Clinical Review

Although evidence suggests that bipolar disorder (BD) and borderline personality disorder (BPD) are distinct entities, their differential diagnosis is often challenging as a result of considerable overlap of phenotypical features. Moreover, BD and BPD frequently co-occur, which makes it even more difficult to differentiate these 2 conditions. Strategies for improving diagnostic accuracy are critical to optimizing patients’ clinical outcomes and long-term prognosis. Misdiagnosing these 2 conditions can be particularly deleterious, and failure to recognize their co-occurrence can result in additional burden to typically complex and severe clinical presentations.

This article describes key aspects of the differential diagnosis between BD and BPD, emphasizing core features and major dissimilarities between these 2 conditions, and discusses the implications of misdiagnosis. The goal is to highlight the clinical and psychopathological aspects of BD and BPD to help clinicians properly distinguish these 2 disorders.

Psychopathological and sociodemographic correlates

Bipolar disorder is a chronic and severe mental illness that is classified based on clusters of symptoms—manic, hypomanic, and depressive.¹ It is among the 10 leading causes of disability worldwide, with significant morbidity arising from acute affective episodes and subacute states.² Data suggest the lifetime prevalence of BPD is 2.1%, and subthreshold forms may affect an additional 2.4% of the US population.³ The onset of symptoms typically occurs during late adolescence or early adulthood, and mood lability and cyclothymic temperament are the most common prodromal features.⁴

In contrast, personality disorders, such as BPD, are characteristically pervasive and maladaptive patterns of emotional responses that usually deviate from an individual’s stage of development and cultural background.¹ These disorders tend to cause significant impairment, particularly in personal, occupational, and social domains. Environmental factors, such as early childhood trauma, seem to play an important role in the genesis of personality disorders, which may be particularly relevant in BPD, a disorder characterized by marked impulsivity and a pattern of instability in personal relationships, self-image, and affect.^1,5,6 Similarly to BD, BPD is also chronic and highly disabling.

According to the National Survey on Alcohol and Related Conditions (NESARC), approximately 15% of US adults were found to have at least one type of personality disorder, and 6% met criteria for a cluster B personality disorder (antisocial, borderline, narcissistic, and histrionic).⁷ The lifetime prevalence of BPD is nearly 2%, with higher estimates observed in psychiatric settings.^7,8

As a result of the phenotypical resemblance between BD and BPD (Figure), the differential diagnosis is often difficult. Recent studies suggest that co-occurrence of BD and BPD is common, with rates of comorbid BPD as high as 29% in BD I and 24% in BD II.^8,9 On the other hand, nearly 20% of individuals with BPD seem to have comorbid BD.^8,9 Several studies suggest that comorbid personality disorders represent a negative prognostic factor in the course of mood disorders, and the presence of BPD in patients with BD seems to be associated with more severe clinical presentations, greater treatment complexity, a higher number of depressive episodes, poor inter-episode functioning, and higher rates of other comorbidities, such as substance use disorders (SUDs).^8-11 The effect of BD on the course of BPD is unclear and fairly unexplored, although it has been suggested that better control of mood symptoms may lead to more stable psychosocial functioning in BPD.⁹

Whether BD and BPD are part of the same spectrum is a matter for debate.^12-14 Multidimensional approaches have been proposed to better characterize these disorders in at-risk populations, based on structured interviews, self-administered and clinician-rated clinical scales (Table 1), neuroimaging studies, biological markers, and machine-learning models.^15,16 Compelling evidence suggests that BD and BPD have distinct underlying neurobiological and psychopathological mechanisms^12,13; however, the differential diagnosis still relies on phenotypical features, since the search for biological markers has not yet identified specific biomarkers that can be used in clinical practice.

Continue to: Core features of BPD...

Core features of BPD, such as mood lability, impulsivity, and risk-taking behaviors, are also part of the diagnostic criteria for BD (Table 2).¹ Similarly, depressive symptoms prevail in the course of BD.^17,18 This adds complexity to the differential because “depressivity” is also part of the diagnostic criteria for BPD.¹ Therefore, comprehensive psychiatric assessments and longitudinal observations are critical to diagnostic accuracy and treatment planning. Further characterization of symptoms, such as onset patterns, clinical course, phenomenology of symptoms (eg, timing, frequency, duration, triggers), and personality traits, will provide information to properly distinguish these 2 syndromes when, for example, it is unclear if the “mood swings” and impulsivity are part of a mood or a personality disorder (Table 3).

Clinical features: A closer look

Borderline personality disorder. Affect dysregulation, emotional instability, impoverished and unstable self-image, and chronic feelings of emptiness are core features of BPD.^1,5,19 These characteristics, when combined with a fear of abandonment or rejection, a compromised ability to recognize the feelings and needs of others, and extremes of idealization-devaluation, tend to culminate in problematic and chaotic relationships.^6,19 Individuals with BPD may become suspicious or paranoid under stressful situations. Under these circumstances, individuals with BPD may also experience depersonalization and other dissociative symptoms.^6,20 The mood lability and emotional instability observed in patients with BPD usually are in response to environmental factors, and although generally intense and out of proportion, they tend to be ephemeral and short-lived, typically lasting a few hours.^1,5 The anxiety and depressive symptoms reported by patients with BPD frequently are associated with feelings of “falling apart” or “losing control,” pessimism, shame, and low self-esteem. Coping strategies tend to be poorly developed and/or maladaptive, and individuals with BPD usually display a hostile and antagonistic demeanor and engage in suicidal or non­suicidal self-injury (NSSI) behaviors as means to alleviate overwhelming emotional distress. Impulsivity, disinhibition, poor tolerance to frustration, and risk-taking behaviors are also characteristic of BPD.^1,5 As a result, BPD is usually associated with significant impairment in functioning, multiple hospitalizations, and high rates of comorbid mood disorders, posttraumatic stress disorder (PTSD), SUDs, and death by suicide.

Bipolar disorder. Conversely, the fluctuations in mood and affect observed in patients with BD are usually episodic rather than pervasive, and tend to last longer (typically days to weeks) compared with the transient mood shifts observed in patients with BPD.^4,17,18 The impulsivity, psychomotor agitation, and increased goal-directed activity reported by patients with BD are usually seen in the context of an acute affective episode, and are far less common during periods of stability or euthymic affect.^4,17,18 Grandiosity and inflated self-esteem—hallmarks of a manic or hypomanic state—seem to oppose the unstable self-image observed in BPD, although indecisiveness and low self-worth may be observed in individuals with BD during depressive episodes. Antidepressant-induced mania or hypomania, atypical depressive episodes, and disruptions in sleep and circadian rhythms may be predictors of BD.^4,21 Furthermore, although psychosocial stressors may be associated with acute affective episodes in early stages of bipolar illness, over time minimal stressors are necessary to ignite new affective episodes.^22,23 Although BD is associated with high rates of suicide, suicide attempts are usually seen in the context of an acute depressive episode, and NSSI behaviors are less common among patients with BD.²⁴

Lastly, other biographical data, such as a history of early life trauma, comorbidity, and a family history of psychiatric illnesses, can be particularly helpful in establishing the differential diagnosis between BD and BPD.²⁵ For instance, evidence suggests that the heritability of BD may be as high as 70%, which usually translates into an extensive family history of bipolar and related disorders.²⁶ In addition, studies suggest a high co-occurrence of anxiety disorders, attention-deficit/hyperactivity disorder, and SUDs in patients with BD, whereas PTSD, SUDs, and eating disorders tend to be highly comorbid with BPD.²⁷ Childhood adversity (ie, a history of physical, sexual, or emotional abuse, or neglect) seems to be pivotal in the genesis of BPD and may predispose these individuals to psychotic and dissociative symptoms, particularly those with a history of sexual abuse, while playing a more secondary role in BD.^28-31

Implications of misdiagnosis

In the view of the limitations of the existing models, multidimensional approaches are necessary to improve diagnostic accuracy. Presently, the differential diagnosis of BD and BPD continues to rely on clinical findings and syndromic classifications. Misdiagnosing BD and BPD has adverse therapeutic and prognostic implications.³² For instance, while psychotropic medications and neuromodulatory therapies (eg, electroconvulsive therapy, repetitive transcranial magnetic stimulation) are considered first-line treatments for patients with BD, psychosocial interventions tend to be adjunctive treatments in BD.³³ Conversely, although pharmacotherapy might be helpful for patients with BPD, psychosocial and behavioral interventions are the mainstay treatment for this disorder, with the strongest evidence supporting cognitive-behavioral therapy, dialectical behavioral therapy, mentalization-based therapy, and transference-focused therapy.^34-36 Thus, misdiagnosing BD as BPD with comorbid depression may result in the use of antidepressants, which can be detrimental in BD. Antidepressant treatment of BD, particularly as monotherapy, has been associated with manic or hypomanic switch, mixed states, and frequent cycling.²¹ Moreover, delays in diagnosis and proper treatment of BD may result in protracted mood symptoms, prolonged affective episodes, higher rates of disability, functional impairment, and overall worse clinical outcomes.²⁴ In addition, because behavioral and psychosocial interventions are usually adjunctive therapies rather than first-line interventions for patients with BD, misdiagnosing BPD as BD may ultimately prevent these individuals from receiving proper treatment, likely resulting in more severe functional impairment, multiple hospitalizations, self-inflicted injuries, and suicide attempts, since psychotropic medications are not particularly effective for improving self-efficacy and coping strategies, nor for correcting cognitive distortions, particularly in self-image, and pathological personality traits, all of which are critical aspects of BPD treatment.

Continue to: Several factors might...

Several factors might make clinicians reluctant to diagnose BPD, or bias them to diagnose BD more frequently. These include a lack of familiarity with the diagnostic criteria for BPD, the phenotypical resemblance between BP and BPD, or even concerns about the stigma and negative implications that are associated with a BPD diagnosis.^32,37,38

Whereas BD is currently perceived as a condition with a strong biological basis, there are considerable misconceptions regarding BPD and its nature.^4-6,22,26 As a consequence, individuals with BPD tend to be perceived as “difficult-to-treat,” “uncooperative,” or “attention-seeking.” These misconceptions may result in poor clinician-patient relationships, unmet clinical and psychiatric needs, and frustration for both clinicians and patients.³⁷

Through advances in biological psychiatry, precision medicine may someday be a part of psychiatric practice. Biological “signatures” may eventually help clinicians in diagnosing and treating psychiatric disorders. Presently, however, rigorous history-taking and comprehensive clinical assessments are still the most powerful tools a clinician can use to accomplish these goals. Finally, destigmatizing psychiatric disorders and educating patients and clinicians are also critical to improving clinical outcomes and promoting mental health in a compassionate and empathetic fashion.

Bottom Line

Despite the phenotypical resemblance between bipolar disorder (BP) and borderline personality disorder (BPD), the 2 are independent conditions with distinct neurobiological and psychopathological underpinnings. Clinicians can use a rigorous assessment of pathological personality traits and characterization of symptoms, such as onset patterns, clinical course, and phenomenology, to properly distinguish between BP and BPD.

Related Resources

• Fiedorowicz JG, Black DW. Borderline, bipolar, or both? Frame your diagnosis on the patient history. Current Psychiatry. 2010; 9(1):21-24,29-32.
• Zimmerman M. Improving the recognition of borderline personality disorder. Current Psychiatry. 2017;16(10):13-19.
• National Institute of Mental Health. Overview on bipolar disorder. www.nimh.nih.gov/health/publications/bipolar-disorder/index.shtml. Revised October 2018.
• National Institute of Mental Health. Overview on borderline personality disorder. www.nimh.nih.gov/health/publications/borderline-personality-disorder-fact-sheet/index.shtml.

Although evidence suggests that bipolar disorder (BD) and borderline personality disorder (BPD) are distinct entities, their differential diagnosis is often challenging as a result of considerable overlap of phenotypical features. Moreover, BD and BPD frequently co-occur, which makes it even more difficult to differentiate these 2 conditions. Strategies for improving diagnostic accuracy are critical to optimizing patients’ clinical outcomes and long-term prognosis. Misdiagnosing these 2 conditions can be particularly deleterious, and failure to recognize their co-occurrence can result in additional burden to typically complex and severe clinical presentations.

This article describes key aspects of the differential diagnosis between BD and BPD, emphasizing core features and major dissimilarities between these 2 conditions, and discusses the implications of misdiagnosis. The goal is to highlight the clinical and psychopathological aspects of BD and BPD to help clinicians properly distinguish these 2 disorders.

Psychopathological and sociodemographic correlates

Bipolar disorder is a chronic and severe mental illness that is classified based on clusters of symptoms—manic, hypomanic, and depressive.¹ It is among the 10 leading causes of disability worldwide, with significant morbidity arising from acute affective episodes and subacute states.² Data suggest the lifetime prevalence of BPD is 2.1%, and subthreshold forms may affect an additional 2.4% of the US population.³ The onset of symptoms typically occurs during late adolescence or early adulthood, and mood lability and cyclothymic temperament are the most common prodromal features.⁴

In contrast, personality disorders, such as BPD, are characteristically pervasive and maladaptive patterns of emotional responses that usually deviate from an individual’s stage of development and cultural background.¹ These disorders tend to cause significant impairment, particularly in personal, occupational, and social domains. Environmental factors, such as early childhood trauma, seem to play an important role in the genesis of personality disorders, which may be particularly relevant in BPD, a disorder characterized by marked impulsivity and a pattern of instability in personal relationships, self-image, and affect.^1,5,6 Similarly to BD, BPD is also chronic and highly disabling.

According to the National Survey on Alcohol and Related Conditions (NESARC), approximately 15% of US adults were found to have at least one type of personality disorder, and 6% met criteria for a cluster B personality disorder (antisocial, borderline, narcissistic, and histrionic).⁷ The lifetime prevalence of BPD is nearly 2%, with higher estimates observed in psychiatric settings.^7,8

As a result of the phenotypical resemblance between BD and BPD (Figure), the differential diagnosis is often difficult. Recent studies suggest that co-occurrence of BD and BPD is common, with rates of comorbid BPD as high as 29% in BD I and 24% in BD II.^8,9 On the other hand, nearly 20% of individuals with BPD seem to have comorbid BD.^8,9 Several studies suggest that comorbid personality disorders represent a negative prognostic factor in the course of mood disorders, and the presence of BPD in patients with BD seems to be associated with more severe clinical presentations, greater treatment complexity, a higher number of depressive episodes, poor inter-episode functioning, and higher rates of other comorbidities, such as substance use disorders (SUDs).^8-11 The effect of BD on the course of BPD is unclear and fairly unexplored, although it has been suggested that better control of mood symptoms may lead to more stable psychosocial functioning in BPD.⁹

Whether BD and BPD are part of the same spectrum is a matter for debate.^12-14 Multidimensional approaches have been proposed to better characterize these disorders in at-risk populations, based on structured interviews, self-administered and clinician-rated clinical scales (Table 1), neuroimaging studies, biological markers, and machine-learning models.^15,16 Compelling evidence suggests that BD and BPD have distinct underlying neurobiological and psychopathological mechanisms^12,13; however, the differential diagnosis still relies on phenotypical features, since the search for biological markers has not yet identified specific biomarkers that can be used in clinical practice.

Continue to: Core features of BPD...

Core features of BPD, such as mood lability, impulsivity, and risk-taking behaviors, are also part of the diagnostic criteria for BD (Table 2).¹ Similarly, depressive symptoms prevail in the course of BD.^17,18 This adds complexity to the differential because “depressivity” is also part of the diagnostic criteria for BPD.¹ Therefore, comprehensive psychiatric assessments and longitudinal observations are critical to diagnostic accuracy and treatment planning. Further characterization of symptoms, such as onset patterns, clinical course, phenomenology of symptoms (eg, timing, frequency, duration, triggers), and personality traits, will provide information to properly distinguish these 2 syndromes when, for example, it is unclear if the “mood swings” and impulsivity are part of a mood or a personality disorder (Table 3).

Clinical features: A closer look

Borderline personality disorder. Affect dysregulation, emotional instability, impoverished and unstable self-image, and chronic feelings of emptiness are core features of BPD.^1,5,19 These characteristics, when combined with a fear of abandonment or rejection, a compromised ability to recognize the feelings and needs of others, and extremes of idealization-devaluation, tend to culminate in problematic and chaotic relationships.^6,19 Individuals with BPD may become suspicious or paranoid under stressful situations. Under these circumstances, individuals with BPD may also experience depersonalization and other dissociative symptoms.^6,20 The mood lability and emotional instability observed in patients with BPD usually are in response to environmental factors, and although generally intense and out of proportion, they tend to be ephemeral and short-lived, typically lasting a few hours.^1,5 The anxiety and depressive symptoms reported by patients with BPD frequently are associated with feelings of “falling apart” or “losing control,” pessimism, shame, and low self-esteem. Coping strategies tend to be poorly developed and/or maladaptive, and individuals with BPD usually display a hostile and antagonistic demeanor and engage in suicidal or non­suicidal self-injury (NSSI) behaviors as means to alleviate overwhelming emotional distress. Impulsivity, disinhibition, poor tolerance to frustration, and risk-taking behaviors are also characteristic of BPD.^1,5 As a result, BPD is usually associated with significant impairment in functioning, multiple hospitalizations, and high rates of comorbid mood disorders, posttraumatic stress disorder (PTSD), SUDs, and death by suicide.

