) are known to be resistant to fluconazole. Species identification and antifungal sensitivities should be done and therapy directed after obtaining these results.⁵⁵

What is the recommended treatment for Candida pyelonephritis?

Treatment for pyelonephritis caused by fluconazole-susceptible Candida species is oral fluconazole 200 to 400 mg (3-6 mg/kg) for a total of 2 weeks.⁶⁵ A fluconazole-resistant organism should be suspected when a non-albicans Candida species is isolated, such as C. krusei or C. glabrata. In this circumstance, in vitro antifungal susceptibility testing should be done. Echinocandins are not a good option in this situation because they do not reach adequate urine concentration and treatment failure is well documented.^66-68 Amphotericin B deoxycholate (AmB) 0.3 to 0.6 mg/kg daily for 1 to 7 days, with or without oral flucytosine (25 mg/kg) 4 times daily, is recommended by the IDSA for the treatment of fluconazole-resistant isolates of C. glabrata and C. krusei.⁶⁵ Further imaging with ultrasound, CT, or magnetic resonance should be done to rule out urinary tract obstruction and/or “fungus ball” formation. Emphysematous pyelonephritis and necrosis can occur and usually require nephrectomy. Perinephric abscess will need drainage, which can be accomplished through interventional radiological techniques.⁵⁵

If a “fungus ball” is suspected in the kidney, how does the management change in a patient with Candida pyelonephritis?

A fungus ball must be treated with both antifungals and surgical intervention. Antifungal therapy should be continued during the surgical removal process to avoid fungemia. Interventional radiology should be consulted and is usually the best option for removal. Fungus ball(s) can and often do cause urinary obstruction. Temporary nephrostomy tube placement may be warranted in these situations to relieve the obstruction.^55,65 AmB can be infused through the nephrostomy tube to increase local concentrations. This route of administration is not known to be nephrotoxic.⁵⁵ Fluconazole infusion through a nephrostomy tube has also been used in the successful treatment of a fungus ball.⁶⁹

Summary

Health care–associated UTIs are the most common nosocomial infection in the United States. UC placement and genitourinary manipulation or instrumentation play a major role in the development of CA-UTI. Clinicians should be aware of the appropriate and inappropriate use of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key in prevention of CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. A multidisciplinary approach is essential when managing chronic indwelling UCs in SCI. PCN and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected.

Candiduria is an emerging nosocomial source of UTI but rarely leads to symptoms unless related to an ascending process. Proper urine collection is crucial in determining whether you are dealing with contamination, colonization, or infection. If candiduria persists in an asymptomatic individual, then further investigations should be done in regards to possible predisposing risks factors. Fluconazole is recommended for treatment of most patients with Candida UTI, while intravenous AmB is the treatment of choice for fluconazole-resistant Candida species. As we continue to take an evidence-based approach to the prevention and management of health care-associated UTI, we will likely see continued improvement in patient outcomes and overall decreased rates of infection.

Corresponding author: Norman Beatty, MD, 1501 N. Campbell Ave., Tucson, AZ 85724; [email protected].

Financial disclosures: None.

From the University of Arizona College of Medicine, Tucson, AZ (Dr. Beatty), and the Baylor College of Medicine, Houston, TX (Dr. Mohajer).

Abstract

• Objective: To review management issues regarding health care–associated urinary tract infections (UTIs) commonly encountered by practicing clinicians.
• Methods: Review of the literature.
• Results: Because urinary catheter (UC) placement plays a major role in the development of catheter-associated UTIs (CA-UTI), clinicians should be aware of the appropriate and inappropriate uses of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key to preventing CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. Percutaneous nephrostomy and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected. Candiduria rarely leads to symptoms unless it is related to an ascending process. Proper urine collection is crucial in determining whether contamination, colonization, or infection is present. Fluconazole is recommended in most cases of Candida UTI, while intravenous amphotericin B is recommended for fluconazole-resistant Candida species.
• Conclusion: Continued use of evidence-based strategies for preventing and managing health care–associated UTI should lead to further improvements in patient outcomes and overall decreased rates of infection.

Keywords: bacteriuria; catheter-associated UTI; catheterization; percutaneous nephrostomy; candiduria.

Health care–associated urinary tract infections (UTIs) are estimated to be the most common adverse infectious event in U.S. hospitals, occurring in 1 of 10 admitted patients.^1-3 Approximately 32% of all health care–associated infections are UTIs.¹ Furthermore, urinary catheters (UCs) are associated with 8% to 21% of health care–associated infections that occur in the intensive care unit.⁴ The most important predisposing factor for nosocomial UTI is urinary catheterization.⁵ Genitourinary manipulation and/or implementation also play a major role in the development of nosocomial UTIs.

In 2008, the U.S. Centers for Medicare & Medicaid Services instituted a new policy that reduced reimbursement rates for hospitalizations linked to health care–associated infections.⁶ Indwelling UCs are among the most overused health care devices in the hospital setting. They are placed in an estimated 15% to 25% of all hospitalized patients,^7,8 and are often inserted in the emergency department (ED) without a physician order or appropriate indication.⁹ Intermittent straight catheterization, male or female condom catheterization, and/or placement of an indwelling UC are the most common causes of catheter-associated asymptomatic bacteriuria (CA-ASB) and catheter-associated UTIs (CA-UTI).⁵ Prevention and management of CA-ASB and CA-UTI can be challenging and require an evidence-based approach. Furthermore, guidelines for the management of UTIs in the setting of active percutaneous nephrostomy (PCN) drainage and/or ureteral stenting are not established.⁵ This may leave clinicians with little mainstream data to aid in management decisions.

In 2009 the Centers for Disease Control and Prevention provided a guideline for the appropriate and inappropriate use of indwelling UCs to help promote their proper use.¹⁰ In the time since the guideline’s initiatives were instituted around the United States, published data have shown some improvement in the use of UCs,^11,12 but other recent reports indicate that rates of UC use have remained unchanged.¹³ This review discusses management issues regarding health care–associated UTIs that are commonly encountered by practicing clinicians, with a focus on current guidelines and evidence.

Catheter-Associated UTI

CA-UTI is defined as the presence of signs or symptoms of UTI with no other explainable infectious source along with ≥ 1000 colony-forming units (cfu) of ≥ 1 bacterial species per milliliter in a urine specimen from a catheter that has been changed within 48 hours of collection of the urine specimen.⁵ Signs and symptoms of CA-UTI include, but are not limited to: new-onset or worsening fever, chills, altered sensorium from baseline, lethargy, malaise, flank pain, pelvic pain, costovertebral angle tenderness, and acute hematuria.⁵ New-onset “foul-smelling” (odorous)urine and “cloudy” urine are neither sensitive nor specific when assessing for CA-UTI, and do not have significant clinical relevance when found alone.^14,15 Patients who have removed or exchanged the UC during this event and then experience dysuria, increased frequency, urgency, or suprapubic pain are likely having symptoms of CA-UTI.⁵

What is the recommended method for collecting urine samples when CA-UTI is suspected?

In a patient with an indwelling catheter that has been in place for more than 2 weeks at the onset of a suspected CA-UTI, the catheter should be replaced (if still indicated) or removed to accelerate resolution of symptoms and to reduce the risk of subsequent catheter-associated bacteriuria and CA-UTI. The urine culture should be acquired from the freshly placed UC.⁵

When should a patient be empirically treated?

A patient presenting with evidence of sepsis should be empirically treated with antimicrobials. Empiric coverage should be based on risk factors for multidrug-resistant organisms and data pertaining to local antimicrobial resistance patterns. A urine specimen for urinalysis and possible culture should be sent prior to administering empiric antibiotics (if possible) in a symptomatic patient.⁵

What bacteria are commonly associated with CA-UTI?

The bacteria most commonly associated with CA-UTI are found in or around the gastrointestinal and genitourinary tracts and also are part of the normal skin flora. The introduction and/or facilitated ascension of these microorganisms is believed to occur during UC insertion.^16,17 Two-thirds of all isolated uropathogens in those with indwelling UCs are extraluminally acquired (via ascension along the catheter-urethral mucosa interface), and one-third are believed to be intraluminally acquired.¹⁸

The most commonly isolated bacteria in CA-UTI are Enterobacteriaceae, which include Escherichia coli (most common), Klebsiella species (K. oxytoca, K. pneumoniae), Serratia species (S. marcescens), Citrobacter species (C. koseri), Enterobacter species (E. cloacae), and Proteus species; non-Enterobacteriaceae such as Pseudomonas species; and gram-positive cocci, which include coagulase-negative staphylococci (S. saprophyticus), Staphylococcus aureus, group B streptococci, and Enterococcus species (E. faecalis, E. faecium).^19-21 Coagulase-negative staphylococci and Enterococcus species can lead to CA-UTI but are usually avirulent and more commonly isolated from asymptomatic individuals.¹⁹ Also, coagulase-negative staphylococci such as S. epidermidis and S. lugdunensis are usually the manifestation of contamination during the collection process and their presence should prompt a repeat sample collection under sterile techniques. Monomicrobial infection is usually seen in those with short-term catheter use and CA-UTI. In contrast, polymicrobial infection is more common in those with long-term indwelling UCs and CA-UTI.¹⁹ Providencia stuartii, Proteus mirabilis, S. aureus, and Morganella morganii have all been associated with CA-UTI in those with long-term indwelling UCs.

Growth of S. aureus in the urine should prompt further investigation with blood cultures to explore the possibility of hematogenous dissemination to the urinary tract. Organisms leading to bacteremia due to CA-UTI are most commonly gram-negative bacilli (E. coli, Klebsiella species, Pseudomonas aeruginosa) and E. faecalis.²¹

What is the difference between CA-ASB and CA-UTI?

CA-ASB is defined as the presence of ≥ 1 bacteria species growing on urine culture at ≥ 100,000 cfu/mL in a patient with a history of urinary catheterization and/or indwelling UC who lacks signs or symptoms of UTI. In a man with a condom catheter, CA-ASB is defined using the same criteria, but the urine sample is collected after a fresh condom catheter is applied.⁵ The difference between CA-ASB and CA-UTI is simply the presence or absence of signs and symptoms related to UTI. Currently, there is no standard definition for significant bacteriuria in a catheterized patient.⁵ Pyuria found on urinalysis is indicative of genitourinary inflammation and can be present in both CA-ASB and CA-UTI. The absence, presence, and/or degree of pyuria in catheterized patients does not accurately differentiate between CA-ASB and CA-UTI.^5,22,23 On the other hand, the absence of pyuria in a symptomatic catheterized patient suggests an etiology other than CA-UTI.⁵

How can CA-UTI be prevented in patients with a short-term indwelling urinary catheter?

If a short-term UC is essential, the most important approach to preventing CA-UTI is limiting the duration of time it will be used. Strategies such as computer-based order entry and care maps with automated discontinuation of UCs have been shown to decrease catheter usage.¹⁹ Using closed-systems for UC collection with ports in the distal catheter for needle aspiration of urine has also been shown to decrease the incidence of CA-UTI.⁵ Securing the UC to avoid urethral trauma, aseptic techniques for insertion and repositioning, and placement of the tubing and collection bag below the level of the bladder to prevent reflux will likely also prevent CA-UTI, but these strategies have not been evaluated thoroughly.¹⁹

When should you screen for and treat CA-ASB?

The 2009 Infectious Diseases Society of America (IDSA) guidelines recommend that the only patients who should be screened and treated for CA-ASB are pregnant women and those who will undergo a potentially traumatic urologic procedure for which mucosal breaching may occur, causing bleeding. Routinely screening or treating patients for CA-ASB in not recommended in any other group of patients and will lead to unnecessary antibiotic use and antibiotic resistance.⁵

UTI Associated with Percutaneous Nephrostomy and Ureteral Stenting

Similar systemic symptoms of infection (fever, rigors, malaise, shock) are present in patients with and without percutaneous nephrostomy (PCN) and/or ureteral stent placement. Dysuria is not commonly present in those with PCN. The first signs of CA-UTI may be decreased urine output and pericatheter leakage due to an obstructive process resulting from the encrustation.^24-27 The most common complaint among patients with either acute or chronic ureteral stenting is discomfort, which has been described as “urinary symptoms” and “body pain.”²⁸ This discomfort can be related to ureteral hyperperistalsis after placement of the stent and is usually self-limiting. Ureteral stent migration, usually at the distal end, can also lead to discomfort, but is easily rectified with cystoscopy.²⁵ Body pain and/or urinary symptoms in the setting of ureteral stenting are not indicative of infection alone.

What is urinary catheter and/or ureteral stent encrustation?

Encrustation is the formation of a conditioning film that develops on the surface of the UC or ureteral stent. The exact mechanism is not well understood, but it is believed to involve electrostatic interactions of urinary proteins that stimulate binding onto the stent or UC surface.²⁵ Encrustation increases exponentially with the dwell time. Among patients with ureteral stents placed due to urolithiasis, encrustation occurred in 9.2% of stents removed prior to 6 weeks, 47.5% of stents removed at 6 weeks, and 76.3% of stents removed at 12 weeks.²⁶ Encrustation is most common at the proximal and distal ends (pigtails) of the ureteral stent and usually spares or presents last within the lumen.²⁹ Attempts have been made to prevent ureteral stent encrustation through the development of biodegradable, drug-eluting, and tissue-engineered substrates. These developments are promising, but currently there is limited observational data from large randomized trials to suggest that these new modalities decrease rates of encrustation.²⁵ Encrustation is highly associated with certain microorganisms, especially those that create biofilms.³⁰ Urease-producing bacteria, most commonly P. mirabilis, play a role in encrustation formation.³¹ Bacteria most commonly associated with encrustation include Proteus species (P. mirabilis is most common), P. aeruginosa, K. pneumoniae, Providencia species (P. stuartii is most common), and M. morganii.

Does ureteral stent bacterial colonization correlate with UTI?

Ureteral stent colonization with bacteria increases with dwell time and is found in 40% to 98.5% of stents placed.^32-35 If UTI is suspected in a patient with an active indwelling ureteral stent, a sample of urine should be cultured while the stent is in place.²⁵ Typically, genitourinary and normal skin flora pathogens are found when the ureteral stent is cultured. The top 3 organisms cultured from ureteral stents are S. aureus, P. aeruginosa, and E. faecalis.³⁴ Urine culture usually does not correlate with stent culture results, which has brought up the debate of how bacterial colonization occurs. It has been postulated that colonization is actually a manifestation of contamination during the insertion procedure, but this has yet to be validated.²⁵ In patients with symptoms of UTI in the setting of an indwelling ureteral stent, a positive culture has low sensitivity, with estimates between 21% and 40%.³⁵ Therefore, a negative urine culture does not rule out UTI alone in a symptomatic patient. Multiple studies have suggested that colonization of the ureteral stent does not correlate strongly with developing a UTI.^25,32-34

How can UTI be prevented in those receiving PCN or ureteral stent placement?