Bipolar disorder. Conversely, the fluctuations in mood and affect observed in patients with BD are usually episodic rather than pervasive, and tend to last longer (typically days to weeks) compared with the transient mood shifts observed in patients with BPD.^4,17,18 The impulsivity, psychomotor agitation, and increased goal-directed activity reported by patients with BD are usually seen in the context of an acute affective episode, and are far less common during periods of stability or euthymic affect.^4,17,18 Grandiosity and inflated self-esteem—hallmarks of a manic or hypomanic state—seem to oppose the unstable self-image observed in BPD, although indecisiveness and low self-worth may be observed in individuals with BD during depressive episodes. Antidepressant-induced mania or hypomania, atypical depressive episodes, and disruptions in sleep and circadian rhythms may be predictors of BD.^4,21 Furthermore, although psychosocial stressors may be associated with acute affective episodes in early stages of bipolar illness, over time minimal stressors are necessary to ignite new affective episodes.^22,23 Although BD is associated with high rates of suicide, suicide attempts are usually seen in the context of an acute depressive episode, and NSSI behaviors are less common among patients with BD.²⁴

Lastly, other biographical data, such as a history of early life trauma, comorbidity, and a family history of psychiatric illnesses, can be particularly helpful in establishing the differential diagnosis between BD and BPD.²⁵ For instance, evidence suggests that the heritability of BD may be as high as 70%, which usually translates into an extensive family history of bipolar and related disorders.²⁶ In addition, studies suggest a high co-occurrence of anxiety disorders, attention-deficit/hyperactivity disorder, and SUDs in patients with BD, whereas PTSD, SUDs, and eating disorders tend to be highly comorbid with BPD.²⁷ Childhood adversity (ie, a history of physical, sexual, or emotional abuse, or neglect) seems to be pivotal in the genesis of BPD and may predispose these individuals to psychotic and dissociative symptoms, particularly those with a history of sexual abuse, while playing a more secondary role in BD.^28-31

Implications of misdiagnosis

In the view of the limitations of the existing models, multidimensional approaches are necessary to improve diagnostic accuracy. Presently, the differential diagnosis of BD and BPD continues to rely on clinical findings and syndromic classifications. Misdiagnosing BD and BPD has adverse therapeutic and prognostic implications.³² For instance, while psychotropic medications and neuromodulatory therapies (eg, electroconvulsive therapy, repetitive transcranial magnetic stimulation) are considered first-line treatments for patients with BD, psychosocial interventions tend to be adjunctive treatments in BD.³³ Conversely, although pharmacotherapy might be helpful for patients with BPD, psychosocial and behavioral interventions are the mainstay treatment for this disorder, with the strongest evidence supporting cognitive-behavioral therapy, dialectical behavioral therapy, mentalization-based therapy, and transference-focused therapy.^34-36 Thus, misdiagnosing BD as BPD with comorbid depression may result in the use of antidepressants, which can be detrimental in BD. Antidepressant treatment of BD, particularly as monotherapy, has been associated with manic or hypomanic switch, mixed states, and frequent cycling.²¹ Moreover, delays in diagnosis and proper treatment of BD may result in protracted mood symptoms, prolonged affective episodes, higher rates of disability, functional impairment, and overall worse clinical outcomes.²⁴ In addition, because behavioral and psychosocial interventions are usually adjunctive therapies rather than first-line interventions for patients with BD, misdiagnosing BPD as BD may ultimately prevent these individuals from receiving proper treatment, likely resulting in more severe functional impairment, multiple hospitalizations, self-inflicted injuries, and suicide attempts, since psychotropic medications are not particularly effective for improving self-efficacy and coping strategies, nor for correcting cognitive distortions, particularly in self-image, and pathological personality traits, all of which are critical aspects of BPD treatment.

Continue to: Several factors might...

Several factors might make clinicians reluctant to diagnose BPD, or bias them to diagnose BD more frequently. These include a lack of familiarity with the diagnostic criteria for BPD, the phenotypical resemblance between BP and BPD, or even concerns about the stigma and negative implications that are associated with a BPD diagnosis.^32,37,38

Whereas BD is currently perceived as a condition with a strong biological basis, there are considerable misconceptions regarding BPD and its nature.^4-6,22,26 As a consequence, individuals with BPD tend to be perceived as “difficult-to-treat,” “uncooperative,” or “attention-seeking.” These misconceptions may result in poor clinician-patient relationships, unmet clinical and psychiatric needs, and frustration for both clinicians and patients.³⁷

Through advances in biological psychiatry, precision medicine may someday be a part of psychiatric practice. Biological “signatures” may eventually help clinicians in diagnosing and treating psychiatric disorders. Presently, however, rigorous history-taking and comprehensive clinical assessments are still the most powerful tools a clinician can use to accomplish these goals. Finally, destigmatizing psychiatric disorders and educating patients and clinicians are also critical to improving clinical outcomes and promoting mental health in a compassionate and empathetic fashion.

Bottom Line

Despite the phenotypical resemblance between bipolar disorder (BP) and borderline personality disorder (BPD), the 2 are independent conditions with distinct neurobiological and psychopathological underpinnings. Clinicians can use a rigorous assessment of pathological personality traits and characterization of symptoms, such as onset patterns, clinical course, and phenomenology, to properly distinguish between BP and BPD.

Related Resources

• Fiedorowicz JG, Black DW. Borderline, bipolar, or both? Frame your diagnosis on the patient history. Current Psychiatry. 2010; 9(1):21-24,29-32.
• Zimmerman M. Improving the recognition of borderline personality disorder. Current Psychiatry. 2017;16(10):13-19.
• National Institute of Mental Health. Overview on bipolar disorder. www.nimh.nih.gov/health/publications/bipolar-disorder/index.shtml. Revised October 2018.
• National Institute of Mental Health. Overview on borderline personality disorder. www.nimh.nih.gov/health/publications/borderline-personality-disorder-fact-sheet/index.shtml.

Although evidence suggests that bipolar disorder (BD) and borderline personality disorder (BPD) are distinct entities, their differential diagnosis is often challenging as a result of considerable overlap of phenotypical features. Moreover, BD and BPD frequently co-occur, which makes it even more difficult to differentiate these 2 conditions. Strategies for improving diagnostic accuracy are critical to optimizing patients’ clinical outcomes and long-term prognosis. Misdiagnosing these 2 conditions can be particularly deleterious, and failure to recognize their co-occurrence can result in additional burden to typically complex and severe clinical presentations.

This article describes key aspects of the differential diagnosis between BD and BPD, emphasizing core features and major dissimilarities between these 2 conditions, and discusses the implications of misdiagnosis. The goal is to highlight the clinical and psychopathological aspects of BD and BPD to help clinicians properly distinguish these 2 disorders.

Psychopathological and sociodemographic correlates

Bipolar disorder is a chronic and severe mental illness that is classified based on clusters of symptoms—manic, hypomanic, and depressive.¹ It is among the 10 leading causes of disability worldwide, with significant morbidity arising from acute affective episodes and subacute states.² Data suggest the lifetime prevalence of BPD is 2.1%, and subthreshold forms may affect an additional 2.4% of the US population.³ The onset of symptoms typically occurs during late adolescence or early adulthood, and mood lability and cyclothymic temperament are the most common prodromal features.⁴

In contrast, personality disorders, such as BPD, are characteristically pervasive and maladaptive patterns of emotional responses that usually deviate from an individual’s stage of development and cultural background.¹ These disorders tend to cause significant impairment, particularly in personal, occupational, and social domains. Environmental factors, such as early childhood trauma, seem to play an important role in the genesis of personality disorders, which may be particularly relevant in BPD, a disorder characterized by marked impulsivity and a pattern of instability in personal relationships, self-image, and affect.^1,5,6 Similarly to BD, BPD is also chronic and highly disabling.

According to the National Survey on Alcohol and Related Conditions (NESARC), approximately 15% of US adults were found to have at least one type of personality disorder, and 6% met criteria for a cluster B personality disorder (antisocial, borderline, narcissistic, and histrionic).⁷ The lifetime prevalence of BPD is nearly 2%, with higher estimates observed in psychiatric settings.^7,8

As a result of the phenotypical resemblance between BD and BPD (Figure), the differential diagnosis is often difficult. Recent studies suggest that co-occurrence of BD and BPD is common, with rates of comorbid BPD as high as 29% in BD I and 24% in BD II.^8,9 On the other hand, nearly 20% of individuals with BPD seem to have comorbid BD.^8,9 Several studies suggest that comorbid personality disorders represent a negative prognostic factor in the course of mood disorders, and the presence of BPD in patients with BD seems to be associated with more severe clinical presentations, greater treatment complexity, a higher number of depressive episodes, poor inter-episode functioning, and higher rates of other comorbidities, such as substance use disorders (SUDs).^8-11 The effect of BD on the course of BPD is unclear and fairly unexplored, although it has been suggested that better control of mood symptoms may lead to more stable psychosocial functioning in BPD.⁹

Whether BD and BPD are part of the same spectrum is a matter for debate.^12-14 Multidimensional approaches have been proposed to better characterize these disorders in at-risk populations, based on structured interviews, self-administered and clinician-rated clinical scales (Table 1), neuroimaging studies, biological markers, and machine-learning models.^15,16 Compelling evidence suggests that BD and BPD have distinct underlying neurobiological and psychopathological mechanisms^12,13; however, the differential diagnosis still relies on phenotypical features, since the search for biological markers has not yet identified specific biomarkers that can be used in clinical practice.

Continue to: Core features of BPD...

Core features of BPD, such as mood lability, impulsivity, and risk-taking behaviors, are also part of the diagnostic criteria for BD (Table 2).¹ Similarly, depressive symptoms prevail in the course of BD.^17,18 This adds complexity to the differential because “depressivity” is also part of the diagnostic criteria for BPD.¹ Therefore, comprehensive psychiatric assessments and longitudinal observations are critical to diagnostic accuracy and treatment planning. Further characterization of symptoms, such as onset patterns, clinical course, phenomenology of symptoms (eg, timing, frequency, duration, triggers), and personality traits, will provide information to properly distinguish these 2 syndromes when, for example, it is unclear if the “mood swings” and impulsivity are part of a mood or a personality disorder (Table 3).

Clinical features: A closer look

Borderline personality disorder. Affect dysregulation, emotional instability, impoverished and unstable self-image, and chronic feelings of emptiness are core features of BPD.^1,5,19 These characteristics, when combined with a fear of abandonment or rejection, a compromised ability to recognize the feelings and needs of others, and extremes of idealization-devaluation, tend to culminate in problematic and chaotic relationships.^6,19 Individuals with BPD may become suspicious or paranoid under stressful situations. Under these circumstances, individuals with BPD may also experience depersonalization and other dissociative symptoms.^6,20 The mood lability and emotional instability observed in patients with BPD usually are in response to environmental factors, and although generally intense and out of proportion, they tend to be ephemeral and short-lived, typically lasting a few hours.^1,5 The anxiety and depressive symptoms reported by patients with BPD frequently are associated with feelings of “falling apart” or “losing control,” pessimism, shame, and low self-esteem. Coping strategies tend to be poorly developed and/or maladaptive, and individuals with BPD usually display a hostile and antagonistic demeanor and engage in suicidal or non­suicidal self-injury (NSSI) behaviors as means to alleviate overwhelming emotional distress. Impulsivity, disinhibition, poor tolerance to frustration, and risk-taking behaviors are also characteristic of BPD.^1,5 As a result, BPD is usually associated with significant impairment in functioning, multiple hospitalizations, and high rates of comorbid mood disorders, posttraumatic stress disorder (PTSD), SUDs, and death by suicide.

Bipolar disorder. Conversely, the fluctuations in mood and affect observed in patients with BD are usually episodic rather than pervasive, and tend to last longer (typically days to weeks) compared with the transient mood shifts observed in patients with BPD.^4,17,18 The impulsivity, psychomotor agitation, and increased goal-directed activity reported by patients with BD are usually seen in the context of an acute affective episode, and are far less common during periods of stability or euthymic affect.^4,17,18 Grandiosity and inflated self-esteem—hallmarks of a manic or hypomanic state—seem to oppose the unstable self-image observed in BPD, although indecisiveness and low self-worth may be observed in individuals with BD during depressive episodes. Antidepressant-induced mania or hypomania, atypical depressive episodes, and disruptions in sleep and circadian rhythms may be predictors of BD.^4,21 Furthermore, although psychosocial stressors may be associated with acute affective episodes in early stages of bipolar illness, over time minimal stressors are necessary to ignite new affective episodes.^22,23 Although BD is associated with high rates of suicide, suicide attempts are usually seen in the context of an acute depressive episode, and NSSI behaviors are less common among patients with BD.²⁴

Lastly, other biographical data, such as a history of early life trauma, comorbidity, and a family history of psychiatric illnesses, can be particularly helpful in establishing the differential diagnosis between BD and BPD.²⁵ For instance, evidence suggests that the heritability of BD may be as high as 70%, which usually translates into an extensive family history of bipolar and related disorders.²⁶ In addition, studies suggest a high co-occurrence of anxiety disorders, attention-deficit/hyperactivity disorder, and SUDs in patients with BD, whereas PTSD, SUDs, and eating disorders tend to be highly comorbid with BPD.²⁷ Childhood adversity (ie, a history of physical, sexual, or emotional abuse, or neglect) seems to be pivotal in the genesis of BPD and may predispose these individuals to psychotic and dissociative symptoms, particularly those with a history of sexual abuse, while playing a more secondary role in BD.^28-31

Implications of misdiagnosis

In the view of the limitations of the existing models, multidimensional approaches are necessary to improve diagnostic accuracy. Presently, the differential diagnosis of BD and BPD continues to rely on clinical findings and syndromic classifications. Misdiagnosing BD and BPD has adverse therapeutic and prognostic implications.³² For instance, while psychotropic medications and neuromodulatory therapies (eg, electroconvulsive therapy, repetitive transcranial magnetic stimulation) are considered first-line treatments for patients with BD, psychosocial interventions tend to be adjunctive treatments in BD.³³ Conversely, although pharmacotherapy might be helpful for patients with BPD, psychosocial and behavioral interventions are the mainstay treatment for this disorder, with the strongest evidence supporting cognitive-behavioral therapy, dialectical behavioral therapy, mentalization-based therapy, and transference-focused therapy.^34-36 Thus, misdiagnosing BD as BPD with comorbid depression may result in the use of antidepressants, which can be detrimental in BD. Antidepressant treatment of BD, particularly as monotherapy, has been associated with manic or hypomanic switch, mixed states, and frequent cycling.²¹ Moreover, delays in diagnosis and proper treatment of BD may result in protracted mood symptoms, prolonged affective episodes, higher rates of disability, functional impairment, and overall worse clinical outcomes.²⁴ In addition, because behavioral and psychosocial interventions are usually adjunctive therapies rather than first-line interventions for patients with BD, misdiagnosing BPD as BD may ultimately prevent these individuals from receiving proper treatment, likely resulting in more severe functional impairment, multiple hospitalizations, self-inflicted injuries, and suicide attempts, since psychotropic medications are not particularly effective for improving self-efficacy and coping strategies, nor for correcting cognitive distortions, particularly in self-image, and pathological personality traits, all of which are critical aspects of BPD treatment.

Continue to: Several factors might...

Several factors might make clinicians reluctant to diagnose BPD, or bias them to diagnose BD more frequently. These include a lack of familiarity with the diagnostic criteria for BPD, the phenotypical resemblance between BP and BPD, or even concerns about the stigma and negative implications that are associated with a BPD diagnosis.^32,37,38

Whereas BD is currently perceived as a condition with a strong biological basis, there are considerable misconceptions regarding BPD and its nature.^4-6,22,26 As a consequence, individuals with BPD tend to be perceived as “difficult-to-treat,” “uncooperative,” or “attention-seeking.” These misconceptions may result in poor clinician-patient relationships, unmet clinical and psychiatric needs, and frustration for both clinicians and patients.³⁷

Through advances in biological psychiatry, precision medicine may someday be a part of psychiatric practice. Biological “signatures” may eventually help clinicians in diagnosing and treating psychiatric disorders. Presently, however, rigorous history-taking and comprehensive clinical assessments are still the most powerful tools a clinician can use to accomplish these goals. Finally, destigmatizing psychiatric disorders and educating patients and clinicians are also critical to improving clinical outcomes and promoting mental health in a compassionate and empathetic fashion.

Bottom Line

Despite the phenotypical resemblance between bipolar disorder (BP) and borderline personality disorder (BPD), the 2 are independent conditions with distinct neurobiological and psychopathological underpinnings. Clinicians can use a rigorous assessment of pathological personality traits and characterization of symptoms, such as onset patterns, clinical course, and phenomenology, to properly distinguish between BP and BPD.

Related Resources

• Fiedorowicz JG, Black DW. Borderline, bipolar, or both? Frame your diagnosis on the patient history. Current Psychiatry. 2010; 9(1):21-24,29-32.
• Zimmerman M. Improving the recognition of borderline personality disorder. Current Psychiatry. 2017;16(10):13-19.
• National Institute of Mental Health. Overview on bipolar disorder. www.nimh.nih.gov/health/publications/bipolar-disorder/index.shtml. Revised October 2018.
• National Institute of Mental Health. Overview on borderline personality disorder. www.nimh.nih.gov/health/publications/borderline-personality-disorder-fact-sheet/index.shtml.

Through the years, the surgical approach to hysterectomy has expanded from its early beginnings of being performed only through an abdominal or transvaginal route with traditional surgical clamps and suture. The late 1980s saw the advent of the laparoscopic-assisted vaginal hysterectomy (LAVH), and from that point forward several additional hysterectomy methods evolved, including today’s robotic approaches.

Although clinical evidence and societal endorsements support vaginal hysterectomy as a superior high-value modality, it remains one of the least performed among all available routes.^1-3 In an analysis of inpatient hysterectomies published by Wright and colleagues in 2013, 16.7% of hysterectomies were performed vaginally, a number that essentially has remained steady throughout the ensuing years.⁴

Attempts to improve the application of vaginal hysterectomy have been made.⁵ These include the development of various curriculum and simulation-based medical education programs on vaginal surgical skills training and acquisition in the hopes of improving utilization.⁶ An interesting recent development is the rethinking of vaginal hysterectomy by several surgeons globally who are applying facets of the various hysterectomy methods to a transvaginal approach known as vaginal natural orifice transluminal endoscopic surgery (vNOTES).^7,8 Unique to this thinking is the incorporation of conventional laparoscopic instrumentation.

Although I have not yet incorporated this approach in my surgical armamentarium at Columbia University Medical Center/New York–Presbyterian Hospital, I am intrigued by the possibility that this technique may serve as a rescue for vaginal hysterectomies that are at risk of conversion or of not being performed at all.⁹

At this time, vNOTES is not a standard of care and should be performed only by highly specialized surgeons. However, in the spirit of this Update on minimally invasive surgery and to keep our readers abreast of burgeoning techniques, I am delighted to bring you this overview by Dr. Xiaoming Guan, one of the pioneers of this surgical approach, and Dr. Tamisa Koythong and Dr. Juan Liu. I hope you find this recent development in hysterectomy of interest.

—Arnold P. Advincula, MD

Continue to: Development and evolution of NOTES...

Development and evolution of NOTES 

Over the past few decades, emphasis has shifted from laparotomy to minimally invasive surgery because of its proven significant advantages in patient care, such as improved cosmesis, shorter hospital stay, shorter postoperative recovery, and decreased postoperative pain and blood loss.¹⁰  Advances in laparoendoscopic surgery and instrumentation, including robot-assisted laparoscopy (RAL), single-incision laparoscopic surgery (SILS), and most recently natural orifice transluminal endoscopic surgery (NOTES), reflect ongoing innovative developments in the field of minimally invasive surgery. 

Here, we provide a brief literature review of the NOTES technique, focus on its application in gynecologic surgery, and describe how we perform NOTES at our institution. 

NOTES application in gynecology 

With NOTES, peritoneal access is gained through a natural orifice (such as the mouth, vagina, urethra, or anus) to perform endoscopic surgery, occasionally without requiring an abdominal incision. First described in 2004, transgastric peritoneoscopy was performed in a porcine model, and shortly thereafter the first transgastric appendectomy was performed in humans.^11,12 The technique has further been adopted in cholecystectomy, appendectomy, gastrectomy, and nephrectomy procedures.¹³ 

Given rapid interest in a possible paradigm shift in the field of minimally invasive surgery, the Natural Orifice Surgery Consortiumfor Assessment and Research (NOSCAR) was formed, and the group published an article on potential barriers to accepted practice and adoption of NOTES as a realistic alternative to traditional laparoscopic surgery.¹⁴ 

While transgastric and transanal access to the peritoneum were initially more popular, the risk of anastomotic leaks associated with incomplete closure and subsequent infection were thought to be prohibitively high.¹⁵ Transvaginal access was considered a safer and simpler alternative, allowing for complete closure without increased risk of infection, and this is now the route through which the majority of NOTES procedures are completed.^16,17 

The eventual application of NOTES in the field of gynecology seemed inevitable. The American College of Obstetricians and Gynecologists stated that transvaginal surgery is the most minimally invasive and preferred surgical route in the management of patients with benign gynecologic diseases.¹⁸ However, performing it can be challenging at times due to limited visualization and lack of the required skills for single-site surgery. NOTES allows a gynecologic surgeon to improve visualization through the use of laparoendoscopic instruments and to complete surgery through a transvaginal route. 

In 2012, Ahn and colleagues demonstrated the feasibility of the NOTES technique in gynecologic surgery after using it to successfully complete benign adnexal surgery in 10 patients.¹⁹ Vaginal NOTES (vNOTES) has since been further developed to include successful hysterectomy, myomectomy, sacrocolpopexy, tubal anastomosis, and even lymphadenectomy in the treatment of early- stage endometrial carcinoma.^20-26 vNOTES also can be considered a rescue approach for traditional vaginal hysterectomy in instances in which it is necessary to evaluate adnexal pathology.⁹ Most recently, vNOTES hysterectomy has been reported with da Vinci Si or Xi robotic platforms.^27,28 

Continue to: Operative time, post-op stay shorter in NAOC-treated patients...

Few studies have compared outcomes with vNOTES to those with traditional laparoscopy. In 2016, Wang and colleagues compared surgical outcomes between NOTES-assisted ovarian cystectomy (NAOC) and laparoscopic ovarian cystectomy (LOC) in a case-matched study that included 277 patients.²⁹ Although mean (SD) blood loss in patients who underwent LOC was significantly less compared with those who underwent NAOC (21.4 [14.7] mL vs 31.6 [24.1] mL; P = .028), absolute blood loss in both groups was deemed minimal. Additionally, mean (SD) operative time and postoperative stay were significantly less in patients undergoing NAOC compared with those having LOC (38.23 [10.19] minutes vs 53.82 [18.61] minutes; P≤.001; and 1.38 [0.55] days vs 1.82 [0.52] days; P≤.001; respectively).²⁹ 

How vNOTES hysterectomy stacked up against TLH 

In 2018, Baekelandt and colleagues compared outcomes between vNOTES hysterectomy and total laparoscopic hysterectomy (TLH) in a noninferiority single-blinded trial of 70 women.⁸ Compared with TLH, vNOTES hysterectomy was associated with shorter operative time (41 vs 75 minutes; P<.001), shorter hospital stay (0.8 vs 1.3 days; P = .004), and lower postoperative analgesic requirement (8 vs 14 U; P = .006). Additionally, there were no differences between the 2 groups in postoperative infection rate, intraoperative complications, or hospital readmissions within 6 weeks.⁸

Approach for performing vNOTES procedures 

At our institution, Baylor College of Medicine, the majority of gynecologic surgeries are performed via either transumbilical robot-assisted single-incision laparoscopy or vNOTES. Preoperative selection of appropriate candidates for vNOTES includes: 

• low suspicion for or prior diagnosis of endometriosis with obliteration of the posterior cul-de-sac 
• no surgical history suggestive of severe adhesive disease, and 
• adequate vaginal sidewall access and sufficient descent for instrumentation for entry into the peritoneal cavity. 

In general, a key concept in vNOTES is "vaginal pull, laparoscopic push," which means that the surgeon must pull the cervix while performing vaginal entry and then push the uterus back in the peritoneal cavity to increase surgical space during laparoscopic surgery. 

Continue to: Overview of vNOTES steps...

Below we break down a description of vNOTES in 6 sections. Our patients are always placed in dorsal lithotomy position with TrenGuard (D.A. Surgical) Trendelenburg restraint. We prep the abdomen in case we need to convert to transabdominal surgery via transumbilical single-incision laparoscopic surgery or traditional laparoscopic surgery. 

1. Vaginal entry 

Accessing the peritoneal cavity through the vagina initially proceeds like a vaginal hysterectomy. We inject dilute vasopressin (20 U in 20 mL of normal saline) circumferentially in the cervix (for hysterectomy) or in the posterior cervix in the cervicovaginal junction (for adnexal surgery without hysterectomy) for vasoconstriction and hydrodissection. 

We then incise the vaginal mucosa circumferentially with electrosurgical cautery and follow with posterior colpotomy. We find that reapproximating the posterior peritoneum to the posterior vagina with either figure-of-8 stitches or a running stitch of polyglactin 910 suture (2-0 Vicryl) assists in port placement, bleeding at the peritoneal edge, and closure of the cuff or colpotomy at the end of the case. We tag this suture with a curved hemostat. 

Depending on whether a hysterectomy is being performed, anterior colpotomy is made. Again, the anterior peritoneum is then tagged to the anterior vaginal cuff in similar fashion, and this suture is tagged with a different instrument; we typically use a straight hemostat or Sarot clamp (FIGURE 1). 

2. Traditional vaginal hysterectomy 

After colpotomy, we prefer to perform progressive clamping of the broad ligament from the uterosacral and cardinal ligaments to the level of uterine artery as in traditional vaginal hysterectomy, if feasible. 

3. Single-site port placement 

The assembled GelPOINT Mini advanced access platform (Applied Medical) (FIGURE 2) is introduced through the vagina after the Alexis wound protector (included with the kit) is first placed through the colpotomy with assistance of Babcock clamps (FIGURE 3). 

After ensuring that the green rigid ring of the Alexis wound protector is contained and completely expanded within the peritoneal cavity, we cross our previously tagged sutures as we find this helps with preventing the GelPOINT Mini access platform from inadvertently shifting out of the peritoneal cavity during surgery. The GelSeal cap is then secured and pneumoperitoneum is established (FIGURE 4). 

Continue to: 4. Laparoendoscopic surgery...

Instruments used in our surgeries include a 10-mm rigid 30° 43-cm working length laparoscope; a 44-cm LigaSure device (Medtronic); a 5-mm, 37-cm laparoscopic cobra grasping forceps and fenestrated grasper (Karl Storz); and a 5-mm, 45-cm laparoscopic suction with hydrodissection tip (Stryker) (FIGURE 5). 

vNOTES allows a gynecologic surgeon the unique ability to survey the upper abdomen. The remainder of the surgery proceeds using basic laparoscopic single-site skills. 

During vNOTES, as with all single-site surgical procedures, understanding the optimal placement of crossed instruments is important for successful completion. For example, when securing the right uterine artery, the surgeon needs to push the cervix toward the patient's left and slightly into the peritoneal cavity using a laparoscopic cobra grasper with his or her left hand while then securing the uterine pedicle using the LigaSure device with his or her right hand. This is then reversed when securing the left uterine artery, where the assistant surgeon pushes the cervix toward the patient's right while the surgeon secures the pedicle ("vaginal pull, laparoscopic push") (FIGURE 6). 

This again is reiterated in securing the ovarian pedicles, which are pushed into the peritoneal cavity while being secured with the LigaSure device. 

5. Specimen removal 

For large uteri or specimens that need morcellation, a 15-mm Endo Catch specimen retrieval bag (Medtronic) is introduced through the GelPOINT Mini system. The specimen is then placed in the bag and delivered to the vagina, where contained bag morcellation is performed in standard fashion (FIGURES 7 AND 8). We utilized the "big C" technique by first grasping the specimen with a penetrating clamp. The clamp is then held in our nondominant hand and a No. 10 blade scalpel is used to create a reverse c-incision, keeping one surface of the specimen intact. This is continued until the specimen can be completely delivered through the vagina. 

Specimens that do not require morcellation can be grasped laparoscopically, brought to the GelPOINT Mini port, which is quickly disassembled, and delivered. The GelSeal cap is then reassembled. 

6. Vaginal cuff closure 

The colpotomy or vaginal cuff is closed with barbed suture continuously, as in traditional vaginal hysterectomy cuff closure. Uterosacral ligament suspension should be performed for vaginal cuff support.  
 

Through the years, the surgical approach to hysterectomy has expanded from its early beginnings of being performed only through an abdominal or transvaginal route with traditional surgical clamps and suture. The late 1980s saw the advent of the laparoscopic-assisted vaginal hysterectomy (LAVH), and from that point forward several additional hysterectomy methods evolved, including today’s robotic approaches.

Although clinical evidence and societal endorsements support vaginal hysterectomy as a superior high-value modality, it remains one of the least performed among all available routes.^1-3 In an analysis of inpatient hysterectomies published by Wright and colleagues in 2013, 16.7% of hysterectomies were performed vaginally, a number that essentially has remained steady throughout the ensuing years.⁴

Attempts to improve the application of vaginal hysterectomy have been made.⁵ These include the development of various curriculum and simulation-based medical education programs on vaginal surgical skills training and acquisition in the hopes of improving utilization.⁶ An interesting recent development is the rethinking of vaginal hysterectomy by several surgeons globally who are applying facets of the various hysterectomy methods to a transvaginal approach known as vaginal natural orifice transluminal endoscopic surgery (vNOTES).^7,8 Unique to this thinking is the incorporation of conventional laparoscopic instrumentation.

Although I have not yet incorporated this approach in my surgical armamentarium at Columbia University Medical Center/New York–Presbyterian Hospital, I am intrigued by the possibility that this technique may serve as a rescue for vaginal hysterectomies that are at risk of conversion or of not being performed at all.⁹

At this time, vNOTES is not a standard of care and should be performed only by highly specialized surgeons. However, in the spirit of this Update on minimally invasive surgery and to keep our readers abreast of burgeoning techniques, I am delighted to bring you this overview by Dr. Xiaoming Guan, one of the pioneers of this surgical approach, and Dr. Tamisa Koythong and Dr. Juan Liu. I hope you find this recent development in hysterectomy of interest.

—Arnold P. Advincula, MD

Continue to: Development and evolution of NOTES...

Development and evolution of NOTES 

Over the past few decades, emphasis has shifted from laparotomy to minimally invasive surgery because of its proven significant advantages in patient care, such as improved cosmesis, shorter hospital stay, shorter postoperative recovery, and decreased postoperative pain and blood loss.¹⁰  Advances in laparoendoscopic surgery and instrumentation, including robot-assisted laparoscopy (RAL), single-incision laparoscopic surgery (SILS), and most recently natural orifice transluminal endoscopic surgery (NOTES), reflect ongoing innovative developments in the field of minimally invasive surgery. 

Here, we provide a brief literature review of the NOTES technique, focus on its application in gynecologic surgery, and describe how we perform NOTES at our institution. 

NOTES application in gynecology 

With NOTES, peritoneal access is gained through a natural orifice (such as the mouth, vagina, urethra, or anus) to perform endoscopic surgery, occasionally without requiring an abdominal incision. First described in 2004, transgastric peritoneoscopy was performed in a porcine model, and shortly thereafter the first transgastric appendectomy was performed in humans.^11,12 The technique has further been adopted in cholecystectomy, appendectomy, gastrectomy, and nephrectomy procedures.¹³ 

Given rapid interest in a possible paradigm shift in the field of minimally invasive surgery, the Natural Orifice Surgery Consortiumfor Assessment and Research (NOSCAR) was formed, and the group published an article on potential barriers to accepted practice and adoption of NOTES as a realistic alternative to traditional laparoscopic surgery.¹⁴ 

While transgastric and transanal access to the peritoneum were initially more popular, the risk of anastomotic leaks associated with incomplete closure and subsequent infection were thought to be prohibitively high.¹⁵ Transvaginal access was considered a safer and simpler alternative, allowing for complete closure without increased risk of infection, and this is now the route through which the majority of NOTES procedures are completed.^16,17 

The eventual application of NOTES in the field of gynecology seemed inevitable. The American College of Obstetricians and Gynecologists stated that transvaginal surgery is the most minimally invasive and preferred surgical route in the management of patients with benign gynecologic diseases.¹⁸ However, performing it can be challenging at times due to limited visualization and lack of the required skills for single-site surgery. NOTES allows a gynecologic surgeon to improve visualization through the use of laparoendoscopic instruments and to complete surgery through a transvaginal route. 

In 2012, Ahn and colleagues demonstrated the feasibility of the NOTES technique in gynecologic surgery after using it to successfully complete benign adnexal surgery in 10 patients.¹⁹ Vaginal NOTES (vNOTES) has since been further developed to include successful hysterectomy, myomectomy, sacrocolpopexy, tubal anastomosis, and even lymphadenectomy in the treatment of early- stage endometrial carcinoma.^20-26 vNOTES also can be considered a rescue approach for traditional vaginal hysterectomy in instances in which it is necessary to evaluate adnexal pathology.⁹ Most recently, vNOTES hysterectomy has been reported with da Vinci Si or Xi robotic platforms.^27,28 

Continue to: Operative time, post-op stay shorter in NAOC-treated patients...