Antibiotic prophylaxis has been recommended to prevent UTI in patients who will undergo PCN or ureteral stent placement. The American Urological Association recommends empiric treatment even in the absence of signs and symptoms of UTI,³⁶ but substantial evidence is lacking that this approach prevents infection.³⁷ Ciprofloxacin or trimethoprim/sulfamethoxazole has been recommended by some for empiric coverage for enteric gram-negative bacilli and enterococcus in those undergoing genitourinary manipulation or instrumentation.^32,38 Most patients who develop CA-UTI and pyelonephritis do so within the first 2 to 6 weeks after placement.^37,39 Bacteriuria, candiduria, and/or pyuria are present in all patients approximately within 9 weeks even when sterile urine is confirmed prior to PCN placement.³⁹ Data on the effectiveness of antibiotic prophylaxis to prevent CA-UTI in those with PCN or ureteral stenting is limited. Currently, there are no recommendations from the IDSA on how to prevent infection in these situations.⁵ Early or frequent stent removal or exchanges has been proven to reduce UTI in those with ureteral stenting.³³ Patients with diabetes mellitus and chronic renal failure are at high-risk for UTI when ureteral stents are in place. This population should undergo close monitoring for UTI development and may warrant more frequent stent exchanges.^27,40

What is the treatment of CA-UTI associated with PCN and/or ureteral stenting?

The IDSA guidelines do not apply to patients with PCN and/or ureteral stenting.⁵ There is no treatment protocol for UTI related to these processes. Generally speaking, they are considered “complicated UTI” by most experts. Broad-spectrum, empiric antibiotic administration along with prompt removal of the PCN and/or ureteral stent is the gold standard of therapy.²⁷ The recommended duration of targeted antibiotic therapy is generally between 5 and 14 days.¹⁹ Most clinicians will treat this complicated UTI for at least 10 to 14 days. Antibiotic administration should be continued even after removal of the catheter and/or stent to complete the full course. Repeat urinalysis and culture is not indicated at the end of therapy if the patient is clinically improving or has remission of symptoms.

What is the exchange rate for those who require chronic PCN and/or ureteral stent use?

On average a PCN or ureteral stent should be exchanged every 2 to 3 months in patients who require chronic usage.^24,27 Some patients with persistent complications may require more frequent exchanges (< 10 weeks).²⁷ Encrustation and bacterial colonization become more prevalent the longer the devices are in place. This process is estimated to begin within the first 2 weeks after placement.^27,33,34 A “forgotten stent” is one that has been left in place after the patient is lost to follow-up. This unfortunate event can lead to massive encrustation, UTI, stent fracturing, and complete ureteral obstruction.²⁴ As noted, patients with diabetes mellitus, chronic renal failure, and frequent UTI may warrant more frequent exchanges, but this should be determined on a case-by-case basis.

 

 

Catheter-Associated UTI in Patients with Spinal Cord Injury

Spinal cord injury (SCI) at any level can cause neurogenic bladder. This process ultimately leads to urinary stasis and colonization of the bladder with bacteria. According to the IDSA, the acceptable indications for UC insertion are: clinically significant urinary retention (if medical therapy is not effective), urinary incontinence, accurate urine output monitoring required, and patient is unable and/or unwilling to collect urine (Table 1).⁵ Recently, further guidelines were published regarding appropriate and inappropriate indwelling UC placement in hospitalized medical patients (Table 2 and Table 3), expanding upon the earlier acceptable criteria provided by the IDSA.⁴¹ According to the IDSA and Ann Arbor Criteria for Appropriate Urinary Catheter Use, patients with SCI and subsequent neurogenic bladder without obstruction where intermittent bladder straight catheterization for the drainage of urine is not feasible will likely need an indwelling UC.⁴¹ SCI patients often experience decubitus ulcers, and an indwelling UC can be used if needed to help with wound healing if other urinary management alternatives have been attempted. Other such situations in which an indwelling UC can used before attempting alternative approaches would be in a patient who is actively dying and is pursuing comfort care and/or hospice.⁴¹

Which indwelling UCs should be used in patients with SCI?

Efforts to reduce the likelihood of infection in patients with SCI have led to several advances in the design and manufacturing of UCs. UCs are made of either latex, plastic, silicone, or polytetrafluoroethylene (Teflon). None of these substrates is free of complications, but of them latex UCs have been studied the most in regards to their associated complications. Aside from being allergenic in nature, latex UCs have an increased propensity to allow bacteria to adhere to their surface due to microscopic planes of unevenness.⁴² Silicone UCs are less frequently associated with infection but are more rigid, leading to increased discomfort.^43,44 Hydrophilic and silver-hydrogel coatings are innovative methods that have been developed to increase comfort and reduce the likelihood of infection. Hydrophilic-coated UCs are associated with reduced microbial adherence, decreased encrustation, and better patient satisfaction.^45,46 In SCI patients, these UCs have demonstrated lower complication rates, including UTI; fewer episodes of post-, intra-, and inter-catheterization bleeding; and decreased rates of antibiotic-resistant bacteria.^45,46 Silver-hydrogel-coated UCs are less well studied but have also demonstrated reduced UTI rates in SCI patients; however, their efficacy over the long term has yet to be determined. Antibiotic-impregnated UCs are not currently recommended for either short- or long-term indwelling UC use.⁵

How can CA-UTI be prevented in a patient who will require a long-term indwelling catheter?

At this time, the data is insufficient to make a recommendation on routine UC exchange (eg, every 2 to 4 weeks) in patients who require long-term indwelling urethral or suprapubic catheters in an attempt to reduce the risk of CA-ASB or CA-UTI. This is also true for those who experience even repeated early catheter blockage from encrustation.⁵ Thus, the rate at which these exchanges occur can be controversial, but typically around every 4 weeks is a common approach. Some would argue that if the patient has repeated CA-UTI, an exchange rate of every 2 weeks might be needed, but data is currently lacking to support this practice.⁵ If intermittent urinary catheterization is feasible, it should be done at least every 6 hours and before bedtime. In general, when the volume of urine in the bladder reaches approximately 400 mL, the patient should undergo bladder catheterization to prevent stasis and infection.⁴⁷ A closed drainage system is recommended in all patients who require long-term indwelling UC use.^48,49 Placement of the collection bag above the catheter or above the level of the bladder and a breach in the closed drainage system have been shown to result in higher rates of catheter-associated bacteriuria.^48,50 Proper hand hygiene and sterile and/or clean techniques should be used when placing or exchanging a UC. However, in one study there was no difference in bacteremia or UTIs when using sterile versus clean techniques.⁵¹

Asymptomatic bacteriuria should not be treated in patients with long-term indwelling UCs, and prophylactic antibiotics have led to the emergence of resistance.⁵² At this time it is not clear whether prophylactic weekly oral cyclic antibiotic administration can effectively reduce the frequency of CA-UTI in patients with SCI and chronic indwelling UC use.

What are the signs and symptoms of CA-UTI in a patient with SCI?

Subjective and objective findings may be limited when a patient with SCI presents with CA-UTI. These patients often lack the usual symptoms of UTI (dysuria, suprapubic discomfort, urgency, increased frequency) and pyelonephritis (flank pain, costovertebral angle tenderness). Caregivers and health care providers should be aware that nonspecific symptoms such as foul-smelling urine, pyuria, increased residual volume of urine in the bladder, change in voiding habits, worsening detrusor spasticity, and aggravation of autonomic dysreflexia can be the only initial presenting symptoms.⁵³

 

 

What is the duration of therapy for CA-UTI in SCI, and how can antibiotic stewardship principles be applied in this patient population?

Antibiotic therapy is indicated for a duration of 7 days if there is prompt resolution of symptoms, or for a total of 10 to 14 days if the response is delayed, regardless of whether the patient remains with a UC.⁵ Antibiotic stewardship is very important to reduce the risk for developing drug resistance in this high-risk population. Methods such as prescriber education practices, institution protocols, guideline implementation, auditing and feedback, restriction and reauthorization practices, computer-assisted programs, de-escalation or streamlining, and antibiotic cycling or dosage optimization have all been shown to assist in antibiotic stewardship in UTIs.⁵⁴

Candida UTI

What is the initial evaluation for a patient with candiduria?

The workup for candiduria hinges on determining whether the candiduria likely represents contamination, colonization, or infection; certain predisposing risk factors are associated with Candida UTI (Table 4).^55-57 The most important aspect to candiduria is the patient’s clinical status and comorbid conditions.⁵⁸ Among funguria, Candida species are the most common and represent 95% of organisms isolated on urine cultures (Table 5).⁵⁹ Candiduria is usually present in those with significant comorbidities and rarely is associated with healthy individuals.^59,60 Candiduria is increasing in prevalence among hospitalized patients, representing 22% to 40% of all nosocomial UTIs.^59,60 Markers in the urine (leukocyte esterase, colony count of culture growth, presence or absence of Candida casts and pseudohyphae) cannot alone differentiate colonization from infection.⁵⁵ When candiduria is discovered in a patient with symptoms related to UTI in the setting of predisposing risk factors, it should be considered a real infection until proven otherwise.

In a situation where an asymptomatic patient without an indwelling UC has Candida species isolated from a urine culture, a repeat culture (clean-catch midstream sample) should be performed to assess for a likely contaminated collection.⁵⁵ If the patient has an indwelling UC then it should be exchanged and urine collected from the fresh catheter.⁶¹ When candiduria is found in healthy asymptomatic adults, it is most commonly associated with poor collection techniques or postcollection contamination.⁵⁹ If candiduria persists in an asymptomatic patient, the patient should be assessed for predisposing factors. This includes checking hemoglobin A1C for developing diabetes and renal ultrasound looking for urolithiasis, renal abscess, hydronephrosis, and fungus ball. Postvoid residual urinary retention should also be ruled out with bladder ultrasound. Treatment of predisposing factors can lead to resolution of candiduria without antifungal treatment, and a urine culture should be repeated (1 to 2 weeks later).⁶¹ Asymptomatic patients lacking any predisposing factors can be observed with repeat urine cultures in 1 to 3 months.⁶¹

Candiduria may actually represent candidemia in those patients who have a predisposing risk factor for disseminated candidiasis. These risk factors include central venous catheters, administration of total parental nutrition, antibiotic use (especially broad spectrum), critical illness, recent surgical intervention (especially intra-abdominal), acute renal failure, nasogastric tube use, and active gastric acid suppression (ie, proton pump inhibitors).^62,63 The hematogenous spread of Candida can lead to the detection of candiduria in 46% to 80% of persons who are experiencing candidemia.⁵⁹ If the patient is at risk for candidemia, then blood fungal cultures should be drawn. It is not unreasonable to also order a serum-D-glucan assay if suspicions are high. A thorough skin assessment should be completed and ophthalmology consulted for a detailed eye exam in the event that the patient has candidemia. Candiduria is highly prevalent among those who are candidemic, but overall candidemia is encountered in less than 5% of patients in most intensive care units.⁵⁹ Thus, most patients with candiduria do not have disseminated candidiasis.

Candiduria rarely leads to symptoms of UTI,⁵⁸ unless the pathogenesis is related to an ascending process.⁵⁶ Symptoms of Candida UTI are no different from those experienced from a bacterial etiology. Some patients may complain of pneumaturia and/or endorse seeing particulate matter in their urine.⁵⁵ Patients showing signs of sepsis (fever, chills, flank pain) should be investigated for possible Candida pyelonephritis in the setting of candiduria.⁶⁴

When should asymptomatic candiduria be treated?

In adult patients with asymptomatic candiduria, there are 2 situations in which antifungal therapy is recommended. A patient undergoing a traumatic urologic procedure would be treated to avoid the risk for candidemia caused by the procedure. Also, in neutropenic patients empiric antifungal therapy should be administered because there is a high likelihood that this candiduria may actually represent hematogenous spread from candidemia.^61,65

What is the treatment for symptomatic Candida cystitis?

Empiric treatment with oral fluconazole 200 to 400 mg daily for a total of 2 weeks is recommended in patients with persisting candiduria and symptoms of cystitis.⁶⁵ Identifying the species is a crucial step in the treatment of Candida UTI. Several species (C. glabrata, C. krusei) are known to be resistant to fluconazole. Species identification and antifungal sensitivities should be done and therapy directed after obtaining these results.⁵⁵

What is the recommended treatment for Candida pyelonephritis?

Treatment for pyelonephritis caused by fluconazole-susceptible Candida species is oral fluconazole 200 to 400 mg (3-6 mg/kg) for a total of 2 weeks.⁶⁵ A fluconazole-resistant organism should be suspected when a non-albicans Candida species is isolated, such as C. krusei or C. glabrata. In this circumstance, in vitro antifungal susceptibility testing should be done. Echinocandins are not a good option in this situation because they do not reach adequate urine concentration and treatment failure is well documented.^66-68 Amphotericin B deoxycholate (AmB) 0.3 to 0.6 mg/kg daily for 1 to 7 days, with or without oral flucytosine (25 mg/kg) 4 times daily, is recommended by the IDSA for the treatment of fluconazole-resistant isolates of C. glabrata and C. krusei.⁶⁵ Further imaging with ultrasound, CT, or magnetic resonance should be done to rule out urinary tract obstruction and/or “fungus ball” formation. Emphysematous pyelonephritis and necrosis can occur and usually require nephrectomy. Perinephric abscess will need drainage, which can be accomplished through interventional radiological techniques.⁵⁵

If a “fungus ball” is suspected in the kidney, how does the management change in a patient with Candida pyelonephritis?

A fungus ball must be treated with both antifungals and surgical intervention. Antifungal therapy should be continued during the surgical removal process to avoid fungemia. Interventional radiology should be consulted and is usually the best option for removal. Fungus ball(s) can and often do cause urinary obstruction. Temporary nephrostomy tube placement may be warranted in these situations to relieve the obstruction.^55,65 AmB can be infused through the nephrostomy tube to increase local concentrations. This route of administration is not known to be nephrotoxic.⁵⁵ Fluconazole infusion through a nephrostomy tube has also been used in the successful treatment of a fungus ball.⁶⁹

Summary

Health care–associated UTIs are the most common nosocomial infection in the United States. UC placement and genitourinary manipulation or instrumentation play a major role in the development of CA-UTI. Clinicians should be aware of the appropriate and inappropriate use of UCs and their association with CA-UTI development. Removal of a UC when no longer necessary is key in prevention of CA-UTI. Treatment of asymptomatic bacteriuria is generally not indicated. A multidisciplinary approach is essential when managing chronic indwelling UCs in SCI. PCN and ureteral stenting need close monitoring, and early removal should be performed if infection is suspected.

Candiduria is an emerging nosocomial source of UTI but rarely leads to symptoms unless related to an ascending process. Proper urine collection is crucial in determining whether you are dealing with contamination, colonization, or infection. If candiduria persists in an asymptomatic individual, then further investigations should be done in regards to possible predisposing risks factors. Fluconazole is recommended for treatment of most patients with Candida UTI, while intravenous AmB is the treatment of choice for fluconazole-resistant Candida species. As we continue to take an evidence-based approach to the prevention and management of health care-associated UTI, we will likely see continued improvement in patient outcomes and overall decreased rates of infection.

Corresponding author: Norman Beatty, MD, 1501 N. Campbell Ave., Tucson, AZ 85724; [email protected].

Financial disclosures: None.

From the Division of General Internal Medicine (Dr. Venkataramani), and the Department of Pediatrics (Dr. Venkataramani and Dr. Solomon), Johns Hopkins University School of Medicine, Baltimore, MD.

In 2003, the American Academy of Pediatrics (AAP) published the recommendations of its Task Force on the Family, an initiative borne of the recognition that pediatricians have an important role in promoting well-functioning families as a means of ultimately promoting pediatric health.¹ Among the various facets of “family pediatrics” discussed in these recommendations was the practice of addressing caregiver health or health behaviors which directly impact children’s health. “Pediatricians have both opportunity and reason to take note of the health of their young patients’ parents,” declared the Task Force.¹ Now, 15 years later, despite growing evidence to support the promotion of caregiver health as a means to improve child health, pediatric providers continue to face challenges in successfully fulfilling this aspect of family pediatrics, challenges that we believe deserve the attention of adult providers and health systems.

Benefits Beyond Pediatric Preventive Care

Drawing upon evidence showing that caregiver health or health behaviors impact children’s health (the “reason” to intervene), current guidelines identify several caregiver-related issues on which pediatric providers are encouraged to focus their caregiver health promotion efforts. Specifically, Bright Futures, the AAP’s comprehensive evidence-driven resource for guidance regarding pediatric preventive care in the United States, highlights several caregiver health-related issues to be addressed during pediatric primary care visits.² For example, in recognition of the multiple detrimental effects secondhand tobacco smoke exposure has on child health,^3-5 the AAP recommends pediatrician-led parental tobacco use screening, counseling, and support of cessation efforts (including prescription of nicotine replacement therapies), practices that are also supported by the American Medical Association.^2,3,5 Similarly, in order to promote the protection of children against pertussis and influenza, Bright Futures recommends screening and encouraging caregiver immunization against these diseases.² Pediatricians are encouraged to routinely screen for maternal depression, given the far-reaching implications of caregiver mental health on children’s health,^2,6,7 and more recently the AAP has recommended screening fathers for depression in the perinatal period as well.⁸ Screening and appropriate referral for caregivers (and thereby children) exposed to intimate partner violence is another practice highlighted by the guidelines.²

Efforts have been made to expand the framework to other issues with similar potential to impact current and future generations of children, such as caregiver family planning.^2,9,10 And there exist still other issues which may be particularly well-suited to being addressed through the caregiver health promotion framework, such as follow-up care for mothers with gestational diabetes. These mothers are at high-risk for the development of type 2 diabetes and having subsequent pregnancies affected by poor glycemic control, but traditionally have had poor follow-up rates in the postpartum period and beyond.¹¹ Their regular interactions with pediatric providers resulting from the frequent visits required for their infants presents an important, and as yet untapped, opportunity to re-engage them in recommended medical care and prevent adverse outcomes for their future children as well as themselves.

The maternal gestational diabetes example highlights an important point: caregiver health promotion in pediatric settings can have direct health benefits for caregivers. As such, there are arguably additional reasons for health systems and adult providers to support the practice of caregiver health promotion in pediatric settings. First, it may represent one of the only exposures to the health care setting and health promotion activities for certain caregivers. Caregivers are often younger adults, an age-group that is less likely to have a usual source of care or access preventive services, and low-income caregivers of any age are more likely to have limited health care access. Given the frequency of routine care (12 health maintenance visits in the child’s first 3 years of life),² caregivers are likely to have more consistent access with the pediatric health care system than with the adult health care system. Therefore, pediatric visits represent an important touchpoint for these adults that could be leveraged to deliver services and further engage them with the adult health care system. Improving the reach of these services is particularly important in the era of population health where health systems, and particularly accountable care organizations, assume responsibility for the health-related outcomes of communities at large.

Second, studies exploring caregiver perspectives on pediatricians addressing their depression or tobacco use suggest that caregivers appreciate and welcome pediatrician engagement in their care.^12,13 Thus, supporting these efforts enables patient-centered care delivery. And third, caregivers may be more motivated to address their own health issues or behaviors (such as substance use) when counseled on the implications of their actions on their children’s health. To the extent such counseling is more routinely (and effectively) delivered in the pediatric setting, supporting pediatrics-based counseling efforts is also in the best interest of adult health care providers.

Challenges to Caregiver Health Promotion in Pediatric Settings

Studies suggest that a fairly broad scope of caregiver health promotion activities do occur in pediatric practice. In our survey of a nationally representative sample of children’s primary care physicians (including pediatricians, family medicine physicians, and medicine-pediatrics physicians), over three-quarters of respondents reported addressing at least 3 caregiver health issues (including maternal depression, tobacco use, family planning, influenza immunization status, intimate partner violence exposure, and caregiver health insurance status) during well-infant or well-child visits.¹⁴ At the same time, we found limited depth in practice in terms of the regularity with which caregiver issues are addressed at visits or, when applicable, services beyond screening are offered to caregivers. For example, we found that only 36% of physicians addressed caregiver exposure to intimate partner violence in at least half of the well-infant or well-child visits they conducted.¹⁴ And while the vast majority of our respondents addressed parental tobacco use with some regularity, less than 15% reported assisting parents with cessation efforts by prescribing cessation therapies. Other studies exploring practices surrounding maternal depression, intimate partner violence screening, or tobacco cessation counseling have revealed similar patterns with regards to the reach of caregiver health promotion in practices across the country.^15-18

Such variability in practice seems to stem primarily from structural and/or organizational barriers to caregiver health promotion in pediatric primary care settings, such as limited time, inability to bill for services provided to caregivers, and lack of efficient systems to refer caregivers to adult providers or services. These structural barriers could lead to attitudinal barriers (ie, pediatric physicians’ reluctance to address caregiver health). Attitudinal or physician-associated barriers may arise in instances when the caregiver health issue’s relevance to child health is less clear or expected actions are perceived as being beyond the scope of pediatric practice, raising concerns about personal effectiveness and liability. But it appears that when caregiver health issues clearly impact child health, and the role of the pediatrician is to screen and counsel in the context of pediatric implications of caregiver health or health behaviors, the majority of pediatric providers do endorse a sense of personal responsibility to address these issues. In our survey, for example, the vast majority of pediatric primary care physicians endorsed maternal depression and caregiver tobacco use as relevant to child well-being, and also endorsed a sense of personal responsibility to address these issues.¹⁹

Structural or organizational barriers thus appear to play a larger role overall in influencing caregiver health promotion practices. Various studies have characterized these barriers as they relate to caregiver health promotion, and lack of time is a paramount concern.^14,20 This is not surprising, given the multiple competing interests for a pediatrician’s time during already time-constrained well-child visits (which include growth and development assessment, anticipatory guidance provision, delivery of children’s preventive care services, and addressing any acute concerns). The time constraints may be even more acutely felt if the results of screening necessitate additional action, such as referral to relevant services. We found that a lack of referral resources or complex referral mechanisms were cited by over half of children’s primary care physicians as general barriers to caregiver health promotion, and in particular by pediatricians (versus medicine-pediatrics or family medicine physicians).¹⁴

This highlights the key difference between family medicine and caregiver health promotion in pediatrics: the latter involves addressing adult health issues in a setting where care for adults is often not provided. While some practices that see children may provide care to adults (such as family medicine or medicine-pediatrics clinics) or are co-located with adult health care providers, most pediatric practices are not integrated with adult health care settings. As a result, the “next steps” in caregiver health promotion can prove challenging to pursue, thereby limiting the beneficial impact of these activities on both child and adult health. For example, in the absence of such integration, pediatricians may find it challenging to connect mothers with positive depression screens to appropriate mental health care or parents who smoke to tobacco cessation services. In addition to leading to missed opportunities to comprehensively address caregiver health issues, such obstacles may also discourage pediatric providers from pursuing caregiver health promotion activities to begin with.

The Way Forward

How can health systems and adult health care providers support the caregiver promotion activities of pediatric primary care providers? There are several ways to enhance integration with adult practices and adult health care services. The co-location and integration of relevant caregiver-related auxiliary services at pediatric clinics is one way. In fact, when asked to identify facilitators to caregiver health promotion, pediatricians who responded to our survey most frequently endorsed the co-location of relevant providers, such as mental health professionals or social workers, as facilitators for addressing caregiver depression or intimate partner violence.¹⁴ For example, at the Harriet Lane Clinic at Johns Hopkins, the integration of a comprehensive maternal mental health team (including a part-time licensed therapist, part-time psychiatrist from an affiliated psychiatric practice, and full-time maternal case manager) has proven to be an effective, patient-oriented approach to providing services for mothers with depression.²¹ The role of health systems and adult health care providers/practices in advancing such models of care delivery is two-fold: to provide necessary staff and financial support. The latter is particularly important as many of the relevant caregiver-related services (eg, social work or case manager visits) may not generate the revenue required to support their sustained presence at pediatric sites.

Pediatric practices would also benefit from enhanced mechanisms for referral to appropriate services that are not co-located, such as tobacco cessation “quitlines.” Adopting protocolized interventions that focus on connecting parents with existing resources for their own health, such as the CEASE intervention developed for parental tobacco control in pediatrics,^22,23 is one way to streamline the referral process for pediatric practices. Another is by advancing a truly integrated electronic medical record (EMR), which enables caregiver health screenings and referral to additional services to be completed during pediatric encounters.

Finally, while only a relative minority of physicians we surveyed suggested that a lack of reimbursement for their activities served as a general barrier to caregiver health promotion, ensuring that pediatric providers are adequately compensated for their efforts on behalf of parents and guardians would undoubtedly help support their activities. Integrated EMRs could be one way to support this, particularly for services that are traditionally billed for (eg, depression screening or tobacco cessation counseling). Novel ways to reimburse pediatric providers for their contribution to adult health indicators could also be considered; for example, to the extent caregiver health promotion activities contribute to adult quality indicators (eg, postpartum depression screening rates and completion of postpartum visits) that are associated with financial rewards, health systems could consider sharing these “bonuses” among pediatric providers.

From Family Pediatrics to Family-Oriented Care

While caregiver health promotion has long been considered part of the practice of “family pediatrics,” it should more accurately be seen as an integral component of the delivery of family-oriented primary care, as it represents a novel opportunity to advance the health of not only children, but also their caregivers. Following existing preventive care guidelines, pediatricians currently engage in a variety of activities to promote child and caregiver health, but require support to more consistently and effectively address issues such as caregiver tobacco use or maternal depression. The barriers faced by pediatricians could be most effectively addressed with the engagement of adult health care providers and health systems; this includes the development of an integrated EMR that would support screening activities and referral to connect caregivers with necessary follow-up resources. Further characterizing the barriers faced in pediatric settings, and exploring how health systems could provide the necessary support to address these barriers, is crucial to realizing the potential of caregiver health promotion to have multi-generational impacts on well-being.

Corresponding author: Maya Venkataramani, MD, MPH, 2024 E. Monument St., Suite 2-502, Baltimore, MD 21287; [email protected].

Financial disclosures: None.

From the Division of General Internal Medicine (Dr. Venkataramani), and the Department of Pediatrics (Dr. Venkataramani and Dr. Solomon), Johns Hopkins University School of Medicine, Baltimore, MD.

In 2003, the American Academy of Pediatrics (AAP) published the recommendations of its Task Force on the Family, an initiative borne of the recognition that pediatricians have an important role in promoting well-functioning families as a means of ultimately promoting pediatric health.¹ Among the various facets of “family pediatrics” discussed in these recommendations was the practice of addressing caregiver health or health behaviors which directly impact children’s health. “Pediatricians have both opportunity and reason to take note of the health of their young patients’ parents,” declared the Task Force.¹ Now, 15 years later, despite growing evidence to support the promotion of caregiver health as a means to improve child health, pediatric providers continue to face challenges in successfully fulfilling this aspect of family pediatrics, challenges that we believe deserve the attention of adult providers and health systems.

Benefits Beyond Pediatric Preventive Care

Drawing upon evidence showing that caregiver health or health behaviors impact children’s health (the “reason” to intervene), current guidelines identify several caregiver-related issues on which pediatric providers are encouraged to focus their caregiver health promotion efforts. Specifically, Bright Futures, the AAP’s comprehensive evidence-driven resource for guidance regarding pediatric preventive care in the United States, highlights several caregiver health-related issues to be addressed during pediatric primary care visits.² For example, in recognition of the multiple detrimental effects secondhand tobacco smoke exposure has on child health,^3-5 the AAP recommends pediatrician-led parental tobacco use screening, counseling, and support of cessation efforts (including prescription of nicotine replacement therapies), practices that are also supported by the American Medical Association.^2,3,5 Similarly, in order to promote the protection of children against pertussis and influenza, Bright Futures recommends screening and encouraging caregiver immunization against these diseases.² Pediatricians are encouraged to routinely screen for maternal depression, given the far-reaching implications of caregiver mental health on children’s health,^2,6,7 and more recently the AAP has recommended screening fathers for depression in the perinatal period as well.⁸ Screening and appropriate referral for caregivers (and thereby children) exposed to intimate partner violence is another practice highlighted by the guidelines.²

Efforts have been made to expand the framework to other issues with similar potential to impact current and future generations of children, such as caregiver family planning.^2,9,10 And there exist still other issues which may be particularly well-suited to being addressed through the caregiver health promotion framework, such as follow-up care for mothers with gestational diabetes. These mothers are at high-risk for the development of type 2 diabetes and having subsequent pregnancies affected by poor glycemic control, but traditionally have had poor follow-up rates in the postpartum period and beyond.¹¹ Their regular interactions with pediatric providers resulting from the frequent visits required for their infants presents an important, and as yet untapped, opportunity to re-engage them in recommended medical care and prevent adverse outcomes for their future children as well as themselves.

The maternal gestational diabetes example highlights an important point: caregiver health promotion in pediatric settings can have direct health benefits for caregivers. As such, there are arguably additional reasons for health systems and adult providers to support the practice of caregiver health promotion in pediatric settings. First, it may represent one of the only exposures to the health care setting and health promotion activities for certain caregivers. Caregivers are often younger adults, an age-group that is less likely to have a usual source of care or access preventive services, and low-income caregivers of any age are more likely to have limited health care access. Given the frequency of routine care (12 health maintenance visits in the child’s first 3 years of life),² caregivers are likely to have more consistent access with the pediatric health care system than with the adult health care system. Therefore, pediatric visits represent an important touchpoint for these adults that could be leveraged to deliver services and further engage them with the adult health care system. Improving the reach of these services is particularly important in the era of population health where health systems, and particularly accountable care organizations, assume responsibility for the health-related outcomes of communities at large.