Few studies have compared outcomes with vNOTES to those with traditional laparoscopy. In 2016, Wang and colleagues compared surgical outcomes between NOTES-assisted ovarian cystectomy (NAOC) and laparoscopic ovarian cystectomy (LOC) in a case-matched study that included 277 patients.²⁹ Although mean (SD) blood loss in patients who underwent LOC was significantly less compared with those who underwent NAOC (21.4 [14.7] mL vs 31.6 [24.1] mL; P = .028), absolute blood loss in both groups was deemed minimal. Additionally, mean (SD) operative time and postoperative stay were significantly less in patients undergoing NAOC compared with those having LOC (38.23 [10.19] minutes vs 53.82 [18.61] minutes; P≤.001; and 1.38 [0.55] days vs 1.82 [0.52] days; P≤.001; respectively).²⁹ 

How vNOTES hysterectomy stacked up against TLH 

In 2018, Baekelandt and colleagues compared outcomes between vNOTES hysterectomy and total laparoscopic hysterectomy (TLH) in a noninferiority single-blinded trial of 70 women.⁸ Compared with TLH, vNOTES hysterectomy was associated with shorter operative time (41 vs 75 minutes; P<.001), shorter hospital stay (0.8 vs 1.3 days; P = .004), and lower postoperative analgesic requirement (8 vs 14 U; P = .006). Additionally, there were no differences between the 2 groups in postoperative infection rate, intraoperative complications, or hospital readmissions within 6 weeks.⁸

Approach for performing vNOTES procedures 

At our institution, Baylor College of Medicine, the majority of gynecologic surgeries are performed via either transumbilical robot-assisted single-incision laparoscopy or vNOTES. Preoperative selection of appropriate candidates for vNOTES includes: 

• low suspicion for or prior diagnosis of endometriosis with obliteration of the posterior cul-de-sac 
• no surgical history suggestive of severe adhesive disease, and 
• adequate vaginal sidewall access and sufficient descent for instrumentation for entry into the peritoneal cavity. 

In general, a key concept in vNOTES is "vaginal pull, laparoscopic push," which means that the surgeon must pull the cervix while performing vaginal entry and then push the uterus back in the peritoneal cavity to increase surgical space during laparoscopic surgery. 

Continue to: Overview of vNOTES steps...

Below we break down a description of vNOTES in 6 sections. Our patients are always placed in dorsal lithotomy position with TrenGuard (D.A. Surgical) Trendelenburg restraint. We prep the abdomen in case we need to convert to transabdominal surgery via transumbilical single-incision laparoscopic surgery or traditional laparoscopic surgery. 

1. Vaginal entry 

Accessing the peritoneal cavity through the vagina initially proceeds like a vaginal hysterectomy. We inject dilute vasopressin (20 U in 20 mL of normal saline) circumferentially in the cervix (for hysterectomy) or in the posterior cervix in the cervicovaginal junction (for adnexal surgery without hysterectomy) for vasoconstriction and hydrodissection. 

We then incise the vaginal mucosa circumferentially with electrosurgical cautery and follow with posterior colpotomy. We find that reapproximating the posterior peritoneum to the posterior vagina with either figure-of-8 stitches or a running stitch of polyglactin 910 suture (2-0 Vicryl) assists in port placement, bleeding at the peritoneal edge, and closure of the cuff or colpotomy at the end of the case. We tag this suture with a curved hemostat. 

Depending on whether a hysterectomy is being performed, anterior colpotomy is made. Again, the anterior peritoneum is then tagged to the anterior vaginal cuff in similar fashion, and this suture is tagged with a different instrument; we typically use a straight hemostat or Sarot clamp (FIGURE 1). 

2. Traditional vaginal hysterectomy 

After colpotomy, we prefer to perform progressive clamping of the broad ligament from the uterosacral and cardinal ligaments to the level of uterine artery as in traditional vaginal hysterectomy, if feasible. 

3. Single-site port placement 

The assembled GelPOINT Mini advanced access platform (Applied Medical) (FIGURE 2) is introduced through the vagina after the Alexis wound protector (included with the kit) is first placed through the colpotomy with assistance of Babcock clamps (FIGURE 3). 

After ensuring that the green rigid ring of the Alexis wound protector is contained and completely expanded within the peritoneal cavity, we cross our previously tagged sutures as we find this helps with preventing the GelPOINT Mini access platform from inadvertently shifting out of the peritoneal cavity during surgery. The GelSeal cap is then secured and pneumoperitoneum is established (FIGURE 4). 

Continue to: 4. Laparoendoscopic surgery...

Instruments used in our surgeries include a 10-mm rigid 30° 43-cm working length laparoscope; a 44-cm LigaSure device (Medtronic); a 5-mm, 37-cm laparoscopic cobra grasping forceps and fenestrated grasper (Karl Storz); and a 5-mm, 45-cm laparoscopic suction with hydrodissection tip (Stryker) (FIGURE 5). 

vNOTES allows a gynecologic surgeon the unique ability to survey the upper abdomen. The remainder of the surgery proceeds using basic laparoscopic single-site skills. 

During vNOTES, as with all single-site surgical procedures, understanding the optimal placement of crossed instruments is important for successful completion. For example, when securing the right uterine artery, the surgeon needs to push the cervix toward the patient's left and slightly into the peritoneal cavity using a laparoscopic cobra grasper with his or her left hand while then securing the uterine pedicle using the LigaSure device with his or her right hand. This is then reversed when securing the left uterine artery, where the assistant surgeon pushes the cervix toward the patient's right while the surgeon secures the pedicle ("vaginal pull, laparoscopic push") (FIGURE 6). 

This again is reiterated in securing the ovarian pedicles, which are pushed into the peritoneal cavity while being secured with the LigaSure device. 

5. Specimen removal 

For large uteri or specimens that need morcellation, a 15-mm Endo Catch specimen retrieval bag (Medtronic) is introduced through the GelPOINT Mini system. The specimen is then placed in the bag and delivered to the vagina, where contained bag morcellation is performed in standard fashion (FIGURES 7 AND 8). We utilized the "big C" technique by first grasping the specimen with a penetrating clamp. The clamp is then held in our nondominant hand and a No. 10 blade scalpel is used to create a reverse c-incision, keeping one surface of the specimen intact. This is continued until the specimen can be completely delivered through the vagina. 

Specimens that do not require morcellation can be grasped laparoscopically, brought to the GelPOINT Mini port, which is quickly disassembled, and delivered. The GelSeal cap is then reassembled. 

6. Vaginal cuff closure 

The colpotomy or vaginal cuff is closed with barbed suture continuously, as in traditional vaginal hysterectomy cuff closure. Uterosacral ligament suspension should be performed for vaginal cuff support.  
 

Through the years, the surgical approach to hysterectomy has expanded from its early beginnings of being performed only through an abdominal or transvaginal route with traditional surgical clamps and suture. The late 1980s saw the advent of the laparoscopic-assisted vaginal hysterectomy (LAVH), and from that point forward several additional hysterectomy methods evolved, including today’s robotic approaches.

Although clinical evidence and societal endorsements support vaginal hysterectomy as a superior high-value modality, it remains one of the least performed among all available routes.^1-3 In an analysis of inpatient hysterectomies published by Wright and colleagues in 2013, 16.7% of hysterectomies were performed vaginally, a number that essentially has remained steady throughout the ensuing years.⁴

Attempts to improve the application of vaginal hysterectomy have been made.⁵ These include the development of various curriculum and simulation-based medical education programs on vaginal surgical skills training and acquisition in the hopes of improving utilization.⁶ An interesting recent development is the rethinking of vaginal hysterectomy by several surgeons globally who are applying facets of the various hysterectomy methods to a transvaginal approach known as vaginal natural orifice transluminal endoscopic surgery (vNOTES).^7,8 Unique to this thinking is the incorporation of conventional laparoscopic instrumentation.

Although I have not yet incorporated this approach in my surgical armamentarium at Columbia University Medical Center/New York–Presbyterian Hospital, I am intrigued by the possibility that this technique may serve as a rescue for vaginal hysterectomies that are at risk of conversion or of not being performed at all.⁹

At this time, vNOTES is not a standard of care and should be performed only by highly specialized surgeons. However, in the spirit of this Update on minimally invasive surgery and to keep our readers abreast of burgeoning techniques, I am delighted to bring you this overview by Dr. Xiaoming Guan, one of the pioneers of this surgical approach, and Dr. Tamisa Koythong and Dr. Juan Liu. I hope you find this recent development in hysterectomy of interest.

—Arnold P. Advincula, MD

Continue to: Development and evolution of NOTES...

Development and evolution of NOTES 

Over the past few decades, emphasis has shifted from laparotomy to minimally invasive surgery because of its proven significant advantages in patient care, such as improved cosmesis, shorter hospital stay, shorter postoperative recovery, and decreased postoperative pain and blood loss.¹⁰  Advances in laparoendoscopic surgery and instrumentation, including robot-assisted laparoscopy (RAL), single-incision laparoscopic surgery (SILS), and most recently natural orifice transluminal endoscopic surgery (NOTES), reflect ongoing innovative developments in the field of minimally invasive surgery. 

Here, we provide a brief literature review of the NOTES technique, focus on its application in gynecologic surgery, and describe how we perform NOTES at our institution. 

NOTES application in gynecology 

With NOTES, peritoneal access is gained through a natural orifice (such as the mouth, vagina, urethra, or anus) to perform endoscopic surgery, occasionally without requiring an abdominal incision. First described in 2004, transgastric peritoneoscopy was performed in a porcine model, and shortly thereafter the first transgastric appendectomy was performed in humans.^11,12 The technique has further been adopted in cholecystectomy, appendectomy, gastrectomy, and nephrectomy procedures.¹³ 

Given rapid interest in a possible paradigm shift in the field of minimally invasive surgery, the Natural Orifice Surgery Consortiumfor Assessment and Research (NOSCAR) was formed, and the group published an article on potential barriers to accepted practice and adoption of NOTES as a realistic alternative to traditional laparoscopic surgery.¹⁴ 

While transgastric and transanal access to the peritoneum were initially more popular, the risk of anastomotic leaks associated with incomplete closure and subsequent infection were thought to be prohibitively high.¹⁵ Transvaginal access was considered a safer and simpler alternative, allowing for complete closure without increased risk of infection, and this is now the route through which the majority of NOTES procedures are completed.^16,17 

The eventual application of NOTES in the field of gynecology seemed inevitable. The American College of Obstetricians and Gynecologists stated that transvaginal surgery is the most minimally invasive and preferred surgical route in the management of patients with benign gynecologic diseases.¹⁸ However, performing it can be challenging at times due to limited visualization and lack of the required skills for single-site surgery. NOTES allows a gynecologic surgeon to improve visualization through the use of laparoendoscopic instruments and to complete surgery through a transvaginal route. 

In 2012, Ahn and colleagues demonstrated the feasibility of the NOTES technique in gynecologic surgery after using it to successfully complete benign adnexal surgery in 10 patients.¹⁹ Vaginal NOTES (vNOTES) has since been further developed to include successful hysterectomy, myomectomy, sacrocolpopexy, tubal anastomosis, and even lymphadenectomy in the treatment of early- stage endometrial carcinoma.^20-26 vNOTES also can be considered a rescue approach for traditional vaginal hysterectomy in instances in which it is necessary to evaluate adnexal pathology.⁹ Most recently, vNOTES hysterectomy has been reported with da Vinci Si or Xi robotic platforms.^27,28 

Continue to: Operative time, post-op stay shorter in NAOC-treated patients...

Few studies have compared outcomes with vNOTES to those with traditional laparoscopy. In 2016, Wang and colleagues compared surgical outcomes between NOTES-assisted ovarian cystectomy (NAOC) and laparoscopic ovarian cystectomy (LOC) in a case-matched study that included 277 patients.²⁹ Although mean (SD) blood loss in patients who underwent LOC was significantly less compared with those who underwent NAOC (21.4 [14.7] mL vs 31.6 [24.1] mL; P = .028), absolute blood loss in both groups was deemed minimal. Additionally, mean (SD) operative time and postoperative stay were significantly less in patients undergoing NAOC compared with those having LOC (38.23 [10.19] minutes vs 53.82 [18.61] minutes; P≤.001; and 1.38 [0.55] days vs 1.82 [0.52] days; P≤.001; respectively).²⁹ 

How vNOTES hysterectomy stacked up against TLH 

In 2018, Baekelandt and colleagues compared outcomes between vNOTES hysterectomy and total laparoscopic hysterectomy (TLH) in a noninferiority single-blinded trial of 70 women.⁸ Compared with TLH, vNOTES hysterectomy was associated with shorter operative time (41 vs 75 minutes; P<.001), shorter hospital stay (0.8 vs 1.3 days; P = .004), and lower postoperative analgesic requirement (8 vs 14 U; P = .006). Additionally, there were no differences between the 2 groups in postoperative infection rate, intraoperative complications, or hospital readmissions within 6 weeks.⁸

Approach for performing vNOTES procedures 

At our institution, Baylor College of Medicine, the majority of gynecologic surgeries are performed via either transumbilical robot-assisted single-incision laparoscopy or vNOTES. Preoperative selection of appropriate candidates for vNOTES includes: 

• low suspicion for or prior diagnosis of endometriosis with obliteration of the posterior cul-de-sac 
• no surgical history suggestive of severe adhesive disease, and 
• adequate vaginal sidewall access and sufficient descent for instrumentation for entry into the peritoneal cavity. 

In general, a key concept in vNOTES is "vaginal pull, laparoscopic push," which means that the surgeon must pull the cervix while performing vaginal entry and then push the uterus back in the peritoneal cavity to increase surgical space during laparoscopic surgery. 

Continue to: Overview of vNOTES steps...

Below we break down a description of vNOTES in 6 sections. Our patients are always placed in dorsal lithotomy position with TrenGuard (D.A. Surgical) Trendelenburg restraint. We prep the abdomen in case we need to convert to transabdominal surgery via transumbilical single-incision laparoscopic surgery or traditional laparoscopic surgery. 

1. Vaginal entry 

Accessing the peritoneal cavity through the vagina initially proceeds like a vaginal hysterectomy. We inject dilute vasopressin (20 U in 20 mL of normal saline) circumferentially in the cervix (for hysterectomy) or in the posterior cervix in the cervicovaginal junction (for adnexal surgery without hysterectomy) for vasoconstriction and hydrodissection. 

We then incise the vaginal mucosa circumferentially with electrosurgical cautery and follow with posterior colpotomy. We find that reapproximating the posterior peritoneum to the posterior vagina with either figure-of-8 stitches or a running stitch of polyglactin 910 suture (2-0 Vicryl) assists in port placement, bleeding at the peritoneal edge, and closure of the cuff or colpotomy at the end of the case. We tag this suture with a curved hemostat. 

Depending on whether a hysterectomy is being performed, anterior colpotomy is made. Again, the anterior peritoneum is then tagged to the anterior vaginal cuff in similar fashion, and this suture is tagged with a different instrument; we typically use a straight hemostat or Sarot clamp (FIGURE 1). 

2. Traditional vaginal hysterectomy 

After colpotomy, we prefer to perform progressive clamping of the broad ligament from the uterosacral and cardinal ligaments to the level of uterine artery as in traditional vaginal hysterectomy, if feasible. 

3. Single-site port placement 

The assembled GelPOINT Mini advanced access platform (Applied Medical) (FIGURE 2) is introduced through the vagina after the Alexis wound protector (included with the kit) is first placed through the colpotomy with assistance of Babcock clamps (FIGURE 3). 

After ensuring that the green rigid ring of the Alexis wound protector is contained and completely expanded within the peritoneal cavity, we cross our previously tagged sutures as we find this helps with preventing the GelPOINT Mini access platform from inadvertently shifting out of the peritoneal cavity during surgery. The GelSeal cap is then secured and pneumoperitoneum is established (FIGURE 4). 

Continue to: 4. Laparoendoscopic surgery...

Instruments used in our surgeries include a 10-mm rigid 30° 43-cm working length laparoscope; a 44-cm LigaSure device (Medtronic); a 5-mm, 37-cm laparoscopic cobra grasping forceps and fenestrated grasper (Karl Storz); and a 5-mm, 45-cm laparoscopic suction with hydrodissection tip (Stryker) (FIGURE 5). 

vNOTES allows a gynecologic surgeon the unique ability to survey the upper abdomen. The remainder of the surgery proceeds using basic laparoscopic single-site skills. 

During vNOTES, as with all single-site surgical procedures, understanding the optimal placement of crossed instruments is important for successful completion. For example, when securing the right uterine artery, the surgeon needs to push the cervix toward the patient's left and slightly into the peritoneal cavity using a laparoscopic cobra grasper with his or her left hand while then securing the uterine pedicle using the LigaSure device with his or her right hand. This is then reversed when securing the left uterine artery, where the assistant surgeon pushes the cervix toward the patient's right while the surgeon secures the pedicle ("vaginal pull, laparoscopic push") (FIGURE 6). 

This again is reiterated in securing the ovarian pedicles, which are pushed into the peritoneal cavity while being secured with the LigaSure device. 

5. Specimen removal 

For large uteri or specimens that need morcellation, a 15-mm Endo Catch specimen retrieval bag (Medtronic) is introduced through the GelPOINT Mini system. The specimen is then placed in the bag and delivered to the vagina, where contained bag morcellation is performed in standard fashion (FIGURES 7 AND 8). We utilized the "big C" technique by first grasping the specimen with a penetrating clamp. The clamp is then held in our nondominant hand and a No. 10 blade scalpel is used to create a reverse c-incision, keeping one surface of the specimen intact. This is continued until the specimen can be completely delivered through the vagina. 