Second, studies exploring caregiver perspectives on pediatricians addressing their depression or tobacco use suggest that caregivers appreciate and welcome pediatrician engagement in their care.^12,13 Thus, supporting these efforts enables patient-centered care delivery. And third, caregivers may be more motivated to address their own health issues or behaviors (such as substance use) when counseled on the implications of their actions on their children’s health. To the extent such counseling is more routinely (and effectively) delivered in the pediatric setting, supporting pediatrics-based counseling efforts is also in the best interest of adult health care providers.

Challenges to Caregiver Health Promotion in Pediatric Settings

Studies suggest that a fairly broad scope of caregiver health promotion activities do occur in pediatric practice. In our survey of a nationally representative sample of children’s primary care physicians (including pediatricians, family medicine physicians, and medicine-pediatrics physicians), over three-quarters of respondents reported addressing at least 3 caregiver health issues (including maternal depression, tobacco use, family planning, influenza immunization status, intimate partner violence exposure, and caregiver health insurance status) during well-infant or well-child visits.¹⁴ At the same time, we found limited depth in practice in terms of the regularity with which caregiver issues are addressed at visits or, when applicable, services beyond screening are offered to caregivers. For example, we found that only 36% of physicians addressed caregiver exposure to intimate partner violence in at least half of the well-infant or well-child visits they conducted.¹⁴ And while the vast majority of our respondents addressed parental tobacco use with some regularity, less than 15% reported assisting parents with cessation efforts by prescribing cessation therapies. Other studies exploring practices surrounding maternal depression, intimate partner violence screening, or tobacco cessation counseling have revealed similar patterns with regards to the reach of caregiver health promotion in practices across the country.^15-18

Such variability in practice seems to stem primarily from structural and/or organizational barriers to caregiver health promotion in pediatric primary care settings, such as limited time, inability to bill for services provided to caregivers, and lack of efficient systems to refer caregivers to adult providers or services. These structural barriers could lead to attitudinal barriers (ie, pediatric physicians’ reluctance to address caregiver health). Attitudinal or physician-associated barriers may arise in instances when the caregiver health issue’s relevance to child health is less clear or expected actions are perceived as being beyond the scope of pediatric practice, raising concerns about personal effectiveness and liability. But it appears that when caregiver health issues clearly impact child health, and the role of the pediatrician is to screen and counsel in the context of pediatric implications of caregiver health or health behaviors, the majority of pediatric providers do endorse a sense of personal responsibility to address these issues. In our survey, for example, the vast majority of pediatric primary care physicians endorsed maternal depression and caregiver tobacco use as relevant to child well-being, and also endorsed a sense of personal responsibility to address these issues.¹⁹

Structural or organizational barriers thus appear to play a larger role overall in influencing caregiver health promotion practices. Various studies have characterized these barriers as they relate to caregiver health promotion, and lack of time is a paramount concern.^14,20 This is not surprising, given the multiple competing interests for a pediatrician’s time during already time-constrained well-child visits (which include growth and development assessment, anticipatory guidance provision, delivery of children’s preventive care services, and addressing any acute concerns). The time constraints may be even more acutely felt if the results of screening necessitate additional action, such as referral to relevant services. We found that a lack of referral resources or complex referral mechanisms were cited by over half of children’s primary care physicians as general barriers to caregiver health promotion, and in particular by pediatricians (versus medicine-pediatrics or family medicine physicians).¹⁴

This highlights the key difference between family medicine and caregiver health promotion in pediatrics: the latter involves addressing adult health issues in a setting where care for adults is often not provided. While some practices that see children may provide care to adults (such as family medicine or medicine-pediatrics clinics) or are co-located with adult health care providers, most pediatric practices are not integrated with adult health care settings. As a result, the “next steps” in caregiver health promotion can prove challenging to pursue, thereby limiting the beneficial impact of these activities on both child and adult health. For example, in the absence of such integration, pediatricians may find it challenging to connect mothers with positive depression screens to appropriate mental health care or parents who smoke to tobacco cessation services. In addition to leading to missed opportunities to comprehensively address caregiver health issues, such obstacles may also discourage pediatric providers from pursuing caregiver health promotion activities to begin with.

The Way Forward

How can health systems and adult health care providers support the caregiver promotion activities of pediatric primary care providers? There are several ways to enhance integration with adult practices and adult health care services. The co-location and integration of relevant caregiver-related auxiliary services at pediatric clinics is one way. In fact, when asked to identify facilitators to caregiver health promotion, pediatricians who responded to our survey most frequently endorsed the co-location of relevant providers, such as mental health professionals or social workers, as facilitators for addressing caregiver depression or intimate partner violence.¹⁴ For example, at the Harriet Lane Clinic at Johns Hopkins, the integration of a comprehensive maternal mental health team (including a part-time licensed therapist, part-time psychiatrist from an affiliated psychiatric practice, and full-time maternal case manager) has proven to be an effective, patient-oriented approach to providing services for mothers with depression.²¹ The role of health systems and adult health care providers/practices in advancing such models of care delivery is two-fold: to provide necessary staff and financial support. The latter is particularly important as many of the relevant caregiver-related services (eg, social work or case manager visits) may not generate the revenue required to support their sustained presence at pediatric sites.

Pediatric practices would also benefit from enhanced mechanisms for referral to appropriate services that are not co-located, such as tobacco cessation “quitlines.” Adopting protocolized interventions that focus on connecting parents with existing resources for their own health, such as the CEASE intervention developed for parental tobacco control in pediatrics,^22,23 is one way to streamline the referral process for pediatric practices. Another is by advancing a truly integrated electronic medical record (EMR), which enables caregiver health screenings and referral to additional services to be completed during pediatric encounters.

Finally, while only a relative minority of physicians we surveyed suggested that a lack of reimbursement for their activities served as a general barrier to caregiver health promotion, ensuring that pediatric providers are adequately compensated for their efforts on behalf of parents and guardians would undoubtedly help support their activities. Integrated EMRs could be one way to support this, particularly for services that are traditionally billed for (eg, depression screening or tobacco cessation counseling). Novel ways to reimburse pediatric providers for their contribution to adult health indicators could also be considered; for example, to the extent caregiver health promotion activities contribute to adult quality indicators (eg, postpartum depression screening rates and completion of postpartum visits) that are associated with financial rewards, health systems could consider sharing these “bonuses” among pediatric providers.

From Family Pediatrics to Family-Oriented Care

While caregiver health promotion has long been considered part of the practice of “family pediatrics,” it should more accurately be seen as an integral component of the delivery of family-oriented primary care, as it represents a novel opportunity to advance the health of not only children, but also their caregivers. Following existing preventive care guidelines, pediatricians currently engage in a variety of activities to promote child and caregiver health, but require support to more consistently and effectively address issues such as caregiver tobacco use or maternal depression. The barriers faced by pediatricians could be most effectively addressed with the engagement of adult health care providers and health systems; this includes the development of an integrated EMR that would support screening activities and referral to connect caregivers with necessary follow-up resources. Further characterizing the barriers faced in pediatric settings, and exploring how health systems could provide the necessary support to address these barriers, is crucial to realizing the potential of caregiver health promotion to have multi-generational impacts on well-being.

Corresponding author: Maya Venkataramani, MD, MPH, 2024 E. Monument St., Suite 2-502, Baltimore, MD 21287; [email protected].

Financial disclosures: None.

From the Division of General Internal Medicine (Dr. Venkataramani), and the Department of Pediatrics (Dr. Venkataramani and Dr. Solomon), Johns Hopkins University School of Medicine, Baltimore, MD.

In 2003, the American Academy of Pediatrics (AAP) published the recommendations of its Task Force on the Family, an initiative borne of the recognition that pediatricians have an important role in promoting well-functioning families as a means of ultimately promoting pediatric health.¹ Among the various facets of “family pediatrics” discussed in these recommendations was the practice of addressing caregiver health or health behaviors which directly impact children’s health. “Pediatricians have both opportunity and reason to take note of the health of their young patients’ parents,” declared the Task Force.¹ Now, 15 years later, despite growing evidence to support the promotion of caregiver health as a means to improve child health, pediatric providers continue to face challenges in successfully fulfilling this aspect of family pediatrics, challenges that we believe deserve the attention of adult providers and health systems.

Benefits Beyond Pediatric Preventive Care

Drawing upon evidence showing that caregiver health or health behaviors impact children’s health (the “reason” to intervene), current guidelines identify several caregiver-related issues on which pediatric providers are encouraged to focus their caregiver health promotion efforts. Specifically, Bright Futures, the AAP’s comprehensive evidence-driven resource for guidance regarding pediatric preventive care in the United States, highlights several caregiver health-related issues to be addressed during pediatric primary care visits.² For example, in recognition of the multiple detrimental effects secondhand tobacco smoke exposure has on child health,^3-5 the AAP recommends pediatrician-led parental tobacco use screening, counseling, and support of cessation efforts (including prescription of nicotine replacement therapies), practices that are also supported by the American Medical Association.^2,3,5 Similarly, in order to promote the protection of children against pertussis and influenza, Bright Futures recommends screening and encouraging caregiver immunization against these diseases.² Pediatricians are encouraged to routinely screen for maternal depression, given the far-reaching implications of caregiver mental health on children’s health,^2,6,7 and more recently the AAP has recommended screening fathers for depression in the perinatal period as well.⁸ Screening and appropriate referral for caregivers (and thereby children) exposed to intimate partner violence is another practice highlighted by the guidelines.²

Efforts have been made to expand the framework to other issues with similar potential to impact current and future generations of children, such as caregiver family planning.^2,9,10 And there exist still other issues which may be particularly well-suited to being addressed through the caregiver health promotion framework, such as follow-up care for mothers with gestational diabetes. These mothers are at high-risk for the development of type 2 diabetes and having subsequent pregnancies affected by poor glycemic control, but traditionally have had poor follow-up rates in the postpartum period and beyond.¹¹ Their regular interactions with pediatric providers resulting from the frequent visits required for their infants presents an important, and as yet untapped, opportunity to re-engage them in recommended medical care and prevent adverse outcomes for their future children as well as themselves.

The maternal gestational diabetes example highlights an important point: caregiver health promotion in pediatric settings can have direct health benefits for caregivers. As such, there are arguably additional reasons for health systems and adult providers to support the practice of caregiver health promotion in pediatric settings. First, it may represent one of the only exposures to the health care setting and health promotion activities for certain caregivers. Caregivers are often younger adults, an age-group that is less likely to have a usual source of care or access preventive services, and low-income caregivers of any age are more likely to have limited health care access. Given the frequency of routine care (12 health maintenance visits in the child’s first 3 years of life),² caregivers are likely to have more consistent access with the pediatric health care system than with the adult health care system. Therefore, pediatric visits represent an important touchpoint for these adults that could be leveraged to deliver services and further engage them with the adult health care system. Improving the reach of these services is particularly important in the era of population health where health systems, and particularly accountable care organizations, assume responsibility for the health-related outcomes of communities at large.

Second, studies exploring caregiver perspectives on pediatricians addressing their depression or tobacco use suggest that caregivers appreciate and welcome pediatrician engagement in their care.^12,13 Thus, supporting these efforts enables patient-centered care delivery. And third, caregivers may be more motivated to address their own health issues or behaviors (such as substance use) when counseled on the implications of their actions on their children’s health. To the extent such counseling is more routinely (and effectively) delivered in the pediatric setting, supporting pediatrics-based counseling efforts is also in the best interest of adult health care providers.

Challenges to Caregiver Health Promotion in Pediatric Settings

Studies suggest that a fairly broad scope of caregiver health promotion activities do occur in pediatric practice. In our survey of a nationally representative sample of children’s primary care physicians (including pediatricians, family medicine physicians, and medicine-pediatrics physicians), over three-quarters of respondents reported addressing at least 3 caregiver health issues (including maternal depression, tobacco use, family planning, influenza immunization status, intimate partner violence exposure, and caregiver health insurance status) during well-infant or well-child visits.¹⁴ At the same time, we found limited depth in practice in terms of the regularity with which caregiver issues are addressed at visits or, when applicable, services beyond screening are offered to caregivers. For example, we found that only 36% of physicians addressed caregiver exposure to intimate partner violence in at least half of the well-infant or well-child visits they conducted.¹⁴ And while the vast majority of our respondents addressed parental tobacco use with some regularity, less than 15% reported assisting parents with cessation efforts by prescribing cessation therapies. Other studies exploring practices surrounding maternal depression, intimate partner violence screening, or tobacco cessation counseling have revealed similar patterns with regards to the reach of caregiver health promotion in practices across the country.^15-18

Such variability in practice seems to stem primarily from structural and/or organizational barriers to caregiver health promotion in pediatric primary care settings, such as limited time, inability to bill for services provided to caregivers, and lack of efficient systems to refer caregivers to adult providers or services. These structural barriers could lead to attitudinal barriers (ie, pediatric physicians’ reluctance to address caregiver health). Attitudinal or physician-associated barriers may arise in instances when the caregiver health issue’s relevance to child health is less clear or expected actions are perceived as being beyond the scope of pediatric practice, raising concerns about personal effectiveness and liability. But it appears that when caregiver health issues clearly impact child health, and the role of the pediatrician is to screen and counsel in the context of pediatric implications of caregiver health or health behaviors, the majority of pediatric providers do endorse a sense of personal responsibility to address these issues. In our survey, for example, the vast majority of pediatric primary care physicians endorsed maternal depression and caregiver tobacco use as relevant to child well-being, and also endorsed a sense of personal responsibility to address these issues.¹⁹

Structural or organizational barriers thus appear to play a larger role overall in influencing caregiver health promotion practices. Various studies have characterized these barriers as they relate to caregiver health promotion, and lack of time is a paramount concern.^14,20 This is not surprising, given the multiple competing interests for a pediatrician’s time during already time-constrained well-child visits (which include growth and development assessment, anticipatory guidance provision, delivery of children’s preventive care services, and addressing any acute concerns). The time constraints may be even more acutely felt if the results of screening necessitate additional action, such as referral to relevant services. We found that a lack of referral resources or complex referral mechanisms were cited by over half of children’s primary care physicians as general barriers to caregiver health promotion, and in particular by pediatricians (versus medicine-pediatrics or family medicine physicians).¹⁴

This highlights the key difference between family medicine and caregiver health promotion in pediatrics: the latter involves addressing adult health issues in a setting where care for adults is often not provided. While some practices that see children may provide care to adults (such as family medicine or medicine-pediatrics clinics) or are co-located with adult health care providers, most pediatric practices are not integrated with adult health care settings. As a result, the “next steps” in caregiver health promotion can prove challenging to pursue, thereby limiting the beneficial impact of these activities on both child and adult health. For example, in the absence of such integration, pediatricians may find it challenging to connect mothers with positive depression screens to appropriate mental health care or parents who smoke to tobacco cessation services. In addition to leading to missed opportunities to comprehensively address caregiver health issues, such obstacles may also discourage pediatric providers from pursuing caregiver health promotion activities to begin with.