Specimens that do not require morcellation can be grasped laparoscopically, brought to the GelPOINT Mini port, which is quickly disassembled, and delivered. The GelSeal cap is then reassembled. 

6. Vaginal cuff closure 

The colpotomy or vaginal cuff is closed with barbed suture continuously, as in traditional vaginal hysterectomy cuff closure. Uterosacral ligament suspension should be performed for vaginal cuff support.  
 

Case 1 Multiparous woman presents with heavy regular menses

Over the past several years, a 34-year-old woman has noted increasing intensity and duration of menstrual flow, which now persists for 8 days and includes clots “the size of quarters” and soaks a pad within 1 hour. Sometimes she misses or leaves work on her heaviest days of flow. She reports that menstrual cramps prior to and during flow are increasingly bothersome and do not respond adequately to ibuprofen. She intermittently uses condoms for contraception. She does not wish to be pregnant currently; however, she recently entered into a new relationship and may wish to conceive in the future.

On bimanual examination, the uterus appears bulky. Her hemoglobin is 10.9 g/dL with low mean corpuscular volume and a serum ferritin level indicating iron depletion. Pelvic ultrasonography suggests uterine adenomyosis; no fibroids are imaged (FIGURE 1).

You advise the patient to take ferrous sulfate 325 mg every other day. After discussion with the patient regarding different treatment options, she chooses to proceed with placement of a 52-mg levonorgestrel (LNG) intrauterine device (IUD; Mirena or Liletta).

Case 2 Older adolescent presents with irregular bleeding

A 19-year-old patient reports approximately 6 bleeding episodes each year. She reports the duration of her bleeding as variable, and sometimes the bleeding is heavy with small clots passed. She has been previously diagnosed with polycystic ovary syndrome (PCOS). Combination estrogen-progestin oral contraceptives have been prescribed several times in the past, but she always has discontinued them due to nausea. The patient is in a same-sex relationship and does not anticipate being sexually active with a male. She reports having to shave her mustache and chin twice weekly for the past 1 to 2 years.

On physical examination, the patient is obese (body mass index [BMI], 32 kg/m²), facial acne and hirsutism are present, and hair extends from the mons toward the umbilicus. Bimanual examination reveals a normal size, mobile, nontender uterus without obvious adnexal pathology. Pelvic ultrasonography demonstrates a normal-appearing uterus with multiplanar endometrium (consistent with proliferative changes) (FIGURE 2). Ovarian imaging demonstrates ≥12 follicles per image (FIGURE 3).

About one-third of all women experience abnormal uterine bleeding (AUB) sometime during their lifetime and AUB can impair quality of life.¹ Surgical management, including hysterectomy and endometrial ablation, plays an important role in the management of AUB in patients who do not desire future pregnancies. However, many cases of AUB occur in women who may not have completed childbearing or in women who prefer to avoid surgery.² AUB can be managed effectively medically in most cases.¹ Accordingly, in this review, we focus on nonsurgical management of AUB.

Continue to: Because previously used terms, including...

Because previously used terms, including menorrhagia and meno-metrorrhagia, were inconsistently defined and confusing, the International Federation of Gynecology and Obstetrics introduced updated terminology in 2011 to better describe and characterize AUB in nonpregnant women. Heavy menstrual bleeding (HMB) refers to ovulatory (cyclic) bleeding that is more than 8 days’ duration, or sufficiently heavy to impair a woman’s quality of life. HMB is a pattern of AUB distinct from the irregular bleeding pattern typically caused by ovulatory dysfunction (AUB-O).¹

Clinical evaluation

Obtain menstrual history. In addition to a medical, surgical, and gynecologic history, a thorough menstrual history should be obtained to further characterize the patient’s bleeding pattern. In contrast to the cyclical or ovulatory bleeding seen with HMB, bleeding associated with inconsistent ovulation (AUB-O) is unpredictable or irregular, and is commonly associated with PCOS. AUB-O is also encountered in recently menarchal girls (secondary to immaturity of the hypothalamic-pituitary-gonadal axis) and in those who are perimenopausal. In addition, medications that can induce hyperprolactinemia (such as certain antipsychotics) can cause AUB-O.

Evaluate for all sources of bleeding. Be sure to evaluate for extrauterine causes of bleeding, including the cervix, vagina, vulva, or the urinary or gastrointestinal tracts for bleeding. Intermenstrual bleeding occurring between normal regular menses may be caused by an endometrial polyp, submucosal fibroid, endometritis, or an IUD. The patient report of postcoital bleeding suggests that cervical disease (cervicitis, polyp, or malignancy) may be present. Uterine leiomyoma or adenomyosis represent common causes of HMB. However, HMB also may be caused by a copper IUD, coagulation disorders (including von Willebrand disease), or use of anticoagulant medications. Hormonal contraceptives also can cause irregular bleeding.

Perform a pelvic examination and measure vital signs. The presence of fever suggests the possible presence of pelvic inflammatory disease (PID), while orthostatic hypotension raises the possibility of hypovolemia. When vaginal speculum examination is performed, a cervical cause of abnormal bleeding may be noted. The presence of fresh or old blood or finding clots in the vaginal vault or at the cervical os are all consistent with AUB. A bimanual examination that reveals an enlarged or lobular uterus suggests leiomyoma or adenomyosis. Cervical or adnexal tenderness is often noted in women with PID, which itself may be associated with endometritis. The presence of hyperandrogenic signs on physical examination (eg, acne, hirsutism, or clitoromegaly) suggests PCOS. The finding of galactorrhea suggests that hyperprolactinemia may be present.

Laboratory assessment

Test for pregnancy, cervical disease, and sexually transmitted infection when appropriate. Pregnancy testing is appropriate for women with AUB aged 55 years or younger. If patients with AUB are not up to date with normal cervical cancer screening results, cervical cytology and/or human papillomavirus testing should be performed. Testing for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis should be performed in patients:

• younger than 25 years
• when the history indicates new or multiple sexual partners, or
• when vaginal discharge, cervicitis, cervical motion, or adnexal tenderness is present.

Continue to: Obtain a complete blood count and serum ferritin levels...

Obtain a complete blood count and serum ferritin levels. In women presenting with HMB, iron depletion and iron deficiency anemia are common. The finding of leukocytosis raises the possibility of PID or postpartum endometritis. In women with presumptive AUB-O, checking the levels of thyroid-stimulating hormone, free T4, and prolactin should be performed.

Screen for a hemostasis disorder. Women with excessive menstrual bleeding should be clinically screened for an underlying disorder of hemostasis (TABLE 1).³ When a hemostasis disorder is suspected, initial laboratory evaluation includes a partial thromboplastin time, prothrombin time, activated partial thromboplastin time, and fibrinogen. Women who have a positive clinical screen for a possible bleeding disorder or abnormal initial laboratory test results for disorders of hemostasis should undergo further laboratory evaluation, including von Willebrand factor antigen, ristocetin cofactor assay, and factor VIII. Consultation with a hematologist should be considered in these cases.

Perform endometrial biopsy when indicated

After excluding pregnancy, endometrial biopsy (through pipelle biospy or brush sampling; FIGURE 4) should be performed in women with AUB who are at increased risk for endometrial neoplasia. The prevalence of endometrial neoplasia is substantially higher among women ≥45 years of age⁴ and among patients with AUB who are also obese (BMI, ≥30 kg/m²).⁵ In addition, AUB patients with unopposed estrogen exposure (presumed anovulation/PCOS), as well as those with persistent AUB or failed medical management, should undergo endometrial biopsy.⁶

Utilize transvaginal ultrasonography

Transvaginal ultrasonography is often useful in the evaluation of patients with AUB, as it may identify uterine fibroids or adenomyosis, suggest intracavitary pathology (such as an endometrial polyp or submucosal fibroid), or raise the possibility of PCOS. In virginal patients or those in whom vaginal ultrasound is not appropriate, abdominal pelvic ultrasonography represents appropriate imaging. If unenhanced ultrasound suggests endometrial polyps or fibroids within the endometrial cavity, an office-based saline infusion sonogram (sonohysterogram) (FIGURE 5) or hysteroscopy should be performed. Targeted endometrial sampling and biopsy of intracavitary pathology can be performed at the time of hysteroscopy.

Treatment

When HMB impairs quality of life, is bothersome to the patient, or results in anemia, treatment is appropriate. Although bleeding episodes in women with AUB-O may be infrequent (as with Case 2), treatment prevents heavy or prolonged bleeding episodes as well as endometrial neoplasia that may otherwise occur in anovulatory women.

Many women with AUB can be managed medically. However, treatment choices will vary with respect to the patient’s desire for future fertility, medical comorbidities, personal preferences, and financial barriers. While many women may prefer outpatient medical management (TABLE 2),^7-14 others might desire surgical therapy, including endometrial ablation or hysterectomy.

Oral contraceptives

Combination estrogen-progestin oral contraceptives represent appropriate initial therapy for many women in the reproductive-age group with AUB, whether women have HMB or AUB-O. However, contraceptive doses of estrogen are not appropriate for some women with risk factors for cardiovascular disease, including those who smoke cigarettes and are age ≥35 years or those who have hypertension (TABLE 3).^15,16

Continue to: Menopausal dosages of HT...

Menopausal dosages of HT

If use of contraceptive doses of estrogen is not appropriate, continuous off-label use of menopausal combination formulations (physiologic dosage) of hormonal therapy (HT; ie, lower doses of estrogen than contraceptives) may be effective in reducing or eliminating AUB. Options for menopausal combination formulations include generic ethinyl estradiol 5 µg/norethindrone acetate 1 mg or estradiol 1 mg/norethindrone acetate 0.5 mg.⁷ High-dose oral progestin therapy (norethindrone acetate 5 mg tablet once daily or medroxyprogesterone acetate 10 mg tablets 1–3 times daily) also can be used when combination contraceptives are contraindicated and may be more effective than lower-dose combination formulations.

Package labeling, as well as some guidelines, indicate that oral progestins used to treat AUB should be taken cyclically.⁸ However, continuous daily use is easier for many patients and may be more effective in reducing bleeding. Accordingly, we counsel patients with AUB who are using progestins and who do not wish to conceive to take these medications continuously. High-dose oral progestin therapy may cause bloating, dysphoria, and increased appetite/weight gain. Women initiating hormonal management (including the progestin IUDs detailed below) for AUB should be counseled that irregular or even continuous light bleeding/spotting is common initially, but this bleeding pattern typically decreases with continued use.

IUDs

The LNG 52 mg IUD (Mirena or Liletta) effectively treats HMB, reducing bleeding in a manner comparable to that of endometrial ablation.^9,10 The Mirena IUD is approved for treatment of HMB in women desiring intrauterine contraception. In contrast to oral medications, use of progestin IUDs does not involve daily administration and may represent an attractive option for women with HMB who would like to avoid surgery or preserve fertility. With ongoing use, continuous oral or intrauterine hormonal management may result in amenorrhea in some women with AUB.

When the LNG 52 mg IUD is used to treat HMB, the menstrual suppression impact may begin to attenuate after approximately 4 years of use; in this setting, replacing the IUD often restores effective menstrual suppression.¹¹ The LNG 52 mg IUD effectively suppresses menses in women with coagulation disorders; if menstrual suppression with the progestin IUD is not adequate in this setting, it may be appropriate to add an oral combination estrogen-progestin contraceptive or high-dose oral progestin.^11,12

NSAIDs and tranexamic acid

Off-label use of nonsteroidal anti-inflammatory drugs (naproxen 500–1,000 mg daily for 5 days beginning at the onset of menstrual flow or tranexamic acid two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can suppress HMB and is useful for women who prefer to avoid or have contraindications to hormonal treatments.^13,14 Unfortunately, these agents are not as effective as hormonal management in treating AUB.

Iron supplementation is often needed

Iron depletion commonly results from HMB, often resulting in iron deficiency anemia. When iron depletion (readily identified by checking a serum ferritin level) or iron deficiency anemia is identified, iron supplementation should be recommended. Every-other-day administration of iron supplements maximizes iron absorption while minimizing the adverse effects of unabsorbed iron, such as nausea. Sixty mg of elemental iron (ferrous sulfate 325 mg) administered every other day represents an inexpensive and effective treatment for iron deficiency/anemia.¹⁷ In patients who cannot tolerate oral iron supplementation or for those in whom oral therapy is not appropriate or effective, newer intravenous iron formulations are safe and effective.¹⁸

Continue to: Case 1 Follow-up...

Case 1 Follow-up

The patient noted marked improvement in her menstrual cramps following LNG-containing IUD placement. Although she also reported that she no longer experienced heavy menstrual flow or cramps, she was bothered by frequent, unpredictable light bleeding/spotting. You prescribed norethindrone acetate (NETA) 5-mg tablet orally once daily, to be used in addition to her IUD. After using the IUD with concomitant NETA for 2 months’ duration, she noted that her bleeding/spotting almost completely resolved; however, she did report feeling irritable with use of the progestin tablets. She subsequently stopped the NETA tablets and, after 6 months of additional follow-up, reported only minimal spotting and no cramps.

At this later follow-up visit, you noted that her hemoglobin level increased to 12.6 g/dL, and the ferritin level no longer indicated iron depletion. After the IUD had been in place for 4 years, she reported that she was beginning to experience frequent light bleeding again. A follow-up vaginal sonogram noted a well-positioned IUD, there was no suggestion of intracavitary pathology, and adenomyosis continued to be imaged. She underwent IUD removal and placement of a new LNG 52 mg IUD. This resulted in marked reduction in her bleeding.

Case 2 Follow-up

Two weeks after beginning continuous oral progestin therapy, the patient called reporting frequent irregular bleeding. She was reassured that this was not unexpected and encouraged to continue oral progestin therapy. During a 3-month follow-up visit, the patient noted little, if any, bleeding over the previous 2 months and was pleased with this result. She continued to note acne and hirsutism and asked about the possibility of adding spironolactone to her oral progestin regimen.

Case 1 Multiparous woman presents with heavy regular menses

Over the past several years, a 34-year-old woman has noted increasing intensity and duration of menstrual flow, which now persists for 8 days and includes clots “the size of quarters” and soaks a pad within 1 hour. Sometimes she misses or leaves work on her heaviest days of flow. She reports that menstrual cramps prior to and during flow are increasingly bothersome and do not respond adequately to ibuprofen. She intermittently uses condoms for contraception. She does not wish to be pregnant currently; however, she recently entered into a new relationship and may wish to conceive in the future.

On bimanual examination, the uterus appears bulky. Her hemoglobin is 10.9 g/dL with low mean corpuscular volume and a serum ferritin level indicating iron depletion. Pelvic ultrasonography suggests uterine adenomyosis; no fibroids are imaged (FIGURE 1).

You advise the patient to take ferrous sulfate 325 mg every other day. After discussion with the patient regarding different treatment options, she chooses to proceed with placement of a 52-mg levonorgestrel (LNG) intrauterine device (IUD; Mirena or Liletta).

Case 2 Older adolescent presents with irregular bleeding

A 19-year-old patient reports approximately 6 bleeding episodes each year. She reports the duration of her bleeding as variable, and sometimes the bleeding is heavy with small clots passed. She has been previously diagnosed with polycystic ovary syndrome (PCOS). Combination estrogen-progestin oral contraceptives have been prescribed several times in the past, but she always has discontinued them due to nausea. The patient is in a same-sex relationship and does not anticipate being sexually active with a male. She reports having to shave her mustache and chin twice weekly for the past 1 to 2 years.

On physical examination, the patient is obese (body mass index [BMI], 32 kg/m²), facial acne and hirsutism are present, and hair extends from the mons toward the umbilicus. Bimanual examination reveals a normal size, mobile, nontender uterus without obvious adnexal pathology. Pelvic ultrasonography demonstrates a normal-appearing uterus with multiplanar endometrium (consistent with proliferative changes) (FIGURE 2). Ovarian imaging demonstrates ≥12 follicles per image (FIGURE 3).

About one-third of all women experience abnormal uterine bleeding (AUB) sometime during their lifetime and AUB can impair quality of life.¹ Surgical management, including hysterectomy and endometrial ablation, plays an important role in the management of AUB in patients who do not desire future pregnancies. However, many cases of AUB occur in women who may not have completed childbearing or in women who prefer to avoid surgery.² AUB can be managed effectively medically in most cases.¹ Accordingly, in this review, we focus on nonsurgical management of AUB.

Continue to: Because previously used terms, including...

Because previously used terms, including menorrhagia and meno-metrorrhagia, were inconsistently defined and confusing, the International Federation of Gynecology and Obstetrics introduced updated terminology in 2011 to better describe and characterize AUB in nonpregnant women. Heavy menstrual bleeding (HMB) refers to ovulatory (cyclic) bleeding that is more than 8 days’ duration, or sufficiently heavy to impair a woman’s quality of life. HMB is a pattern of AUB distinct from the irregular bleeding pattern typically caused by ovulatory dysfunction (AUB-O).¹

Clinical evaluation

Obtain menstrual history. In addition to a medical, surgical, and gynecologic history, a thorough menstrual history should be obtained to further characterize the patient’s bleeding pattern. In contrast to the cyclical or ovulatory bleeding seen with HMB, bleeding associated with inconsistent ovulation (AUB-O) is unpredictable or irregular, and is commonly associated with PCOS. AUB-O is also encountered in recently menarchal girls (secondary to immaturity of the hypothalamic-pituitary-gonadal axis) and in those who are perimenopausal. In addition, medications that can induce hyperprolactinemia (such as certain antipsychotics) can cause AUB-O.

Evaluate for all sources of bleeding. Be sure to evaluate for extrauterine causes of bleeding, including the cervix, vagina, vulva, or the urinary or gastrointestinal tracts for bleeding. Intermenstrual bleeding occurring between normal regular menses may be caused by an endometrial polyp, submucosal fibroid, endometritis, or an IUD. The patient report of postcoital bleeding suggests that cervical disease (cervicitis, polyp, or malignancy) may be present. Uterine leiomyoma or adenomyosis represent common causes of HMB. However, HMB also may be caused by a copper IUD, coagulation disorders (including von Willebrand disease), or use of anticoagulant medications. Hormonal contraceptives also can cause irregular bleeding.

Perform a pelvic examination and measure vital signs. The presence of fever suggests the possible presence of pelvic inflammatory disease (PID), while orthostatic hypotension raises the possibility of hypovolemia. When vaginal speculum examination is performed, a cervical cause of abnormal bleeding may be noted. The presence of fresh or old blood or finding clots in the vaginal vault or at the cervical os are all consistent with AUB. A bimanual examination that reveals an enlarged or lobular uterus suggests leiomyoma or adenomyosis. Cervical or adnexal tenderness is often noted in women with PID, which itself may be associated with endometritis. The presence of hyperandrogenic signs on physical examination (eg, acne, hirsutism, or clitoromegaly) suggests PCOS. The finding of galactorrhea suggests that hyperprolactinemia may be present.

Laboratory assessment

Test for pregnancy, cervical disease, and sexually transmitted infection when appropriate. Pregnancy testing is appropriate for women with AUB aged 55 years or younger. If patients with AUB are not up to date with normal cervical cancer screening results, cervical cytology and/or human papillomavirus testing should be performed. Testing for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis should be performed in patients:

• younger than 25 years
• when the history indicates new or multiple sexual partners, or
• when vaginal discharge, cervicitis, cervical motion, or adnexal tenderness is present.

Continue to: Obtain a complete blood count and serum ferritin levels...

Obtain a complete blood count and serum ferritin levels. In women presenting with HMB, iron depletion and iron deficiency anemia are common. The finding of leukocytosis raises the possibility of PID or postpartum endometritis. In women with presumptive AUB-O, checking the levels of thyroid-stimulating hormone, free T4, and prolactin should be performed.

Screen for a hemostasis disorder. Women with excessive menstrual bleeding should be clinically screened for an underlying disorder of hemostasis (TABLE 1).³ When a hemostasis disorder is suspected, initial laboratory evaluation includes a partial thromboplastin time, prothrombin time, activated partial thromboplastin time, and fibrinogen. Women who have a positive clinical screen for a possible bleeding disorder or abnormal initial laboratory test results for disorders of hemostasis should undergo further laboratory evaluation, including von Willebrand factor antigen, ristocetin cofactor assay, and factor VIII. Consultation with a hematologist should be considered in these cases.

Perform endometrial biopsy when indicated

After excluding pregnancy, endometrial biopsy (through pipelle biospy or brush sampling; FIGURE 4) should be performed in women with AUB who are at increased risk for endometrial neoplasia. The prevalence of endometrial neoplasia is substantially higher among women ≥45 years of age⁴ and among patients with AUB who are also obese (BMI, ≥30 kg/m²).⁵ In addition, AUB patients with unopposed estrogen exposure (presumed anovulation/PCOS), as well as those with persistent AUB or failed medical management, should undergo endometrial biopsy.⁶

Utilize transvaginal ultrasonography

Transvaginal ultrasonography is often useful in the evaluation of patients with AUB, as it may identify uterine fibroids or adenomyosis, suggest intracavitary pathology (such as an endometrial polyp or submucosal fibroid), or raise the possibility of PCOS. In virginal patients or those in whom vaginal ultrasound is not appropriate, abdominal pelvic ultrasonography represents appropriate imaging. If unenhanced ultrasound suggests endometrial polyps or fibroids within the endometrial cavity, an office-based saline infusion sonogram (sonohysterogram) (FIGURE 5) or hysteroscopy should be performed. Targeted endometrial sampling and biopsy of intracavitary pathology can be performed at the time of hysteroscopy.

Treatment

When HMB impairs quality of life, is bothersome to the patient, or results in anemia, treatment is appropriate. Although bleeding episodes in women with AUB-O may be infrequent (as with Case 2), treatment prevents heavy or prolonged bleeding episodes as well as endometrial neoplasia that may otherwise occur in anovulatory women.

Many women with AUB can be managed medically. However, treatment choices will vary with respect to the patient’s desire for future fertility, medical comorbidities, personal preferences, and financial barriers. While many women may prefer outpatient medical management (TABLE 2),^7-14 others might desire surgical therapy, including endometrial ablation or hysterectomy.

Oral contraceptives

Combination estrogen-progestin oral contraceptives represent appropriate initial therapy for many women in the reproductive-age group with AUB, whether women have HMB or AUB-O. However, contraceptive doses of estrogen are not appropriate for some women with risk factors for cardiovascular disease, including those who smoke cigarettes and are age ≥35 years or those who have hypertension (TABLE 3).^15,16

Continue to: Menopausal dosages of HT...

Menopausal dosages of HT

If use of contraceptive doses of estrogen is not appropriate, continuous off-label use of menopausal combination formulations (physiologic dosage) of hormonal therapy (HT; ie, lower doses of estrogen than contraceptives) may be effective in reducing or eliminating AUB. Options for menopausal combination formulations include generic ethinyl estradiol 5 µg/norethindrone acetate 1 mg or estradiol 1 mg/norethindrone acetate 0.5 mg.⁷ High-dose oral progestin therapy (norethindrone acetate 5 mg tablet once daily or medroxyprogesterone acetate 10 mg tablets 1–3 times daily) also can be used when combination contraceptives are contraindicated and may be more effective than lower-dose combination formulations.

Package labeling, as well as some guidelines, indicate that oral progestins used to treat AUB should be taken cyclically.⁸ However, continuous daily use is easier for many patients and may be more effective in reducing bleeding. Accordingly, we counsel patients with AUB who are using progestins and who do not wish to conceive to take these medications continuously. High-dose oral progestin therapy may cause bloating, dysphoria, and increased appetite/weight gain. Women initiating hormonal management (including the progestin IUDs detailed below) for AUB should be counseled that irregular or even continuous light bleeding/spotting is common initially, but this bleeding pattern typically decreases with continued use.

IUDs

The LNG 52 mg IUD (Mirena or Liletta) effectively treats HMB, reducing bleeding in a manner comparable to that of endometrial ablation.^9,10 The Mirena IUD is approved for treatment of HMB in women desiring intrauterine contraception. In contrast to oral medications, use of progestin IUDs does not involve daily administration and may represent an attractive option for women with HMB who would like to avoid surgery or preserve fertility. With ongoing use, continuous oral or intrauterine hormonal management may result in amenorrhea in some women with AUB.

When the LNG 52 mg IUD is used to treat HMB, the menstrual suppression impact may begin to attenuate after approximately 4 years of use; in this setting, replacing the IUD often restores effective menstrual suppression.¹¹ The LNG 52 mg IUD effectively suppresses menses in women with coagulation disorders; if menstrual suppression with the progestin IUD is not adequate in this setting, it may be appropriate to add an oral combination estrogen-progestin contraceptive or high-dose oral progestin.^11,12

NSAIDs and tranexamic acid

Off-label use of nonsteroidal anti-inflammatory drugs (naproxen 500–1,000 mg daily for 5 days beginning at the onset of menstrual flow or tranexamic acid two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can suppress HMB and is useful for women who prefer to avoid or have contraindications to hormonal treatments.^13,14 Unfortunately, these agents are not as effective as hormonal management in treating AUB.

Iron supplementation is often needed

Iron depletion commonly results from HMB, often resulting in iron deficiency anemia. When iron depletion (readily identified by checking a serum ferritin level) or iron deficiency anemia is identified, iron supplementation should be recommended. Every-other-day administration of iron supplements maximizes iron absorption while minimizing the adverse effects of unabsorbed iron, such as nausea. Sixty mg of elemental iron (ferrous sulfate 325 mg) administered every other day represents an inexpensive and effective treatment for iron deficiency/anemia.¹⁷ In patients who cannot tolerate oral iron supplementation or for those in whom oral therapy is not appropriate or effective, newer intravenous iron formulations are safe and effective.¹⁸

Continue to: Case 1 Follow-up...

Case 1 Follow-up

The patient noted marked improvement in her menstrual cramps following LNG-containing IUD placement. Although she also reported that she no longer experienced heavy menstrual flow or cramps, she was bothered by frequent, unpredictable light bleeding/spotting. You prescribed norethindrone acetate (NETA) 5-mg tablet orally once daily, to be used in addition to her IUD. After using the IUD with concomitant NETA for 2 months’ duration, she noted that her bleeding/spotting almost completely resolved; however, she did report feeling irritable with use of the progestin tablets. She subsequently stopped the NETA tablets and, after 6 months of additional follow-up, reported only minimal spotting and no cramps.

At this later follow-up visit, you noted that her hemoglobin level increased to 12.6 g/dL, and the ferritin level no longer indicated iron depletion. After the IUD had been in place for 4 years, she reported that she was beginning to experience frequent light bleeding again. A follow-up vaginal sonogram noted a well-positioned IUD, there was no suggestion of intracavitary pathology, and adenomyosis continued to be imaged. She underwent IUD removal and placement of a new LNG 52 mg IUD. This resulted in marked reduction in her bleeding.

Case 2 Follow-up

Two weeks after beginning continuous oral progestin therapy, the patient called reporting frequent irregular bleeding. She was reassured that this was not unexpected and encouraged to continue oral progestin therapy. During a 3-month follow-up visit, the patient noted little, if any, bleeding over the previous 2 months and was pleased with this result. She continued to note acne and hirsutism and asked about the possibility of adding spironolactone to her oral progestin regimen.

Case 1 Multiparous woman presents with heavy regular menses

Over the past several years, a 34-year-old woman has noted increasing intensity and duration of menstrual flow, which now persists for 8 days and includes clots “the size of quarters” and soaks a pad within 1 hour. Sometimes she misses or leaves work on her heaviest days of flow. She reports that menstrual cramps prior to and during flow are increasingly bothersome and do not respond adequately to ibuprofen. She intermittently uses condoms for contraception. She does not wish to be pregnant currently; however, she recently entered into a new relationship and may wish to conceive in the future.

On bimanual examination, the uterus appears bulky. Her hemoglobin is 10.9 g/dL with low mean corpuscular volume and a serum ferritin level indicating iron depletion. Pelvic ultrasonography suggests uterine adenomyosis; no fibroids are imaged (FIGURE 1).

You advise the patient to take ferrous sulfate 325 mg every other day. After discussion with the patient regarding different treatment options, she chooses to proceed with placement of a 52-mg levonorgestrel (LNG) intrauterine device (IUD; Mirena or Liletta).

Case 2 Older adolescent presents with irregular bleeding

A 19-year-old patient reports approximately 6 bleeding episodes each year. She reports the duration of her bleeding as variable, and sometimes the bleeding is heavy with small clots passed. She has been previously diagnosed with polycystic ovary syndrome (PCOS). Combination estrogen-progestin oral contraceptives have been prescribed several times in the past, but she always has discontinued them due to nausea. The patient is in a same-sex relationship and does not anticipate being sexually active with a male. She reports having to shave her mustache and chin twice weekly for the past 1 to 2 years.

On physical examination, the patient is obese (body mass index [BMI], 32 kg/m²), facial acne and hirsutism are present, and hair extends from the mons toward the umbilicus. Bimanual examination reveals a normal size, mobile, nontender uterus without obvious adnexal pathology. Pelvic ultrasonography demonstrates a normal-appearing uterus with multiplanar endometrium (consistent with proliferative changes) (FIGURE 2). Ovarian imaging demonstrates ≥12 follicles per image (FIGURE 3).

About one-third of all women experience abnormal uterine bleeding (AUB) sometime during their lifetime and AUB can impair quality of life.¹ Surgical management, including hysterectomy and endometrial ablation, plays an important role in the management of AUB in patients who do not desire future pregnancies. However, many cases of AUB occur in women who may not have completed childbearing or in women who prefer to avoid surgery.² AUB can be managed effectively medically in most cases.¹ Accordingly, in this review, we focus on nonsurgical management of AUB.

Continue to: Because previously used terms, including...

Because previously used terms, including menorrhagia and meno-metrorrhagia, were inconsistently defined and confusing, the International Federation of Gynecology and Obstetrics introduced updated terminology in 2011 to better describe and characterize AUB in nonpregnant women. Heavy menstrual bleeding (HMB) refers to ovulatory (cyclic) bleeding that is more than 8 days’ duration, or sufficiently heavy to impair a woman’s quality of life. HMB is a pattern of AUB distinct from the irregular bleeding pattern typically caused by ovulatory dysfunction (AUB-O).¹

Clinical evaluation

Obtain menstrual history. In addition to a medical, surgical, and gynecologic history, a thorough menstrual history should be obtained to further characterize the patient’s bleeding pattern. In contrast to the cyclical or ovulatory bleeding seen with HMB, bleeding associated with inconsistent ovulation (AUB-O) is unpredictable or irregular, and is commonly associated with PCOS. AUB-O is also encountered in recently menarchal girls (secondary to immaturity of the hypothalamic-pituitary-gonadal axis) and in those who are perimenopausal. In addition, medications that can induce hyperprolactinemia (such as certain antipsychotics) can cause AUB-O.

Evaluate for all sources of bleeding. Be sure to evaluate for extrauterine causes of bleeding, including the cervix, vagina, vulva, or the urinary or gastrointestinal tracts for bleeding. Intermenstrual bleeding occurring between normal regular menses may be caused by an endometrial polyp, submucosal fibroid, endometritis, or an IUD. The patient report of postcoital bleeding suggests that cervical disease (cervicitis, polyp, or malignancy) may be present. Uterine leiomyoma or adenomyosis represent common causes of HMB. However, HMB also may be caused by a copper IUD, coagulation disorders (including von Willebrand disease), or use of anticoagulant medications. Hormonal contraceptives also can cause irregular bleeding.

Perform a pelvic examination and measure vital signs. The presence of fever suggests the possible presence of pelvic inflammatory disease (PID), while orthostatic hypotension raises the possibility of hypovolemia. When vaginal speculum examination is performed, a cervical cause of abnormal bleeding may be noted. The presence of fresh or old blood or finding clots in the vaginal vault or at the cervical os are all consistent with AUB. A bimanual examination that reveals an enlarged or lobular uterus suggests leiomyoma or adenomyosis. Cervical or adnexal tenderness is often noted in women with PID, which itself may be associated with endometritis. The presence of hyperandrogenic signs on physical examination (eg, acne, hirsutism, or clitoromegaly) suggests PCOS. The finding of galactorrhea suggests that hyperprolactinemia may be present.

Laboratory assessment

Test for pregnancy, cervical disease, and sexually transmitted infection when appropriate. Pregnancy testing is appropriate for women with AUB aged 55 years or younger. If patients with AUB are not up to date with normal cervical cancer screening results, cervical cytology and/or human papillomavirus testing should be performed. Testing for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis should be performed in patients:

• younger than 25 years
• when the history indicates new or multiple sexual partners, or
• when vaginal discharge, cervicitis, cervical motion, or adnexal tenderness is present.

Continue to: Obtain a complete blood count and serum ferritin levels...

Obtain a complete blood count and serum ferritin levels. In women presenting with HMB, iron depletion and iron deficiency anemia are common. The finding of leukocytosis raises the possibility of PID or postpartum endometritis. In women with presumptive AUB-O, checking the levels of thyroid-stimulating hormone, free T4, and prolactin should be performed.

Screen for a hemostasis disorder. Women with excessive menstrual bleeding should be clinically screened for an underlying disorder of hemostasis (TABLE 1).³ When a hemostasis disorder is suspected, initial laboratory evaluation includes a partial thromboplastin time, prothrombin time, activated partial thromboplastin time, and fibrinogen. Women who have a positive clinical screen for a possible bleeding disorder or abnormal initial laboratory test results for disorders of hemostasis should undergo further laboratory evaluation, including von Willebrand factor antigen, ristocetin cofactor assay, and factor VIII. Consultation with a hematologist should be considered in these cases.

Perform endometrial biopsy when indicated

After excluding pregnancy, endometrial biopsy (through pipelle biospy or brush sampling; FIGURE 4) should be performed in women with AUB who are at increased risk for endometrial neoplasia. The prevalence of endometrial neoplasia is substantially higher among women ≥45 years of age⁴ and among patients with AUB who are also obese (BMI, ≥30 kg/m²).⁵ In addition, AUB patients with unopposed estrogen exposure (presumed anovulation/PCOS), as well as those with persistent AUB or failed medical management, should undergo endometrial biopsy.⁶

Utilize transvaginal ultrasonography

Transvaginal ultrasonography is often useful in the evaluation of patients with AUB, as it may identify uterine fibroids or adenomyosis, suggest intracavitary pathology (such as an endometrial polyp or submucosal fibroid), or raise the possibility of PCOS. In virginal patients or those in whom vaginal ultrasound is not appropriate, abdominal pelvic ultrasonography represents appropriate imaging. If unenhanced ultrasound suggests endometrial polyps or fibroids within the endometrial cavity, an office-based saline infusion sonogram (sonohysterogram) (FIGURE 5) or hysteroscopy should be performed. Targeted endometrial sampling and biopsy of intracavitary pathology can be performed at the time of hysteroscopy.