The Way Forward

How can health systems and adult health care providers support the caregiver promotion activities of pediatric primary care providers? There are several ways to enhance integration with adult practices and adult health care services. The co-location and integration of relevant caregiver-related auxiliary services at pediatric clinics is one way. In fact, when asked to identify facilitators to caregiver health promotion, pediatricians who responded to our survey most frequently endorsed the co-location of relevant providers, such as mental health professionals or social workers, as facilitators for addressing caregiver depression or intimate partner violence.¹⁴ For example, at the Harriet Lane Clinic at Johns Hopkins, the integration of a comprehensive maternal mental health team (including a part-time licensed therapist, part-time psychiatrist from an affiliated psychiatric practice, and full-time maternal case manager) has proven to be an effective, patient-oriented approach to providing services for mothers with depression.²¹ The role of health systems and adult health care providers/practices in advancing such models of care delivery is two-fold: to provide necessary staff and financial support. The latter is particularly important as many of the relevant caregiver-related services (eg, social work or case manager visits) may not generate the revenue required to support their sustained presence at pediatric sites.

Pediatric practices would also benefit from enhanced mechanisms for referral to appropriate services that are not co-located, such as tobacco cessation “quitlines.” Adopting protocolized interventions that focus on connecting parents with existing resources for their own health, such as the CEASE intervention developed for parental tobacco control in pediatrics,^22,23 is one way to streamline the referral process for pediatric practices. Another is by advancing a truly integrated electronic medical record (EMR), which enables caregiver health screenings and referral to additional services to be completed during pediatric encounters.

Finally, while only a relative minority of physicians we surveyed suggested that a lack of reimbursement for their activities served as a general barrier to caregiver health promotion, ensuring that pediatric providers are adequately compensated for their efforts on behalf of parents and guardians would undoubtedly help support their activities. Integrated EMRs could be one way to support this, particularly for services that are traditionally billed for (eg, depression screening or tobacco cessation counseling). Novel ways to reimburse pediatric providers for their contribution to adult health indicators could also be considered; for example, to the extent caregiver health promotion activities contribute to adult quality indicators (eg, postpartum depression screening rates and completion of postpartum visits) that are associated with financial rewards, health systems could consider sharing these “bonuses” among pediatric providers.

From Family Pediatrics to Family-Oriented Care

While caregiver health promotion has long been considered part of the practice of “family pediatrics,” it should more accurately be seen as an integral component of the delivery of family-oriented primary care, as it represents a novel opportunity to advance the health of not only children, but also their caregivers. Following existing preventive care guidelines, pediatricians currently engage in a variety of activities to promote child and caregiver health, but require support to more consistently and effectively address issues such as caregiver tobacco use or maternal depression. The barriers faced by pediatricians could be most effectively addressed with the engagement of adult health care providers and health systems; this includes the development of an integrated EMR that would support screening activities and referral to connect caregivers with necessary follow-up resources. Further characterizing the barriers faced in pediatric settings, and exploring how health systems could provide the necessary support to address these barriers, is crucial to realizing the potential of caregiver health promotion to have multi-generational impacts on well-being.

Corresponding author: Maya Venkataramani, MD, MPH, 2024 E. Monument St., Suite 2-502, Baltimore, MD 21287; [email protected].

Financial disclosures: None.

Study Overview

Objective. To investigate the relationship between prescription drug coverage, receipt of active myeloma therapy, and overall survival (OS) among Medicare beneficiaries with multiple myeloma.

Design. Case-control and retrospective cohort archival data research.

Setting and participants. Authors examined SEER-Medicare registry and extracted patients with histologically confirmed multiple myeloma diagnosed in the period 2006 to 2011. Availability of complete Medicare part A/B claims from 1 year before diagnosis until December 2013 was required for analysis. Patients with Medicare advantage or managed care plans did not have claims data available and hence were excluded. Beneficiaries with a diagnosis of diffuse large B-cell lymphoma (DLBCL), who typically receive parenteral drugs for lymphoma therapy, were used as a control cohort.

Main outcome measures. Association between prescription drug coverage status and OS was the primary outcome measure of interest. Authors reported 3-year restricted survival time (RMST) ratios to compare OS among the beneficiaries with different prescription drug coverages. Receipt of active myeloma therapy among beneficiaries was also studied. Relative risk, adjusting for patient and disease-related characteristics, was reported to examine receipt of active myeloma therapy.

Results. Records of 9755 Medicare beneficiaries were evaluated. Of these, 1460 (15%) had no prescription coverage at diagnosis, 3283 (34%) had part D plan prescription benefits, 3607 (37%) had sponsored prescription coverage through an employer, federal employer, or veterans plan, and 1405 (14%) had a Medicaid prescription plan. Beneficiaries without coverage had fewer comorbidities, including anemia, neuropathy, or renal disease, than those with part D prescription coverage or Medicaid. Of those without any prescription drug coverage, 41% obtained prescription plan coverage after diagnosis of myeloma by the following January. Conversely, only 19% of patients with DLBCL and no coverage obtained a prescription plan.

Patients with myeloma were followed for 4.9 years and median survival was 2.3 years, with a 3-year OS rate of 43.1% (95% confidence interval [CI], 42.1%-44.1%). Relative to the group without coverage, survival was 16% longer in the Medicare part D group and sponsored plan group (RMST 1.16; 95% CI, 1.12-1.21). Medicaid/Medicare dual beneficiaries had worse OS in both myeloma and DLBCL consistent with poor performance status and unfavorable baseline comorbidities. However, among patients with myeloma, Medicaid/Medicare dual beneficiaries had better survival (RMST 1.08; 95% CI, 1.03-1.13) compared to the group without coverage. There was no difference in OS for those with or without prescription drug coverage in the DLBCL cohort.

There were significant differences in treatment of myeloma based on types of prescription drug coverage. Due to increasing use of bortezomib following its approval by the U.S. Food and Drug Administration (FDA), parenteral chemotherapy use doubled from 24% to 48% from 2006 to 2011, and utility of active myeloma care increased from 88% to 91%. Medicare part D plan enrollees were 6% more likely to receive active myeloma care, and both Medicaid group and sponsored plan group beneficiaries were equally likely to receive active myeloma care compared to beneficiaries without prescription coverage. Medicaid enrollees were less likely to receive parenteral therapy.

Conclusion. Medicare beneficiaries with prescription drug coverage and multiple myeloma are more likely to receive myeloma therapy and have longer OS compared to those without prescription drug coverage.

Commentary

First-line therapy of multiple myeloma has evolved over the past 2 decades. Parenteral agents such as vincristine, adriamycin, dexamethasone, and cyclophosphamide and oral therapy with melphalan and prednisone were the mainstay of treatment in the past. In the past decade, the arrival of oral therapy using thalidomide or lenalidomide and parenteral therapy using bortezomib has increased OS in patients with myeloma. Most recently, a combination of lenalidomide, bortezomib, and dexamethasone has emerged as one of the frontline therapies of choice.¹ Incorporation of bortezomib or an oral immunomodulatory drug is almost universal in first-line therapy.

Oral antineoplastic therapy is increasingly being approved by the FDA and being utilized in the community. During the period 2016-2018, more than half the new FDA-approved oncology drugs were in oral formulation.² As such, access to these agents is crucial in cancer therapy. The cost of oral therapy in patients without prescription drug coverage is sometimes more than $10,000 per month, which represents a significant impediment to its adoption. Forty-three states and Washington, DC, have enacted drug parity laws that require patients to pay no more for an oral cancer treatment than they would for an infusion. However, currently there is no such federal law, and Medicare beneficiaries must participate either through part D, state Medicaid, or a sponsored program to obtain prescription drug coverage. Despite being enrolled in part D, many beneficiaries fall into the “doughnut hole” (the requirement of Part D beneficiaries with high prescription drug expenses to pay more once the total cost of their medicines reaches a certain threshold) for prescription drugs at the time of need. From 2019 onward, enrollees will see significant, yet sometimes still insufficient, coverage benefits due to ending of the doughnut hole.³ Only a very limited number of oral chemotherapy agents are covered through Medicare part B, and of those covered, only oral melphalan is used for myeloma.

The authors have acknowledged multiple limitations of their investigation, including possible unobserved clinical differences between beneficiaries. SEER-Medicare registry has limitations in obtaining individual level data and may not contain specific results of cytogenetics, laboratory risk markers, and response to therapy, which are important to determine overall outcome. A prospective evaluation may be more suitable to assess these variables independently or through a multivariate analysis in determining receipt of therapy on OS, although such a study is currently not feasible.

The indicator of active myeloma care was defined as 2 or more outpatient physician visits or receipt of parenteral chemotherapy. This definition is somewhat suboptimal, as often patients with myeloma are under surveillance and may not necessarily be receiving active treatment. Moreover, the exact prescription pattern of lenalidomide, the most active first-line oral therapy, could not be captured from this retrospective registry review. Therefore, definitive conclusions regarding use of lenalidomide and thalidomide and receipt of therapy in this population cannot be made.

A significant improvement in OS has been established using maintenance lenalidomide following high-dose chemotherapy and stem cell transplantation.⁴ Only 5% of this study population received stem cell transplantation. This may be due to a median age of 77 years at diagnosis in the group studied, higher than the 66 to 70 years previously published.⁵ Stem cell transplantation is now commonly being used even in the older population. The 3-year survival of 83% following stem cell transplantation in myeloma patients aged 75 to 84 years was nearly identical to that of the younger population.⁶ Since stem cell transplantation is feasible in older Medicare beneficiaries and maintenance lenalidomide for 2 years following transplant improves survival, the option of providing maintenance therapy with oral lenalidomide must be made available to Medicare beneficiaries. Due to a very limited use of transplantation in this study, the impact of oral lenalidomide maintenance in OS cannot be judged.

Of the patients reviewed in this study, 6% had a listed diagnosis of plasmacytoma. These individuals typically are treated with radiation therapy only. It is unclear if these patients also received any systemic myeloma therapy or if they ever progressed to myeloma. Availability of prescription drug coverage may not be relevant to this group. Also, the authors reported that part D participants were less likely to receive classic cytotoxic chemotherapy. This may be somewhat irrelevant in Medicare beneficiaries with a median age of 77 years for current practice, as frontline induction with old classic cytotoxic chemotherapy is less commonly used in this population.

Investigators have appropriately recognized a lack of ability to discern whether inferior survival in the group without prescription drug coverage was the result of not receiving therapy at all or inability to receive oral immunomodulatory drugs. There would have been little reason for not proceeding to parenteral therapy. As noted, 41% of beneficiaries without coverage at diagnosis subsequently obtained coverage but continued to have significantly worse survival. Cause of death, including whether related to myeloma, was not reported. The authors suggest that early separation of survival curves could therefore be reflective of suboptimal first-line therapy that lacked oral immunomodulatory drugs. During the study period 2006-2011, first-line use of lenalidomide was common.

Median survival of patients with myeloma in this study was only 27 months. According to the American Cancer Society, in 2018 median survival for stage I myeloma has not been reached, stage II myeloma is 83 months, and stage III myeloma is 43 months. A robust and dynamic landscape in myeloma therapy prevents a clear attribution to individual agents, whether oral or parenteral, in improving OS. Thus, 3-year RMST, while appropriate for 2006-2011, may not be relevant today.

Applications for Clinical Practice

The oncology community routinely encounters difficulty in initiating therapy using oral agents rapidly after diagnosis of myeloma. The retrospective data analyzed in the current study suggests that delay in initiating or unavailability of oral agents may adversely impact OS. The common approach of initiating parenteral therapy while awaiting approvals from payers or charity programs and subsequently adding oral therapy when available has not been studied in assessing OS. The oncology community should initiate plans to obtain prescription drug coverage through either Medicare part D, Medicaid, a sponsored plan, or financial assistance charity programs as soon as possible after diagnosis of myeloma. Moreover, continuation of these prescription drug plans should be strongly considered throughout the course of myeloma, as subsequent lines of treatment will quite likely involve other active and approved oral agents, such as pomalidomide, ixazomib, and panobinostat, besides other supportive therapy.

One of the mechanisms to obtain prescription drug coverage includes enrollment in state Medicaid programs for those who are eligible. Currently, 17 states have not yet adopted Medicaid expansion under the Affordable Care Act. Expansion of Medicaid in these states could increase availability of prescription drug benefits. In this study, 15.8% of Medicare and Medicaid dual enrollees with access to oral agents at low or no cost did not receive myeloma care, slightly higher than the 13.1% with no prescription drug coverage. Lower utilization in this population may be explained based on differences in comorbidities or socioeconomic conditions rather than availability of a prescription plan.

The incidence of myeloma is expected to be higher in Medicare beneficiaries, and according to one estimate, in 2030 and beyond nearly 75% of diagnosed myeloma patients will be aged 64 to 84 years, an increase from nearly 66% today.⁷ Changing demographics, increasing oral therapy options, and patient convenience demand attention to providing prescription drug coverage to all Medicare beneficiaries. This study lends support to that demand.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To investigate the relationship between prescription drug coverage, receipt of active myeloma therapy, and overall survival (OS) among Medicare beneficiaries with multiple myeloma.

Design. Case-control and retrospective cohort archival data research.

Setting and participants. Authors examined SEER-Medicare registry and extracted patients with histologically confirmed multiple myeloma diagnosed in the period 2006 to 2011. Availability of complete Medicare part A/B claims from 1 year before diagnosis until December 2013 was required for analysis. Patients with Medicare advantage or managed care plans did not have claims data available and hence were excluded. Beneficiaries with a diagnosis of diffuse large B-cell lymphoma (DLBCL), who typically receive parenteral drugs for lymphoma therapy, were used as a control cohort.

Main outcome measures. Association between prescription drug coverage status and OS was the primary outcome measure of interest. Authors reported 3-year restricted survival time (RMST) ratios to compare OS among the beneficiaries with different prescription drug coverages. Receipt of active myeloma therapy among beneficiaries was also studied. Relative risk, adjusting for patient and disease-related characteristics, was reported to examine receipt of active myeloma therapy.

Results. Records of 9755 Medicare beneficiaries were evaluated. Of these, 1460 (15%) had no prescription coverage at diagnosis, 3283 (34%) had part D plan prescription benefits, 3607 (37%) had sponsored prescription coverage through an employer, federal employer, or veterans plan, and 1405 (14%) had a Medicaid prescription plan. Beneficiaries without coverage had fewer comorbidities, including anemia, neuropathy, or renal disease, than those with part D prescription coverage or Medicaid. Of those without any prescription drug coverage, 41% obtained prescription plan coverage after diagnosis of myeloma by the following January. Conversely, only 19% of patients with DLBCL and no coverage obtained a prescription plan.

Patients with myeloma were followed for 4.9 years and median survival was 2.3 years, with a 3-year OS rate of 43.1% (95% confidence interval [CI], 42.1%-44.1%). Relative to the group without coverage, survival was 16% longer in the Medicare part D group and sponsored plan group (RMST 1.16; 95% CI, 1.12-1.21). Medicaid/Medicare dual beneficiaries had worse OS in both myeloma and DLBCL consistent with poor performance status and unfavorable baseline comorbidities. However, among patients with myeloma, Medicaid/Medicare dual beneficiaries had better survival (RMST 1.08; 95% CI, 1.03-1.13) compared to the group without coverage. There was no difference in OS for those with or without prescription drug coverage in the DLBCL cohort.