Treatment

When HMB impairs quality of life, is bothersome to the patient, or results in anemia, treatment is appropriate. Although bleeding episodes in women with AUB-O may be infrequent (as with Case 2), treatment prevents heavy or prolonged bleeding episodes as well as endometrial neoplasia that may otherwise occur in anovulatory women.

Many women with AUB can be managed medically. However, treatment choices will vary with respect to the patient’s desire for future fertility, medical comorbidities, personal preferences, and financial barriers. While many women may prefer outpatient medical management (TABLE 2),^7-14 others might desire surgical therapy, including endometrial ablation or hysterectomy.

Oral contraceptives

Combination estrogen-progestin oral contraceptives represent appropriate initial therapy for many women in the reproductive-age group with AUB, whether women have HMB or AUB-O. However, contraceptive doses of estrogen are not appropriate for some women with risk factors for cardiovascular disease, including those who smoke cigarettes and are age ≥35 years or those who have hypertension (TABLE 3).^15,16

Continue to: Menopausal dosages of HT...

Menopausal dosages of HT

If use of contraceptive doses of estrogen is not appropriate, continuous off-label use of menopausal combination formulations (physiologic dosage) of hormonal therapy (HT; ie, lower doses of estrogen than contraceptives) may be effective in reducing or eliminating AUB. Options for menopausal combination formulations include generic ethinyl estradiol 5 µg/norethindrone acetate 1 mg or estradiol 1 mg/norethindrone acetate 0.5 mg.⁷ High-dose oral progestin therapy (norethindrone acetate 5 mg tablet once daily or medroxyprogesterone acetate 10 mg tablets 1–3 times daily) also can be used when combination contraceptives are contraindicated and may be more effective than lower-dose combination formulations.

Package labeling, as well as some guidelines, indicate that oral progestins used to treat AUB should be taken cyclically.⁸ However, continuous daily use is easier for many patients and may be more effective in reducing bleeding. Accordingly, we counsel patients with AUB who are using progestins and who do not wish to conceive to take these medications continuously. High-dose oral progestin therapy may cause bloating, dysphoria, and increased appetite/weight gain. Women initiating hormonal management (including the progestin IUDs detailed below) for AUB should be counseled that irregular or even continuous light bleeding/spotting is common initially, but this bleeding pattern typically decreases with continued use.

IUDs

The LNG 52 mg IUD (Mirena or Liletta) effectively treats HMB, reducing bleeding in a manner comparable to that of endometrial ablation.^9,10 The Mirena IUD is approved for treatment of HMB in women desiring intrauterine contraception. In contrast to oral medications, use of progestin IUDs does not involve daily administration and may represent an attractive option for women with HMB who would like to avoid surgery or preserve fertility. With ongoing use, continuous oral or intrauterine hormonal management may result in amenorrhea in some women with AUB.

When the LNG 52 mg IUD is used to treat HMB, the menstrual suppression impact may begin to attenuate after approximately 4 years of use; in this setting, replacing the IUD often restores effective menstrual suppression.¹¹ The LNG 52 mg IUD effectively suppresses menses in women with coagulation disorders; if menstrual suppression with the progestin IUD is not adequate in this setting, it may be appropriate to add an oral combination estrogen-progestin contraceptive or high-dose oral progestin.^11,12

NSAIDs and tranexamic acid

Off-label use of nonsteroidal anti-inflammatory drugs (naproxen 500–1,000 mg daily for 5 days beginning at the onset of menstrual flow or tranexamic acid two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can suppress HMB and is useful for women who prefer to avoid or have contraindications to hormonal treatments.^13,14 Unfortunately, these agents are not as effective as hormonal management in treating AUB.

Iron supplementation is often needed

Iron depletion commonly results from HMB, often resulting in iron deficiency anemia. When iron depletion (readily identified by checking a serum ferritin level) or iron deficiency anemia is identified, iron supplementation should be recommended. Every-other-day administration of iron supplements maximizes iron absorption while minimizing the adverse effects of unabsorbed iron, such as nausea. Sixty mg of elemental iron (ferrous sulfate 325 mg) administered every other day represents an inexpensive and effective treatment for iron deficiency/anemia.¹⁷ In patients who cannot tolerate oral iron supplementation or for those in whom oral therapy is not appropriate or effective, newer intravenous iron formulations are safe and effective.¹⁸

Continue to: Case 1 Follow-up...

Case 1 Follow-up

The patient noted marked improvement in her menstrual cramps following LNG-containing IUD placement. Although she also reported that she no longer experienced heavy menstrual flow or cramps, she was bothered by frequent, unpredictable light bleeding/spotting. You prescribed norethindrone acetate (NETA) 5-mg tablet orally once daily, to be used in addition to her IUD. After using the IUD with concomitant NETA for 2 months’ duration, she noted that her bleeding/spotting almost completely resolved; however, she did report feeling irritable with use of the progestin tablets. She subsequently stopped the NETA tablets and, after 6 months of additional follow-up, reported only minimal spotting and no cramps.

At this later follow-up visit, you noted that her hemoglobin level increased to 12.6 g/dL, and the ferritin level no longer indicated iron depletion. After the IUD had been in place for 4 years, she reported that she was beginning to experience frequent light bleeding again. A follow-up vaginal sonogram noted a well-positioned IUD, there was no suggestion of intracavitary pathology, and adenomyosis continued to be imaged. She underwent IUD removal and placement of a new LNG 52 mg IUD. This resulted in marked reduction in her bleeding.

Case 2 Follow-up

Two weeks after beginning continuous oral progestin therapy, the patient called reporting frequent irregular bleeding. She was reassured that this was not unexpected and encouraged to continue oral progestin therapy. During a 3-month follow-up visit, the patient noted little, if any, bleeding over the previous 2 months and was pleased with this result. She continued to note acne and hirsutism and asked about the possibility of adding spironolactone to her oral progestin regimen.

Autoimmune hemolytic anemia (AIHA) is mediated by antibodies, and in most cases immunoglobulin (Ig) G is the mediating antibody. This type of AIHA is referred to as "warm" AIHA because IgG antibodies bind best at body temperature. "Cold" AIHA is mediated by IgM antibodies, which bind maximally at temperatures below 37°C. AIHA caused by a drug reaction is rare, with an estimated annual incidence of 1:1,000,000 for severe drug-related AIHA.¹ This article reviews the management of the more common types of AIHA, with a focus on warm, cold, and drug-induced AIHA; the evaluation and diagnosis of AIHA is reviewed in a separate article.

Warm Autoimmune Hemolytic Anemia

In AIHA, hemolysis is mediated by antibodies that bind to the surface of red blood cells. AIHA in which IgG antibodies are the offending antibodies is referred to as warm AIHA. “Warm” refers to the fact that the antibody binds best at body temperature (37°C). In warm AIHA, testing will show IgG molecules attached to the surface of the red cells, with 50% of patients also showing C3. Between 50% and 90% of AIHA cases are due to warm antibodies.^2,3 The incidence of warm AIHA varies by series but is approximately 1 case per 100,000 patients per year; this form of hemolysis affects women more frequently than men.^4,5

Therapeutic Options

First Line

Steroids. The goal of therapy in warm AIHA can be hard to define. However, most would agree that a hematocrit above 30% (or higher to prevent symptoms) with a minimal increase in the reticulocyte count—reflective of a significantly slowed hemolytic process—is a reasonable goal. Initial management of warm AIHA is prednisone at a standard dose of 1 mg/kg daily (Table 1).^6,7 Patients should be also started on proton-pump inhibitors to prevent ulcers. It can take up to 3 weeks for patients to respond to prednisone therapy. Once the patient’s hematocrit is above 30%, the prednisone is slowly tapered. Although approximately 80% of patients will respond to steroids, only 30% can be fully tapered off steroids. For patients who can be maintained on a daily steroid dose of 10 mg or less, steroids may be the most reasonable long-term therapy. In addition, because active hemolysis leads to an increased demand for folic acid, patients with warm AIHA are often prescribed folic acid 1 mg daily to prevent megaloblastic anemia due to folic acid deficiency.

Rituximab. Increasingly, rituximab (anti-CD20) therapy is added to the initial steroids. Two clinical trials showed both increased long-term and short-term responses with the use of rituximab.^8,9 An important consideration is that most patients respond gradually to rituximab over weeks, so a rapid response should not be expected. Most studies have used the traditional dosing of 375 mg/m² weekly for 4 weeks. These responses appear to be durable, but as in immune thrombocytopenia (ITP), repeat treatment with rituximab is effective.

The major side effects of rituximab are infusion reactions, which are often worse with the first dose. These reactions can be controlled with antihistamines, steroids, and, for severe rigors, meperidine. Rarely, patients can develop neutropenia (approximately 1:500) that appears to be autoimmune in nature. Infections appear to be only minimally increased with the use of rituximab.¹⁰ One group at risk is chronic carriers of hepatitis B virus, who may experience a reactivation of the virus that can be fatal. Thus, patients being considered for rituximab need to be screened for hepatitis B virus carrier state.¹¹ Patients receiving rituximab are at very slight risk for progressive multifocal leukoencephalopathy, which is more common in patients with cancer and in heavily immunosuppressed patients. The overall risk is unknown but is less than 1:50,000.

Second Line

Splenectomy. For patients who cannot be weaned from steroids or in whom steroid therapy fails, there is no standard therapy. Currently, the 2 main choices are splenectomy or rituximab (anti-CD20) therapy if the patient did not receive it first line. Splenectomy is the classic therapy for warm AIHA. Reported response rates in the literature range from 50% to 80%, with 50% to 60% remaining in remission.^12-16 Timing of the procedure is a balance between allowing time for the steroids to work and the risk of toxicity of steroids. In a patient who has low presurgical risk and has either refractory disease or cannot be weaned from high doses of steroids, splenectomy should be done sooner. Splenectomy can be delayed or other therapy tried first in patients who require lower doses of steroids or have medical risk factors for surgery. Most splenectomies are performed via laparoscopy. The small incisions allow for quicker healing, and the laparoscopic approach provides better visualization of the abdomen to find and remove accessory spleens. When splenectomy is performed by experienced surgeons, the mortality rate is low (< 0.5%).¹⁷

The most concerning complication of splenectomy is overwhelming post-splenectomy infection (OPSI).¹⁸ In adults, the spleen appears to play a minimal role in immunity except for protecting against certain encap-sulated organisms. Splenectomized patients infected with an encapsulated organism (eg, Pneumococcus) will develop overwhelming sepsis within hours. These patients will often have disseminated intravascular coagulation and will rapidly progress to purpura fulminans. Approximately 40% to 50% of patients will die of sepsis even when the infection is detected early. The overall lifetime risk of sepsis may be as high as 1:500. The organism that most commonly causes sepsis in splenectomized patients is Streptococcus pneumoniae, reported in over 50% of cases. Neisseria meningitidis and Haemophilus influenzae have also been implicated in many cases.¹⁹ Overwhelming sepsis after dog bites has been reported due to Capnocytophaga canimorsus infections. Patients are also at increased risk of developing severe malaria and severe babesiosis.¹⁸

Patients who have undergone splenectomy need to be warned about the risk of OPSI and instructed to report to the emergency department readily if they develop a fever greater than 101°F (38.3°C) or shaking chills. Once in the emergency department, blood cultures should be obtained rapidly and the patient started on antibiotic coverage with vancomycin and ceftriaxone (or levofloxacin if allergic to beta-lactams).²⁰ For patients in remote areas, some physicians will prescribe prophylactic antibiotics to take while they are traveling to a health care provider or even recommend a “standby” antibiotic dose to take while traveling to health care.⁵ This usually consists of amoxicillin or a macrolide for penicillin-allergic patients.

Patients in whom splenectomy is being planned or considered should be vaccinated for pneumococcal, meningococcal, and influenza infections (Table 2).¹⁸ If there is a plan to treat with rituximab, patients should first be vaccinated since they will not be able to mount an immune response after being treated with rituximab.

Third Line

The therapeutic options for patients who do not respond to either splenectomy or rituximab are much less certain.^5,6 Although intravenous immune globulin is a standard therapy for ITP, response rates are low in warm AIHA.¹⁷ Numerous therapies have been reported in small series, but no clear approach has emerged. Options include azathioprine, cyclophosphamide, mycophenolate, cyclosporine, danazol, and alemtuzumab. Our approach has been to use mycophenolate for patients requiring high doses of steroids or transfusions. Patients who respond to lower doses of steroids may be good candidates for danazol to help wean them off steroids.

Warm AIHA can complicate several diseases. Patients with systemic lupus erythematosus (SLE) can develop warm AIHA as part of their disease complex. The initial treatment approach is the same, but data suggest that splenectomy may not be as effective.^13,17 Also, many SLE patients have complex medical conditions, making surgeries riskier. For SLE patients who are refractory or cannot be weaned from steroids, rituximab may be the better choice. Babesiosis, particularly in asplenic patients, has been associated with the development of AIHA.^21,22

Of the malignances associated with AIHA, chronic lymphocytic leukemia (CLL) has the strongest association.^4,23 Series show that 5% to 10% of patients with CLL will have warm AIHA. AIHA can appear concurrent with CLL or develop during the course of the disease. The introduction of purine analogs such as fludarabine led to a dramatic increase in the incidence of warm AIHA in treated patients.²⁴ It is speculated that these powerful agents reduce the number and effectiveness of T cells that hold in check the autoantibody response, leading to warm AIHA.²⁵ However, when these purine analogs are used in com-bination with agents such as cyclophosphamide or rituximab (with their immunosuppressive effects), the rates of warm AIHA have been lower.²³

The approach to patients with CLL and warm AIHA depends on the state of their CLL.²³ For patients who have low-stage CLL that does not need treatment, the standard approach to warm AIHA should be steroids, splenectomy, and rituximab.²⁴ For patients with higher-stage CLL, the treatment for the leukemia will often provide therapy for the warm AIHA. The combination of rituximab-cyclophosphamide-dexamethasone has been reported to be effective for both the AIHA and CLL components.²⁶ The use of ibrutinib has also been reported to be effective.²⁷

A rare but important variant of warm AIHA is Evans syndrome.^28,29 This is the combination of AIHA and ITP. Approximately 1% to 3% of AIHA cases are the Evans variant. The ITP can precede, be concurrent with, or develop after the AIHA. The diagnosis of Evans syndrome should raise concern for underlying disorders. In young adults, immunodeficiency disorders such as autoimmune lymphoproliferative disease (ALPS) need to be considered. In older patients, Evans syndrome is often associated with T cell lymphomas. The sparse literature on Evans syndrome suggests that it can be more refractory to standard therapy, with response rates to splenectomy in the 50% range.^28,30 In patients with lymphoma, antineoplastic therapy is crucial. There is increasing data showing that mycophenolate or sirolimus may be effective for patients with ALPS in whom splenectomy or rituximab therapy is unsuccessful.³¹

Warm AIHA with IgA or IgM Antibodies

In rare patients with warm AIHA, IgA or IgM is the implicated antibody. The literature suggests that patients with IgA AIHA may have more severe hemolysis.³² Patients with IgM AIHA often have a severe course with a fatal outcome.³³ In such cases, the patient’s plasma may show spontaneous hemolysis and agglutination. The DAT may not be strongly positive or may show C3 reactivity only. The clinical clues are C3 reactivity with no cold agglutinins and severe hemolysis, sometimes with an intravascular component. Treatment is the same as for warm AIHA, including the use of rituximab.³⁴

In cold AIHA, the hemolysis is mediated by IgM antibodies directed against red cells.³⁵ As discussed earlier, the term “cold” refers to the fact that the antibody binds maximally at temperatures below 37°C. The most efficient temperature for binding is called the “thermal amplitude,” and, in theory, the higher the thermal amplitude, the more virulent the antibody. An antibody titer can be calculated at each reaction temperature from 4°C to 37°C by serial dilutions of the patient’s serum prior to incubating with reagent red cells. Rarely, the IgM can fix complement rapidly, leading to intravascular hemolysis. In most patients, complement is fixed through C3, and the C3-coated red cells are taken up by macrophages in the mononuclear phagocyte system, primarily in the liver.³

The DAT in patients with cold AIHA will show cells coated with C3. The blood smear will often show ag-glutination of the blood, and if the blood cools before being analyzed, the agglutination will interfere with the analysis. Titers of cold agglutinin can range from 1:1000 to over 1 million. The IgM autoantibodies are most often directed against the I/i antigens on the red blood cell membrane, with 90% against I antigen.³⁵ The I antigen specificity is typical with primary cold agglutinin disease and after Mycoplasma infection. The i antigen specificity is most typical of Epstein-Barr virus and cytomegalovirus infections in children. In young patients, cold AIHA often occurs following an infection, including viral and Mycoplasma infections, and the course is self-limited.^35,36 The hemolysis usually starts 2 to 3 weeks after the illness and will last for 4 to 6 weeks. In older patients, the etiology in over 90% of cases is a B-cell lymphoproliferative disorder, usually with monoclonal kappa B-cells.³⁷ The most common disorders are marginal zone lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma.³

Therapeutic Options

It is important to diagnose cold AIHA because the standard therapy for warm AIHA (steroids) is ineffective in cold AIHA. Because C3-coated red cells are taken up primarily in the liver, removing the spleen is also an ineffective therapy. Simple measures to help with cold AIHA should be employed.³⁷ Patients should be kept in a warm environment and should try to avoid the cold. If transfusions are needed, they should be infused via blood warmers to prevent hemolysis. In rare patients with severe hemolysis, therapeutic plasma exchange (TPE) can be considered.³⁸ Given that the culprit antibody is IgM—mostly intravascular—use of TPE may slow the hemolysis to give time for other therapies to take effect.