There were significant differences in treatment of myeloma based on types of prescription drug coverage. Due to increasing use of bortezomib following its approval by the U.S. Food and Drug Administration (FDA), parenteral chemotherapy use doubled from 24% to 48% from 2006 to 2011, and utility of active myeloma care increased from 88% to 91%. Medicare part D plan enrollees were 6% more likely to receive active myeloma care, and both Medicaid group and sponsored plan group beneficiaries were equally likely to receive active myeloma care compared to beneficiaries without prescription coverage. Medicaid enrollees were less likely to receive parenteral therapy.

Conclusion. Medicare beneficiaries with prescription drug coverage and multiple myeloma are more likely to receive myeloma therapy and have longer OS compared to those without prescription drug coverage.

Commentary

First-line therapy of multiple myeloma has evolved over the past 2 decades. Parenteral agents such as vincristine, adriamycin, dexamethasone, and cyclophosphamide and oral therapy with melphalan and prednisone were the mainstay of treatment in the past. In the past decade, the arrival of oral therapy using thalidomide or lenalidomide and parenteral therapy using bortezomib has increased OS in patients with myeloma. Most recently, a combination of lenalidomide, bortezomib, and dexamethasone has emerged as one of the frontline therapies of choice.¹ Incorporation of bortezomib or an oral immunomodulatory drug is almost universal in first-line therapy.

Oral antineoplastic therapy is increasingly being approved by the FDA and being utilized in the community. During the period 2016-2018, more than half the new FDA-approved oncology drugs were in oral formulation.² As such, access to these agents is crucial in cancer therapy. The cost of oral therapy in patients without prescription drug coverage is sometimes more than $10,000 per month, which represents a significant impediment to its adoption. Forty-three states and Washington, DC, have enacted drug parity laws that require patients to pay no more for an oral cancer treatment than they would for an infusion. However, currently there is no such federal law, and Medicare beneficiaries must participate either through part D, state Medicaid, or a sponsored program to obtain prescription drug coverage. Despite being enrolled in part D, many beneficiaries fall into the “doughnut hole” (the requirement of Part D beneficiaries with high prescription drug expenses to pay more once the total cost of their medicines reaches a certain threshold) for prescription drugs at the time of need. From 2019 onward, enrollees will see significant, yet sometimes still insufficient, coverage benefits due to ending of the doughnut hole.³ Only a very limited number of oral chemotherapy agents are covered through Medicare part B, and of those covered, only oral melphalan is used for myeloma.

The authors have acknowledged multiple limitations of their investigation, including possible unobserved clinical differences between beneficiaries. SEER-Medicare registry has limitations in obtaining individual level data and may not contain specific results of cytogenetics, laboratory risk markers, and response to therapy, which are important to determine overall outcome. A prospective evaluation may be more suitable to assess these variables independently or through a multivariate analysis in determining receipt of therapy on OS, although such a study is currently not feasible.

The indicator of active myeloma care was defined as 2 or more outpatient physician visits or receipt of parenteral chemotherapy. This definition is somewhat suboptimal, as often patients with myeloma are under surveillance and may not necessarily be receiving active treatment. Moreover, the exact prescription pattern of lenalidomide, the most active first-line oral therapy, could not be captured from this retrospective registry review. Therefore, definitive conclusions regarding use of lenalidomide and thalidomide and receipt of therapy in this population cannot be made.

A significant improvement in OS has been established using maintenance lenalidomide following high-dose chemotherapy and stem cell transplantation.⁴ Only 5% of this study population received stem cell transplantation. This may be due to a median age of 77 years at diagnosis in the group studied, higher than the 66 to 70 years previously published.⁵ Stem cell transplantation is now commonly being used even in the older population. The 3-year survival of 83% following stem cell transplantation in myeloma patients aged 75 to 84 years was nearly identical to that of the younger population.⁶ Since stem cell transplantation is feasible in older Medicare beneficiaries and maintenance lenalidomide for 2 years following transplant improves survival, the option of providing maintenance therapy with oral lenalidomide must be made available to Medicare beneficiaries. Due to a very limited use of transplantation in this study, the impact of oral lenalidomide maintenance in OS cannot be judged.

Of the patients reviewed in this study, 6% had a listed diagnosis of plasmacytoma. These individuals typically are treated with radiation therapy only. It is unclear if these patients also received any systemic myeloma therapy or if they ever progressed to myeloma. Availability of prescription drug coverage may not be relevant to this group. Also, the authors reported that part D participants were less likely to receive classic cytotoxic chemotherapy. This may be somewhat irrelevant in Medicare beneficiaries with a median age of 77 years for current practice, as frontline induction with old classic cytotoxic chemotherapy is less commonly used in this population.

Investigators have appropriately recognized a lack of ability to discern whether inferior survival in the group without prescription drug coverage was the result of not receiving therapy at all or inability to receive oral immunomodulatory drugs. There would have been little reason for not proceeding to parenteral therapy. As noted, 41% of beneficiaries without coverage at diagnosis subsequently obtained coverage but continued to have significantly worse survival. Cause of death, including whether related to myeloma, was not reported. The authors suggest that early separation of survival curves could therefore be reflective of suboptimal first-line therapy that lacked oral immunomodulatory drugs. During the study period 2006-2011, first-line use of lenalidomide was common.

Median survival of patients with myeloma in this study was only 27 months. According to the American Cancer Society, in 2018 median survival for stage I myeloma has not been reached, stage II myeloma is 83 months, and stage III myeloma is 43 months. A robust and dynamic landscape in myeloma therapy prevents a clear attribution to individual agents, whether oral or parenteral, in improving OS. Thus, 3-year RMST, while appropriate for 2006-2011, may not be relevant today.

Applications for Clinical Practice

The oncology community routinely encounters difficulty in initiating therapy using oral agents rapidly after diagnosis of myeloma. The retrospective data analyzed in the current study suggests that delay in initiating or unavailability of oral agents may adversely impact OS. The common approach of initiating parenteral therapy while awaiting approvals from payers or charity programs and subsequently adding oral therapy when available has not been studied in assessing OS. The oncology community should initiate plans to obtain prescription drug coverage through either Medicare part D, Medicaid, a sponsored plan, or financial assistance charity programs as soon as possible after diagnosis of myeloma. Moreover, continuation of these prescription drug plans should be strongly considered throughout the course of myeloma, as subsequent lines of treatment will quite likely involve other active and approved oral agents, such as pomalidomide, ixazomib, and panobinostat, besides other supportive therapy.

One of the mechanisms to obtain prescription drug coverage includes enrollment in state Medicaid programs for those who are eligible. Currently, 17 states have not yet adopted Medicaid expansion under the Affordable Care Act. Expansion of Medicaid in these states could increase availability of prescription drug benefits. In this study, 15.8% of Medicare and Medicaid dual enrollees with access to oral agents at low or no cost did not receive myeloma care, slightly higher than the 13.1% with no prescription drug coverage. Lower utilization in this population may be explained based on differences in comorbidities or socioeconomic conditions rather than availability of a prescription plan.

The incidence of myeloma is expected to be higher in Medicare beneficiaries, and according to one estimate, in 2030 and beyond nearly 75% of diagnosed myeloma patients will be aged 64 to 84 years, an increase from nearly 66% today.⁷ Changing demographics, increasing oral therapy options, and patient convenience demand attention to providing prescription drug coverage to all Medicare beneficiaries. This study lends support to that demand.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To investigate the relationship between prescription drug coverage, receipt of active myeloma therapy, and overall survival (OS) among Medicare beneficiaries with multiple myeloma.

Design. Case-control and retrospective cohort archival data research.

Setting and participants. Authors examined SEER-Medicare registry and extracted patients with histologically confirmed multiple myeloma diagnosed in the period 2006 to 2011. Availability of complete Medicare part A/B claims from 1 year before diagnosis until December 2013 was required for analysis. Patients with Medicare advantage or managed care plans did not have claims data available and hence were excluded. Beneficiaries with a diagnosis of diffuse large B-cell lymphoma (DLBCL), who typically receive parenteral drugs for lymphoma therapy, were used as a control cohort.

Main outcome measures. Association between prescription drug coverage status and OS was the primary outcome measure of interest. Authors reported 3-year restricted survival time (RMST) ratios to compare OS among the beneficiaries with different prescription drug coverages. Receipt of active myeloma therapy among beneficiaries was also studied. Relative risk, adjusting for patient and disease-related characteristics, was reported to examine receipt of active myeloma therapy.

Results. Records of 9755 Medicare beneficiaries were evaluated. Of these, 1460 (15%) had no prescription coverage at diagnosis, 3283 (34%) had part D plan prescription benefits, 3607 (37%) had sponsored prescription coverage through an employer, federal employer, or veterans plan, and 1405 (14%) had a Medicaid prescription plan. Beneficiaries without coverage had fewer comorbidities, including anemia, neuropathy, or renal disease, than those with part D prescription coverage or Medicaid. Of those without any prescription drug coverage, 41% obtained prescription plan coverage after diagnosis of myeloma by the following January. Conversely, only 19% of patients with DLBCL and no coverage obtained a prescription plan.

Patients with myeloma were followed for 4.9 years and median survival was 2.3 years, with a 3-year OS rate of 43.1% (95% confidence interval [CI], 42.1%-44.1%). Relative to the group without coverage, survival was 16% longer in the Medicare part D group and sponsored plan group (RMST 1.16; 95% CI, 1.12-1.21). Medicaid/Medicare dual beneficiaries had worse OS in both myeloma and DLBCL consistent with poor performance status and unfavorable baseline comorbidities. However, among patients with myeloma, Medicaid/Medicare dual beneficiaries had better survival (RMST 1.08; 95% CI, 1.03-1.13) compared to the group without coverage. There was no difference in OS for those with or without prescription drug coverage in the DLBCL cohort.

There were significant differences in treatment of myeloma based on types of prescription drug coverage. Due to increasing use of bortezomib following its approval by the U.S. Food and Drug Administration (FDA), parenteral chemotherapy use doubled from 24% to 48% from 2006 to 2011, and utility of active myeloma care increased from 88% to 91%. Medicare part D plan enrollees were 6% more likely to receive active myeloma care, and both Medicaid group and sponsored plan group beneficiaries were equally likely to receive active myeloma care compared to beneficiaries without prescription coverage. Medicaid enrollees were less likely to receive parenteral therapy.

Conclusion. Medicare beneficiaries with prescription drug coverage and multiple myeloma are more likely to receive myeloma therapy and have longer OS compared to those without prescription drug coverage.

Commentary

First-line therapy of multiple myeloma has evolved over the past 2 decades. Parenteral agents such as vincristine, adriamycin, dexamethasone, and cyclophosphamide and oral therapy with melphalan and prednisone were the mainstay of treatment in the past. In the past decade, the arrival of oral therapy using thalidomide or lenalidomide and parenteral therapy using bortezomib has increased OS in patients with myeloma. Most recently, a combination of lenalidomide, bortezomib, and dexamethasone has emerged as one of the frontline therapies of choice.¹ Incorporation of bortezomib or an oral immunomodulatory drug is almost universal in first-line therapy.

Oral antineoplastic therapy is increasingly being approved by the FDA and being utilized in the community. During the period 2016-2018, more than half the new FDA-approved oncology drugs were in oral formulation.² As such, access to these agents is crucial in cancer therapy. The cost of oral therapy in patients without prescription drug coverage is sometimes more than $10,000 per month, which represents a significant impediment to its adoption. Forty-three states and Washington, DC, have enacted drug parity laws that require patients to pay no more for an oral cancer treatment than they would for an infusion. However, currently there is no such federal law, and Medicare beneficiaries must participate either through part D, state Medicaid, or a sponsored program to obtain prescription drug coverage. Despite being enrolled in part D, many beneficiaries fall into the “doughnut hole” (the requirement of Part D beneficiaries with high prescription drug expenses to pay more once the total cost of their medicines reaches a certain threshold) for prescription drugs at the time of need. From 2019 onward, enrollees will see significant, yet sometimes still insufficient, coverage benefits due to ending of the doughnut hole.³ Only a very limited number of oral chemotherapy agents are covered through Medicare part B, and of those covered, only oral melphalan is used for myeloma.

The authors have acknowledged multiple limitations of their investigation, including possible unobserved clinical differences between beneficiaries. SEER-Medicare registry has limitations in obtaining individual level data and may not contain specific results of cytogenetics, laboratory risk markers, and response to therapy, which are important to determine overall outcome. A prospective evaluation may be more suitable to assess these variables independently or through a multivariate analysis in determining receipt of therapy on OS, although such a study is currently not feasible.

The indicator of active myeloma care was defined as 2 or more outpatient physician visits or receipt of parenteral chemotherapy. This definition is somewhat suboptimal, as often patients with myeloma are under surveillance and may not necessarily be receiving active treatment. Moreover, the exact prescription pattern of lenalidomide, the most active first-line oral therapy, could not be captured from this retrospective registry review. Therefore, definitive conclusions regarding use of lenalidomide and thalidomide and receipt of therapy in this population cannot be made.

A significant improvement in OS has been established using maintenance lenalidomide following high-dose chemotherapy and stem cell transplantation.⁴ Only 5% of this study population received stem cell transplantation. This may be due to a median age of 77 years at diagnosis in the group studied, higher than the 66 to 70 years previously published.⁵ Stem cell transplantation is now commonly being used even in the older population. The 3-year survival of 83% following stem cell transplantation in myeloma patients aged 75 to 84 years was nearly identical to that of the younger population.⁶ Since stem cell transplantation is feasible in older Medicare beneficiaries and maintenance lenalidomide for 2 years following transplant improves survival, the option of providing maintenance therapy with oral lenalidomide must be made available to Medicare beneficiaries. Due to a very limited use of transplantation in this study, the impact of oral lenalidomide maintenance in OS cannot be judged.

Of the patients reviewed in this study, 6% had a listed diagnosis of plasmacytoma. These individuals typically are treated with radiation therapy only. It is unclear if these patients also received any systemic myeloma therapy or if they ever progressed to myeloma. Availability of prescription drug coverage may not be relevant to this group. Also, the authors reported that part D participants were less likely to receive classic cytotoxic chemotherapy. This may be somewhat irrelevant in Medicare beneficiaries with a median age of 77 years for current practice, as frontline induction with old classic cytotoxic chemotherapy is less commonly used in this population.

Investigators have appropriately recognized a lack of ability to discern whether inferior survival in the group without prescription drug coverage was the result of not receiving therapy at all or inability to receive oral immunomodulatory drugs. There would have been little reason for not proceeding to parenteral therapy. As noted, 41% of beneficiaries without coverage at diagnosis subsequently obtained coverage but continued to have significantly worse survival. Cause of death, including whether related to myeloma, was not reported. The authors suggest that early separation of survival curves could therefore be reflective of suboptimal first-line therapy that lacked oral immunomodulatory drugs. During the study period 2006-2011, first-line use of lenalidomide was common.

Median survival of patients with myeloma in this study was only 27 months. According to the American Cancer Society, in 2018 median survival for stage I myeloma has not been reached, stage II myeloma is 83 months, and stage III myeloma is 43 months. A robust and dynamic landscape in myeloma therapy prevents a clear attribution to individual agents, whether oral or parenteral, in improving OS. Thus, 3-year RMST, while appropriate for 2006-2011, may not be relevant today.

Applications for Clinical Practice

The oncology community routinely encounters difficulty in initiating therapy using oral agents rapidly after diagnosis of myeloma. The retrospective data analyzed in the current study suggests that delay in initiating or unavailability of oral agents may adversely impact OS. The common approach of initiating parenteral therapy while awaiting approvals from payers or charity programs and subsequently adding oral therapy when available has not been studied in assessing OS. The oncology community should initiate plans to obtain prescription drug coverage through either Medicare part D, Medicaid, a sponsored plan, or financial assistance charity programs as soon as possible after diagnosis of myeloma. Moreover, continuation of these prescription drug plans should be strongly considered throughout the course of myeloma, as subsequent lines of treatment will quite likely involve other active and approved oral agents, such as pomalidomide, ixazomib, and panobinostat, besides other supportive therapy.

One of the mechanisms to obtain prescription drug coverage includes enrollment in state Medicaid programs for those who are eligible. Currently, 17 states have not yet adopted Medicaid expansion under the Affordable Care Act. Expansion of Medicaid in these states could increase availability of prescription drug benefits. In this study, 15.8% of Medicare and Medicaid dual enrollees with access to oral agents at low or no cost did not receive myeloma care, slightly higher than the 13.1% with no prescription drug coverage. Lower utilization in this population may be explained based on differences in comorbidities or socioeconomic conditions rather than availability of a prescription plan.

The incidence of myeloma is expected to be higher in Medicare beneficiaries, and according to one estimate, in 2030 and beyond nearly 75% of diagnosed myeloma patients will be aged 64 to 84 years, an increase from nearly 66% today.⁷ Changing demographics, increasing oral therapy options, and patient convenience demand attention to providing prescription drug coverage to all Medicare beneficiaries. This study lends support to that demand.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

References

1. CDC. From https://www.cdc.gov/obesity/data/adult.html. Accessed on 11 September 2018.

2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

4. Allison DB et al. Obesity. 2012;20:330-42.

5. Smith SR et al. N Engl J Med. 2010;363:245-56.

6. Apovian CM et al. Obesity. 2013;21:935-43.

7. Pi-Sunyer X et al. N Engl J Med. 2015;373:11-22.

8. Colguitt JL et al. Cochrane Database Syst Rev. 2014;8(8):CD003641.

9. Ponce J et al. Surg Obes Relat Dis. 2015;11(6):1199-200.

10. Jirapinyo P, Thompson CC et al. Clin Gastroenterol Hepatol. 2017;15(5):619-30.

11. Sullivan S et al.Gastroenterology. 2017;152(7):1791-801.

12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

14. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;81:AB147.

15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

16. Ponce J et al. Surg Obes Relat Dis. 2015;11:874-81.

17. Food and Drug Administration. Summary and effectiveness data (SSED): Obalon Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160001b.pdf. 2016:1-46.

18. Sullivan S et al. Gastroenterology. 2016;150:S1267.

19. Popov VB et al. Am J Gastroenterol. 2017;112:429-39.

20. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;82(3):425-38.

21. Espinos JC et al. Obes Surg. 2013;23(9):1375-83.

22. Sullivan S et al. Obesity. 2017;25:294-301.

23. Miller K et al. Obesity Surg. 2017;27(2):310-22.

24. Jirapinyo P et al. Gastrointest Endosc. 2018;87(6):AB604-AB605.

25. Jirapinyo P, Thompson CC. Video GIE. 2018;3(10):296-300.

26. Campos J et al. SAGES 2013 Presentation. Baltimore, MD. 19 April 2013.

27. Kumar N et al. Gastroenterology. 2014;146(5):S571-2.

28. Kumar N et al. Surg Endosc. 2018;32(4):2159-64.

29. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2017;15:37-43.

30. Lopez-Nava G et al. Obes Surg. 2017;27(10):2649-55.

31. Food and Drug Administration. Summary of safety and effectiveness (SSED): AspireAssist. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150024b.pdf. FDA,ed,2016:1-36.

32. Thompson CC et al. Am J Gastroenterol. 2017;112:447-57.

33. SAGES abstract archives. SAGES. Available from: http://www.sages.org/meetings/annual-meeting/abstracts-archive/first-clinical-experience-with-the-transpyloric-shuttle-tpsr-device-a-non-surgical-endoscopic treatment-for-obesity-results-from-a-3-month-and-6-month-study. Accessed Sept. 12, 2018.

34. Sjostrom L et al. N Engl J Med. 2007;357:741-52.

35. Adams TD et al. N Engl J Med. 2017;377:1143-55.

36. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2011;9:228-33.

37. Thompson CC et al. Gastroenterology. 2013;145(1):129-37.

38. Jirapinyo P et al. Endoscopy. 2018;50(4):371-7.

39. Kumar N, Thompson CC. Gastrointest Endosc. 2016;83(4):776-9.

40. Jirapinyo P et al. Gastrointest Endosc. 2017;85(5):AB93-94.

41. Jirapinyo P, Thompson CC et al. Comparison of a novel plication technique to suturing for endoscopic outlet reduction for the treatment of weight regain after Roux-en-Y gastric bypass. Obesity Week 2018. Poster presentation.

42. Kaplan LM et al. EndoBarrier therapy is associated with glycemic improvement, weight loss and safety issues in patients with obesity and type 2 diabetes on oral anti-hyperglycemic agents (The ENDO Trial). In: Oral Presentation at the 76th American Diabetes Association (ADA) Annual Meeting: 2016 June 10-14: New Orleans. Abstract number 362-LB.

43. Jirapinyo P et al. Diabetes Care. 2018;41(5):1106-15.

44. Rajagopalan H et al. Diabetes Care. 2016;39(12):2254-61.

45. Sandler BJ et al. Surgical Endosc. 2015;29:3298-303.

46. Machytka E et al. Gastrointest Endosc. 2017;86(5):904-12.

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

References

1. CDC. From https://www.cdc.gov/obesity/data/adult.html. Accessed on 11 September 2018.

2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

4. Allison DB et al. Obesity. 2012;20:330-42.

5. Smith SR et al. N Engl J Med. 2010;363:245-56.

6. Apovian CM et al. Obesity. 2013;21:935-43.

7. Pi-Sunyer X et al. N Engl J Med. 2015;373:11-22.

8. Colguitt JL et al. Cochrane Database Syst Rev. 2014;8(8):CD003641.

9. Ponce J et al. Surg Obes Relat Dis. 2015;11(6):1199-200.

10. Jirapinyo P, Thompson CC et al. Clin Gastroenterol Hepatol. 2017;15(5):619-30.

11. Sullivan S et al.Gastroenterology. 2017;152(7):1791-801.

12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

14. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;81:AB147.

15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

16. Ponce J et al. Surg Obes Relat Dis. 2015;11:874-81.

17. Food and Drug Administration. Summary and effectiveness data (SSED): Obalon Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160001b.pdf. 2016:1-46.

18. Sullivan S et al. Gastroenterology. 2016;150:S1267.

19. Popov VB et al. Am J Gastroenterol. 2017;112:429-39.

20. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;82(3):425-38.

21. Espinos JC et al. Obes Surg. 2013;23(9):1375-83.

22. Sullivan S et al. Obesity. 2017;25:294-301.

23. Miller K et al. Obesity Surg. 2017;27(2):310-22.

24. Jirapinyo P et al. Gastrointest Endosc. 2018;87(6):AB604-AB605.

25. Jirapinyo P, Thompson CC. Video GIE. 2018;3(10):296-300.

26. Campos J et al. SAGES 2013 Presentation. Baltimore, MD. 19 April 2013.

27. Kumar N et al. Gastroenterology. 2014;146(5):S571-2.

28. Kumar N et al. Surg Endosc. 2018;32(4):2159-64.

29. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2017;15:37-43.

30. Lopez-Nava G et al. Obes Surg. 2017;27(10):2649-55.

31. Food and Drug Administration. Summary of safety and effectiveness (SSED): AspireAssist. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150024b.pdf. FDA,ed,2016:1-36.

32. Thompson CC et al. Am J Gastroenterol. 2017;112:447-57.

33. SAGES abstract archives. SAGES. Available from: http://www.sages.org/meetings/annual-meeting/abstracts-archive/first-clinical-experience-with-the-transpyloric-shuttle-tpsr-device-a-non-surgical-endoscopic treatment-for-obesity-results-from-a-3-month-and-6-month-study. Accessed Sept. 12, 2018.

34. Sjostrom L et al. N Engl J Med. 2007;357:741-52.

35. Adams TD et al. N Engl J Med. 2017;377:1143-55.

36. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2011;9:228-33.

37. Thompson CC et al. Gastroenterology. 2013;145(1):129-37.

38. Jirapinyo P et al. Endoscopy. 2018;50(4):371-7.

39. Kumar N, Thompson CC. Gastrointest Endosc. 2016;83(4):776-9.

40. Jirapinyo P et al. Gastrointest Endosc. 2017;85(5):AB93-94.

41. Jirapinyo P, Thompson CC et al. Comparison of a novel plication technique to suturing for endoscopic outlet reduction for the treatment of weight regain after Roux-en-Y gastric bypass. Obesity Week 2018. Poster presentation.

42. Kaplan LM et al. EndoBarrier therapy is associated with glycemic improvement, weight loss and safety issues in patients with obesity and type 2 diabetes on oral anti-hyperglycemic agents (The ENDO Trial). In: Oral Presentation at the 76th American Diabetes Association (ADA) Annual Meeting: 2016 June 10-14: New Orleans. Abstract number 362-LB.

43. Jirapinyo P et al. Diabetes Care. 2018;41(5):1106-15.

44. Rajagopalan H et al. Diabetes Care. 2016;39(12):2254-61.

45. Sandler BJ et al. Surgical Endosc. 2015;29:3298-303.

46. Machytka E et al. Gastrointest Endosc. 2017;86(5):904-12.

Editor's Note

Gastroenterologists are becoming increasingly involved in the management of obesity. While prior therapy for obesity was mainly based on lifestyle changes, medication, or surgery, the new and exciting field of endoscopic bariatric and metabolic therapies has recently garnered incredible attention and momentum.

In this quarter’s In Focus article, brought to you by The New Gastroenterologist, Pichamol Jirapinyo and Christopher Thompson (Brigham and Women’s Hospital) provide an outstanding overview of the gastric and small bowel endoscopic interventions that are either already approved for use in obesity or currently being studied. This field is moving incredibly fast, and knowledge and understanding of these endoscopic therapies for obesity will undoubtedly be important for our field.

Bryson W. Katona, MD, PhD
Editor in Chief, The New Gastroenterologist

Introduction

Obesity is a rising pandemic. As of 2016, 93.3 million U.S. adults had obesity, representing 39.8% of our adult population.¹ It is estimated that approximately $147 billion is spent annually on caring for patients with obesity. Traditionally, the management of obesity includes lifestyle therapy (diet and exercise), pharmacotherapy (six Food and Drug Administration–approved medications for obesity), and bariatric surgery (sleeve gastrectomy [SG] and Roux-en-Y gastric bypass [RYGB]). Nevertheless, intensive lifestyle intervention and pharmacotherapy are associated with approximately 3.1%-6.6% total weight loss (TWL),^2-7 and bariatric surgery is associated with 20%-33.3% TWL.⁸ However, less than 2% of patients who are eligible for bariatric surgery elect to undergo surgery, leaving a large proportion of patients with obesity untreated or undertreated.⁹

Copyright Elsevier and AGA Institute (2017)

Endoscopic bariatric and metabolic therapies (EBMTs) encompass an emerging field for the treatment of obesity. In general, EBMTs are associated with greater weight loss than are lifestyle intervention and pharmacotherapy, but with a less- invasive risk profile than bariatric surgery. EBMTs may be divided into two general categories – gastric and small bowel interventions (Figure 1 and Table 1). Gastric EBMTs are effective at treating obesity, while small bowel EBMTs are effective at treating metabolic diseases with a variable weight loss profile depending on the device.^10,11

Of note, a variety of study designs (including retrospective series, prospective series, and randomized trials with and without shams) have been employed, which can affect outcomes. Therefore, weight loss comparisons among studies are challenging and should be considered in this context.
 

Gastric interventions

Currently, there are three types of EBMTs that are FDA approved and used for the treatment of obesity. These include intragastric balloons (IGBs), plications and suturing, and aspiration therapy (AT). Other technologies that are under investigation also will be briefly covered.

Intragastric balloons

An intragastric balloon is a space-occupying device that is placed in the stomach. The mechanism of action of IGBs involves delaying gastric emptying, which leads to increased satiety.¹² There are several types of IGBs available worldwide differing in techniques of placement and removal (endoscopic versus fluoroscopic versus swallowable), materials used to fill the balloon (fluid-filled versus air-filled), and the number of balloons placed (single versus duo versus three-balloon). At the time of this writing, three IGBs are approved by the FDA (Orbera, ReShape, and Obalon), all for patients with body mass indexes of 30-40 kg/m², and two others are in the process of obtaining FDA approval (Spatz and Elipse).

Orbera gastric balloon (Apollo Endosurgery, Austin, Tex.) is a single fluid-filled IGB that is endoscopically placed and removed at 6 months. The balloon is filled with 400-700 cc of saline with or without methylene blue (to identify leakage or rupture). Recently, Orbera365, which allows the balloon to stay for 12 months instead of 6 months, has become available in Europe; however, it is yet to be approved in the United States. The U.S. pivotal trial (Orbera trial) including 255 subjects (125 Orbera arm versus 130 non-sham control arm) demonstrated 10.2% TWL in the Orbera group compared with 3.3% TWL in the control group at 6 months based on intention-to-treat (ITT) analysis. This difference persisted at 12 months (6 months after explantation) with 7.6% TWL for the Orbera group versus 3.1% TWL for the control group.^13,14

ReShape integrated dual balloon system (ReShape Lifesciences, San Clemente, Calif.) consists of two connected fluid-filled balloons that are endoscopically placed and removed at 6 months. Each balloon is filled with 375-450 cc of saline mixed with methylene blue. The U.S. pivotal trial (REDUCE trial) including 326 subjects (187 ReShape arm versus 139 sham arm) demonstrated 6.8% TWL in the ReShape group compared with 3.3% TWL in the sham group at 6 months based on ITT analysis.^15,16

Obalon balloon system (Obalon Therapeutics, Carlsbad, Calif.) is a swallowable, gas-filled balloon system that requires endoscopy only for removal. During placement, a capsule is swallowed under fluoroscopic guidance. The balloon is then inflated with 250 cc of nitrogen mix gas prior to tube detachment. Up to three balloons may be swallowed sequentially at 1-month intervals. At 6 months from the first balloon placement, all balloons are removed endoscopically. The U.S. pivotal trial (SMART trial) including 366 subjects (185 Obalon arm versus 181 sham capsule arm) demonstrated 6.6% TWL in the Obalon group compared with 3.4% TWL in the sham group at 6 months based on ITT analysis.^17,18

Two other balloons that are currently under investigation in the United States are the Spatz3 adjustable balloon system (Spatz Medical, Great Neck, N.Y.) and Elipse balloon (Allurion Technologies, Wellesley, Mass.). The Spatz3 is a fluid-filled balloon that is placed and removed endoscopically. It consists of a single balloon and a connecting tube that allows volume adjustment for control of symptoms and possible augmentation of weight loss. The U.S. pivotal trial was recently completed and the data are being reviewed by the FDA. The Elipse is a swallowable fluid-filled balloon that does not require endoscopy for placement or removal. At 4 months, the balloon releases fluid allowing it to empty and pass naturally. The U.S. pivotal trial (ENLIGHTEN trial) is currently underway.

A meta-analysis of randomized controlled trials revealed improvement in most metabolic parameters (diastolic blood pressure, fasting glucose, hemoglobin A_1c, and waist circumference) following IGB compared with controls.¹⁹ Nausea and vomiting are seen in approximately 30% and should be addressed appropriately. Pooled serious adverse event (SAE) rate was 1.5%, which included migration, perforation, and death. Since 2016, 14 deaths have been reported according to the FDA MAUDE database. Corporate response was that over 295,000 balloons had been distributed worldwide with a mortality rate of less than 0.01%.²⁰
 

Plication and suturing

Currently, there are two endoscopic devices that are approved for the general indication of tissue apposition. These include the Incisionless Operating Platform (IOP) (USGI Medical, San Clemente, Calif.) and the Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Tex.). These devices are used to remodel the stomach to create a sleeve-like structure to induce weight loss.

The IOP system consists of a transport, which is a 54-Fr flexible endoscope. It consists of four working channels that accommodate a G-Prox (for tissue approximation), a G-Lix (for tissue grasping), and an ultrathin endoscope (for visualization). In April 2008, Horgan performed the first-in-human primary obesity surgery endoluminal (POSE) procedure in Argentina. The procedure involves the use of the IOP system to place plications primarily in the fundus to modify gastric accommodation.²¹ The U.S. pivotal trial (ESSENTIAL trial) including 332 subjects (221 POSE arm versus 111 sham arm) demonstrated 5.0% TWL in the POSE group compared with 1.4% in the sham group at 12 months based on ITT analysis.²² A European multicenter randomized controlled trial (MILEPOST trial) including 44 subjects (34 POSE arm versus 10 non-sham control arm) demonstrated 13.0% TWL in the POSE group compared with 5.3% TWL in the control group at 12 months.²³ A recent meta-analysis including five studies with 586 subjects showed pooled weight loss of 13.2% at 12-15 months following POSE with a pooled serious adverse event rate of 3.2%.²⁴ These included extraluminal bleeding, minor bleeding at the suture site, hepatic abscess, chest pain, nausea, vomiting, and abdominal pain. A distal POSE procedure with a new plication pattern focusing on the gastric body to augment the effect on gastric emptying has also been described.²⁵

The Overstitch is an endoscopic suturing device that is mounted on a double-channel endoscope. At the tip of the scope, there is a curved suture arm and an anchor exchange that allow the needle to pass back and forth to perform full-thickness bites. The tissue helix may also be placed through the second channel to grasp tissue. In April 2012, Thompson performed the first-in-human endoscopic sutured/sleeve gastroplasty (ESG) procedure in India, which was published together with cases performed in Panama and the Dominican Republic.^26-28 This procedure involves the use of the Overstitch device to place several sets of running sutures along the greater curvature of the stomach to create a sleeve-like structure. It is thought to delay gastric emptying and therefore increase satiety.²⁹ The largest multicenter retrospective study including 248 patients demonstrated 18.6% TWL at 2 years with 2% SAE rate including perigastric fluid collections, extraluminal hemorrhage, pulmonary embolism, pneumoperitoneum, and pneumothorax.³⁰

Aspiration therapy

Aspiration therapy (AT; Aspire Bariatrics, King of Prussia, Pa.) allows patients to remove 25%-30% of ingested calories at approximately 30 minutes after meals. AT consists of an A-tube, which is a 26-Fr gastrostomy tube with a 15-cm fenestrated drainage catheter placed endoscopically via a standard pull technique. At 1-2 weeks after A-tube placement, the tube is cut down to the skin and connected to the port prior to aspiration. AT is approved for patients with a BMI of 35-55 kg/m².³¹ The U.S. pivotal trial (PATHWAY trial) including 207 subjects (137 AT arm versus 70 non-sham control arm) demonstrated 12.1% TWL in the AT group compared to 3.5% in the control group at 12 months based on ITT analysis. The SAE rate was 3.6% including severe abdominal pain, peritonitis, prepyloric ulcer, and A-tube replacement due to skin-port malfunction.³²

Transpyloric shuttle

The transpyloric shuttle (TPS; BAROnova, Goleta, Calif.) consists of a spherical bulb that is attached to a smaller cylindrical bulb by a flexible tether. It is placed and removed endoscopically at 6 months. TPS resides across the pylorus creating intermittent obstruction that may result in delayed gastric emptying. A pilot study including 20 patients demonstrated 14.5% TWL at 6 months.³³ The U.S. pivotal trial (ENDObesity II trial) was recently completed and the data are being reviewed by the FDA.

Revision for weight regain following bariatric surgery

Weight regain is common following RYGB^34,35 and can be associated with dilation of the gastrojejunal anastomosis (GJA).³⁶ Several procedures have been developed to treat this condition by focusing on reduction of GJA size and are available in the United States (Figure 2). These procedures have level I evidence supporting their use and include transoral outlet reduction (TORe) and restorative obesity surgery endoluminal (ROSE).³⁷ TORe involves the use of the Overstitch to place sutures at the GJA. At 1 year, patients had 8.4% TWL with improvement in comorbidities.³⁸ Weight loss remained significant up to 3-5 years.^39,40 The modern ROSE procedure utilizes the IOP system to place plications at the GJA and distal gastric pouch following argon plasma coagulation (APC). A small series showed 12.4% TWL at 6 months.⁴¹ APC is also currently being investigated as a standalone therapy for weight regain in this population.

Small bowel interventions

There are several small bowel interventions, with different mechanisms of action, available internationally. Many of these are under investigation in the United States; however, none are currently FDA approved.

Duodenal-jejunal bypass liner

Duodenal-jejunal bypass liner (DJBL; GI Dynamics, Boston, Mass.) is a 60-cm fluoropolymer liner that is endoscopically placed and removed at 12 months. It is anchored at the duodenal bulb and ends at the jejunum. By excluding direct contact between chyme and the proximal small bowel, DJBL is thought to work via foregut mechanism where there is less inhibition of the incretin effect (greater increase in insulin secretion following oral glucose administration compared to intravenous glucose administration due to gut-derived factors that enhance insulin secretion) leading to improved insulin resistance. In addition, the enteral transit of chyme and bile is altered suggesting the possible role of the hindgut mechanism. The previous U.S. pivotal trial (ENDO trial) met efficacy endpoints. However, the study was stopped early by the company because of a hepatic abscess rate of 3.5%, all of which were treated conservatively.⁴² A new U.S. pivotal study is currently planned. A meta-analysis of 17 published studies, all of which were from outside the United States, demonstrated a significant decrease in hemoglobin A_1c of 1.3% and 18.9% TWL at 1 year following implantation in patients with obesity with concomitant diabetes.⁴³
 

Duodenal mucosal resurfacing

Duodenal mucosal resurfacing (Fractyl, Lexington, Mass.) involves saline lifting of the duodenal mucosa circumferentially prior to thermal ablation using an inflated balloon filled with heated water. It is hypothesized that this may reset the diseased duodenal enteroendocrine cells leading to restoration of the incretin effect. A pilot study including 39 patients with poorly controlled diabetes demonstrated a decrease in hemoglobin A_1c of 1.2%. The SAE rate was 7.7% including duodenal stenosis, all of which were treated with balloon dilation.⁴⁴ The U.S. pivotal trial is currently planned.

Gastroduodenal-jejunal bypass

Gastroduodenal-jejunal bypass (ValenTx., Hopkins, Minn.) is a 120-cm sleeve that is anchored at the gastroesophageal junction to create the anatomic changes of RYGB. It is placed and removed endoscopically with laparoscopic assistance. A pilot study including 12 patients demonstrated 35.9% excess weight loss at 12 months. Two out of 12 patients had early device removal due to intolerance and they were not included in the weight loss analysis.⁴⁵

Incisionless magnetic anastomosis system

The incisionless magnetic anastomosis system (GI Windows, West Bridgewater, Mass.) consists of self-assembling magnets that are deployed under fluoroscopic guidance through the working channel of colonoscopes to form magnetic octagons in the jejunum and ileum. After a week, a compression anastomosis is formed and the coupled magnets pass spontaneously. A pilot study including 10 patients showed 14.6% TWL and a decrease in hemoglobin A_1c of 1.9% (for patients with diabetes) at 1 year.⁴⁶ A randomized study outside the United States is currently underway.

Summary

Endoscopic bariatric and metabolic therapies are emerging as first-line treatments for obesity in many populations. They can serve as a gap therapy for patients who do not qualify for surgery, but also may have a specific role in the treatment of metabolic comorbidities. This field will continue to develop and improve with the introduction of personalized medicine leading to better patient selection, and newer combination therapies. It is time for gastroenterologists to become more involved in the management of this challenging condition.

Dr. Jirapinyo is an advanced and bariatric endoscopy fellow, Brigham and Women’s Hospital, Harvard Medical School, Boston; Dr. Thompson is director of therapeutic endoscopy, Brigham and Women’s Hospital, and associate professor of medicine, Harvard Medical School. Dr. Jirapinyo has served as a consultant for GI Dynamics and holds royalties for Endosim. Dr. Thompson has contracted research for Aspire Bariatrics, USGI Medical, Spatz, and Apollo Endosurgery; has served as a consultant for Boston Scientific, Covidien, USGI Medical, Olympus, and Fractyl; holds stocks and royalties for GI Windows and Endosim, and has served as an expert reviewer for GI Dynamics.
 

References

1. CDC. From https://www.cdc.gov/obesity/data/adult.html. Accessed on 11 September 2018.

2. Aronne LJ et al. Obesity. 2013;21:2163-71.

3. Torgerson JS et al. Diabetes Care. 2004;27:155-61.

4. Allison DB et al. Obesity. 2012;20:330-42.

5. Smith SR et al. N Engl J Med. 2010;363:245-56.

6. Apovian CM et al. Obesity. 2013;21:935-43.

7. Pi-Sunyer X et al. N Engl J Med. 2015;373:11-22.

8. Colguitt JL et al. Cochrane Database Syst Rev. 2014;8(8):CD003641.

9. Ponce J et al. Surg Obes Relat Dis. 2015;11(6):1199-200.

10. Jirapinyo P, Thompson CC et al. Clin Gastroenterol Hepatol. 2017;15(5):619-30.

11. Sullivan S et al.Gastroenterology. 2017;152(7):1791-801.

12. Gomez V et al. Obesity. 2016;24(9):1849-53.

13. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ORBERA Intragastric Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140008b.pdf. 2015:1-32.

14. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;81:AB147.

15. Food and Drug Administration. Summary of safety and effectiveness data (SSED) ReShape Integrated Dual Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140012b.pdf. 2015:1-43.

16. Ponce J et al. Surg Obes Relat Dis. 2015;11:874-81.

17. Food and Drug Administration. Summary and effectiveness data (SSED): Obalon Balloon System. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160001b.pdf. 2016:1-46.

18. Sullivan S et al. Gastroenterology. 2016;150:S1267.

19. Popov VB et al. Am J Gastroenterol. 2017;112:429-39.

20. Abu Dayyeh BK et al. Gastrointest Endosc. 2015;82(3):425-38.

21. Espinos JC et al. Obes Surg. 2013;23(9):1375-83.

22. Sullivan S et al. Obesity. 2017;25:294-301.

23. Miller K et al. Obesity Surg. 2017;27(2):310-22.

24. Jirapinyo P et al. Gastrointest Endosc. 2018;87(6):AB604-AB605.

25. Jirapinyo P, Thompson CC. Video GIE. 2018;3(10):296-300.

26. Campos J et al. SAGES 2013 Presentation. Baltimore, MD. 19 April 2013.

27. Kumar N et al. Gastroenterology. 2014;146(5):S571-2.

28. Kumar N et al. Surg Endosc. 2018;32(4):2159-64.

29. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2017;15:37-43.

30. Lopez-Nava G et al. Obes Surg. 2017;27(10):2649-55.

31. Food and Drug Administration. Summary of safety and effectiveness (SSED): AspireAssist. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150024b.pdf. FDA,ed,2016:1-36.

32. Thompson CC et al. Am J Gastroenterol. 2017;112:447-57.

33. SAGES abstract archives. SAGES. Available from: http://www.sages.org/meetings/annual-meeting/abstracts-archive/first-clinical-experience-with-the-transpyloric-shuttle-tpsr-device-a-non-surgical-endoscopic treatment-for-obesity-results-from-a-3-month-and-6-month-study. Accessed Sept. 12, 2018.

34. Sjostrom L et al. N Engl J Med. 2007;357:741-52.

35. Adams TD et al. N Engl J Med. 2017;377:1143-55.

36. Abu Dayyeh BK et al. Clin Gastroenterol Hepatol. 2011;9:228-33.

37. Thompson CC et al. Gastroenterology. 2013;145(1):129-37.

38. Jirapinyo P et al. Endoscopy. 2018;50(4):371-7.

39. Kumar N, Thompson CC. Gastrointest Endosc. 2016;83(4):776-9.

40. Jirapinyo P et al. Gastrointest Endosc. 2017;85(5):AB93-94.

41. Jirapinyo P, Thompson CC et al. Comparison of a novel plication technique to suturing for endoscopic outlet reduction for the treatment of weight regain after Roux-en-Y gastric bypass. Obesity Week 2018. Poster presentation.

42. Kaplan LM et al. EndoBarrier therapy is associated with glycemic improvement, weight loss and safety issues in patients with obesity and type 2 diabetes on oral anti-hyperglycemic agents (The ENDO Trial). In: Oral Presentation at the 76th American Diabetes Association (ADA) Annual Meeting: 2016 June 10-14: New Orleans. Abstract number 362-LB.

43. Jirapinyo P et al. Diabetes Care. 2018;41(5):1106-15.

44. Rajagopalan H et al. Diabetes Care. 2016;39(12):2254-61.

45. Sandler BJ et al. Surgical Endosc. 2015;29:3298-303.

46. Machytka E et al. Gastrointest Endosc. 2017;86(5):904-12.