Treatment of cold AIHA remains difficult (Table 3). Because most patients with primary AIHA have underlying lymphoproliferative diseases, chlorambucil has been used in the past to treat cold AIHA. However, responses were rare and the drug could worsen the anemia.³⁸ Currently, the drug of choice is rituximab. Response is seen in 45% to 75% of patients, but is almost always a partial response and retreatment is often necessary.^17,37,39 As with other autoimmune hematologic diseases, there can be a delay in response that ranges from 2 weeks to 4 months (median time, 1.5 months).³⁷ Given the lack of robust response (complete and durable) with rituximab, the Berentsen group has explored adding bendamustine to rituximab.⁴⁰ In a prospective trial, 71% of patients responded with a 40% complete response rate. Therapy was well tolerated, with only 29% of patients needing dose reduction Although more toxic, this combination can be considered in patients with aggressive disease. A small study of the use of bortezomib showed a good response in one-third of patients.⁴¹ There is increasing use of the C5 complement inhibitor eculizumab to halt the hemolysis, but further study of this agent is also required.^36,42,43 Blockers of C1s complement, which block hemolysis by preventing complement activation, are currently being studied in clinical trials.⁴⁴

Since most patients with cold AIHA are older, a frequent issue that must be considered is cardiac surgery. The concern is that the hypothermia involved with most heart bypass procedures will lead to agglutination and hemolysis. The development of normothermic bypass has expanded treatment options. A recommended approach in patients who have known cold agglutinins is to measure the thermal amplitude of the antibody preoperatively. If the thermal amplitude is above 18°C, normothermic bypass should be done, if feasible.⁴⁵ If not feasible, preoperative TPE should be considered.

Paroxysmal Cold Hemoglobinuria

A unique cold AIHA is paroxysmal cold hemoglobinuria (PCH).^3,46 This cold hemolytic syndrome most often occurs in children following a viral infection, but in the past it complicated any stage of syphilis.⁴⁷ The mediating antibody in PCH is an IgG antibody directed against the P antigen on the red blood cell. This antibody binds best at temperatures below 37°C, fixing complement at cold temperatures, but then activates the complement cascade at body temperature.⁴⁸ Because this antibody can fix complement, hemolysis can be rapid and severe, leading to extreme anemia. The DAT is often weakly positive but can be negative. The diagnostic test for PCH is the Donath–Landsteiner test. This complex test is performed by incubating 3 blood samples, 1 at 0° to 4°C, another at 37°C, and a third at 0° to 4°C and then at 37°C. The diagnosis of PCH is made if only the third tube shows hemolysis.³⁵ PCH can persist for 1 to 3 months but is almost always self-limiting. In severe case, steroids may be of benefit.

Drug-Induced Hemolytic Anemia

AIHA caused by a drug reaction is rare, with a lower incidence than drug-related ITP. The rate of severe drug-related AIHA is estimated at 1:1,000,000, but less severe cases may be missed.¹ Most patients will have a positive DAT without signs of hemolysis, but in rare cases patients will have relentless hemolysis resulting in death.

Mechanisms

Multiple mechanisms for drug-induced immune hemolysis have been proposed, including drug-absorption (hapten-induced) and immune complex mechanisms.^1,49 The hapten mechanism is most often associated with the use of high-dose penicillin.⁵⁰ High doses of penicillin or similar drugs such as piperacillin lead to incorporation of the drug into the red cell membrane by binding to proteins. Patients will manifest a positive DAT with IgG antibody but not complement.⁵¹ The patient’s plasma will be reactive only with penicillin-coated red cells and not with normal cells. As mentioned, very few patients will have hemolysis, and if they have hemolysis, it will resolve in a few days after discontinuation of the offending drug.⁵²

Binding of a drug-antibody complex to the red cell membrane may cause hemolysis via the immune com-plex mechanism.⁵³ Again, most often the patient will have just a positive DAT, but rarely patients will have life-threatening hemolysis upon exposure or reexposure to the drug. The onset of hemolysis is rapid, with signs of acute illness and intravascular hemolysis. The paradigm drug is quinine, but many other drugs have been implicated. Testing shows a positive Coombs test with anti-complement but not anti-IgG.⁵⁰ This pattern is due to the effectiveness of the tertiary complex at fixing complement. The patient’s plasma reacts with red cells only when the drug is added.

A form of immune complex hemolysis associated with both disseminated intravascular coagulation (DIC) and brisk hemolysis has been recognized. Patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone.^53,54) have developed this syndrome.^50,55-59 The clinical symptoms start 7 to 10 days after the drug is administered; often the patient has only received the antibiotic for surgical prophylaxis. Immune hemolysis with acute hematocrit drop, hypotension, and DIC ensues. The patients are often believed to have sepsis and are often reexposed to the cephalosporin, resulting in worsening of the clinical status. The outcome is often fatal due to massive hemolysis and thrombosis.^56,60,62

Finally, 8% to 36% of patients taking methyldopa will develop a positive DAT after 6 months of therapy, with less than 1% showing hemolysis.^52,63 The hemolysis in these patients is indistinguishable from warm AIHA, consistent with the notion that methyldopa induces an AIHA. The hemolysis often resolves rapidly after the methyldopa is stopped, but the Coombs test may remain positive for months.⁶³ This type of drug-induced hemolytic anemia has been reported with levodopa, procainamide, and chlorpromazine, but fludarabine is the most common cause currently. This form of AIHA is now being seen with increased use of checkpoint inhibitors.⁶⁴

Diagnosis

In many patients, the first clue to the presence of drug AIHA is the finding of a positive DAT. Rarely, patients will have severe hemolysis, but in many patients the hemolytic process is mild and may be wrongly assumed to be part of the underlying illness. Finding the offending drug can be a challenge, unless a patient has recently started a new drug; in a hospitalized patient on multiple agents, identifying the problem drug is difficult. Patients recently started on “suspect drugs,” especially the most common agents cefotetan, ceftriaxone, and piperacillin, should have these agents stopped (Table 4).^1,49,65 Specialty laboratories such as the Blood Center of Wisconsin or the Los Angeles Red Cross can perform in vitro studies of drug interactions that can confirm the clinical diagnosis of drug-induced AIHA.

Treatment

Therapy for patients with positive DAT without signs of hemolysis is uncertain. If the drug is essential, then the patient can be observed. If the patient has hemolysis, the drug needs to be stopped and the patient observed for signs of end-organ damage. It is doubtful that steroids or other autoimmune-directed therapy is effective. For patients with the DIC-hemolysis syndrome, there are anecdotal reports that TPE may be helpful.¹

Summary

AIHA can range from an abnormal laboratory test (positive DAT and signs of hemolysis) to an acute, life-threatening illness. Treatment is guided by the laboratory work-up and evaluation of the patient’s clinical status. While rituximab is promising for many patients, the lack of robust clinical trials hinders the treatment of patients who fail standard therapies.

Autoimmune hemolytic anemia (AIHA) is mediated by antibodies, and in most cases immunoglobulin (Ig) G is the mediating antibody. This type of AIHA is referred to as "warm" AIHA because IgG antibodies bind best at body temperature. "Cold" AIHA is mediated by IgM antibodies, which bind maximally at temperatures below 37°C. AIHA caused by a drug reaction is rare, with an estimated annual incidence of 1:1,000,000 for severe drug-related AIHA.¹ This article reviews the management of the more common types of AIHA, with a focus on warm, cold, and drug-induced AIHA; the evaluation and diagnosis of AIHA is reviewed in a separate article.

Warm Autoimmune Hemolytic Anemia

In AIHA, hemolysis is mediated by antibodies that bind to the surface of red blood cells. AIHA in which IgG antibodies are the offending antibodies is referred to as warm AIHA. “Warm” refers to the fact that the antibody binds best at body temperature (37°C). In warm AIHA, testing will show IgG molecules attached to the surface of the red cells, with 50% of patients also showing C3. Between 50% and 90% of AIHA cases are due to warm antibodies.^2,3 The incidence of warm AIHA varies by series but is approximately 1 case per 100,000 patients per year; this form of hemolysis affects women more frequently than men.^4,5

Therapeutic Options

First Line

Steroids. The goal of therapy in warm AIHA can be hard to define. However, most would agree that a hematocrit above 30% (or higher to prevent symptoms) with a minimal increase in the reticulocyte count—reflective of a significantly slowed hemolytic process—is a reasonable goal. Initial management of warm AIHA is prednisone at a standard dose of 1 mg/kg daily (Table 1).^6,7 Patients should be also started on proton-pump inhibitors to prevent ulcers. It can take up to 3 weeks for patients to respond to prednisone therapy. Once the patient’s hematocrit is above 30%, the prednisone is slowly tapered. Although approximately 80% of patients will respond to steroids, only 30% can be fully tapered off steroids. For patients who can be maintained on a daily steroid dose of 10 mg or less, steroids may be the most reasonable long-term therapy. In addition, because active hemolysis leads to an increased demand for folic acid, patients with warm AIHA are often prescribed folic acid 1 mg daily to prevent megaloblastic anemia due to folic acid deficiency.

Rituximab. Increasingly, rituximab (anti-CD20) therapy is added to the initial steroids. Two clinical trials showed both increased long-term and short-term responses with the use of rituximab.^8,9 An important consideration is that most patients respond gradually to rituximab over weeks, so a rapid response should not be expected. Most studies have used the traditional dosing of 375 mg/m² weekly for 4 weeks. These responses appear to be durable, but as in immune thrombocytopenia (ITP), repeat treatment with rituximab is effective.

The major side effects of rituximab are infusion reactions, which are often worse with the first dose. These reactions can be controlled with antihistamines, steroids, and, for severe rigors, meperidine. Rarely, patients can develop neutropenia (approximately 1:500) that appears to be autoimmune in nature. Infections appear to be only minimally increased with the use of rituximab.¹⁰ One group at risk is chronic carriers of hepatitis B virus, who may experience a reactivation of the virus that can be fatal. Thus, patients being considered for rituximab need to be screened for hepatitis B virus carrier state.¹¹ Patients receiving rituximab are at very slight risk for progressive multifocal leukoencephalopathy, which is more common in patients with cancer and in heavily immunosuppressed patients. The overall risk is unknown but is less than 1:50,000.

Second Line

Splenectomy. For patients who cannot be weaned from steroids or in whom steroid therapy fails, there is no standard therapy. Currently, the 2 main choices are splenectomy or rituximab (anti-CD20) therapy if the patient did not receive it first line. Splenectomy is the classic therapy for warm AIHA. Reported response rates in the literature range from 50% to 80%, with 50% to 60% remaining in remission.^12-16 Timing of the procedure is a balance between allowing time for the steroids to work and the risk of toxicity of steroids. In a patient who has low presurgical risk and has either refractory disease or cannot be weaned from high doses of steroids, splenectomy should be done sooner. Splenectomy can be delayed or other therapy tried first in patients who require lower doses of steroids or have medical risk factors for surgery. Most splenectomies are performed via laparoscopy. The small incisions allow for quicker healing, and the laparoscopic approach provides better visualization of the abdomen to find and remove accessory spleens. When splenectomy is performed by experienced surgeons, the mortality rate is low (< 0.5%).¹⁷

The most concerning complication of splenectomy is overwhelming post-splenectomy infection (OPSI).¹⁸ In adults, the spleen appears to play a minimal role in immunity except for protecting against certain encap-sulated organisms. Splenectomized patients infected with an encapsulated organism (eg, Pneumococcus) will develop overwhelming sepsis within hours. These patients will often have disseminated intravascular coagulation and will rapidly progress to purpura fulminans. Approximately 40% to 50% of patients will die of sepsis even when the infection is detected early. The overall lifetime risk of sepsis may be as high as 1:500. The organism that most commonly causes sepsis in splenectomized patients is Streptococcus pneumoniae, reported in over 50% of cases. Neisseria meningitidis and Haemophilus influenzae have also been implicated in many cases.¹⁹ Overwhelming sepsis after dog bites has been reported due to Capnocytophaga canimorsus infections. Patients are also at increased risk of developing severe malaria and severe babesiosis.¹⁸

Patients who have undergone splenectomy need to be warned about the risk of OPSI and instructed to report to the emergency department readily if they develop a fever greater than 101°F (38.3°C) or shaking chills. Once in the emergency department, blood cultures should be obtained rapidly and the patient started on antibiotic coverage with vancomycin and ceftriaxone (or levofloxacin if allergic to beta-lactams).²⁰ For patients in remote areas, some physicians will prescribe prophylactic antibiotics to take while they are traveling to a health care provider or even recommend a “standby” antibiotic dose to take while traveling to health care.⁵ This usually consists of amoxicillin or a macrolide for penicillin-allergic patients.

Patients in whom splenectomy is being planned or considered should be vaccinated for pneumococcal, meningococcal, and influenza infections (Table 2).¹⁸ If there is a plan to treat with rituximab, patients should first be vaccinated since they will not be able to mount an immune response after being treated with rituximab.

Third Line

The therapeutic options for patients who do not respond to either splenectomy or rituximab are much less certain.^5,6 Although intravenous immune globulin is a standard therapy for ITP, response rates are low in warm AIHA.¹⁷ Numerous therapies have been reported in small series, but no clear approach has emerged. Options include azathioprine, cyclophosphamide, mycophenolate, cyclosporine, danazol, and alemtuzumab. Our approach has been to use mycophenolate for patients requiring high doses of steroids or transfusions. Patients who respond to lower doses of steroids may be good candidates for danazol to help wean them off steroids.

Warm AIHA can complicate several diseases. Patients with systemic lupus erythematosus (SLE) can develop warm AIHA as part of their disease complex. The initial treatment approach is the same, but data suggest that splenectomy may not be as effective.^13,17 Also, many SLE patients have complex medical conditions, making surgeries riskier. For SLE patients who are refractory or cannot be weaned from steroids, rituximab may be the better choice. Babesiosis, particularly in asplenic patients, has been associated with the development of AIHA.^21,22

Of the malignances associated with AIHA, chronic lymphocytic leukemia (CLL) has the strongest association.^4,23 Series show that 5% to 10% of patients with CLL will have warm AIHA. AIHA can appear concurrent with CLL or develop during the course of the disease. The introduction of purine analogs such as fludarabine led to a dramatic increase in the incidence of warm AIHA in treated patients.²⁴ It is speculated that these powerful agents reduce the number and effectiveness of T cells that hold in check the autoantibody response, leading to warm AIHA.²⁵ However, when these purine analogs are used in com-bination with agents such as cyclophosphamide or rituximab (with their immunosuppressive effects), the rates of warm AIHA have been lower.²³

The approach to patients with CLL and warm AIHA depends on the state of their CLL.²³ For patients who have low-stage CLL that does not need treatment, the standard approach to warm AIHA should be steroids, splenectomy, and rituximab.²⁴ For patients with higher-stage CLL, the treatment for the leukemia will often provide therapy for the warm AIHA. The combination of rituximab-cyclophosphamide-dexamethasone has been reported to be effective for both the AIHA and CLL components.²⁶ The use of ibrutinib has also been reported to be effective.²⁷

A rare but important variant of warm AIHA is Evans syndrome.^28,29 This is the combination of AIHA and ITP. Approximately 1% to 3% of AIHA cases are the Evans variant. The ITP can precede, be concurrent with, or develop after the AIHA. The diagnosis of Evans syndrome should raise concern for underlying disorders. In young adults, immunodeficiency disorders such as autoimmune lymphoproliferative disease (ALPS) need to be considered. In older patients, Evans syndrome is often associated with T cell lymphomas. The sparse literature on Evans syndrome suggests that it can be more refractory to standard therapy, with response rates to splenectomy in the 50% range.^28,30 In patients with lymphoma, antineoplastic therapy is crucial. There is increasing data showing that mycophenolate or sirolimus may be effective for patients with ALPS in whom splenectomy or rituximab therapy is unsuccessful.³¹

Warm AIHA with IgA or IgM Antibodies

In rare patients with warm AIHA, IgA or IgM is the implicated antibody. The literature suggests that patients with IgA AIHA may have more severe hemolysis.³² Patients with IgM AIHA often have a severe course with a fatal outcome.³³ In such cases, the patient’s plasma may show spontaneous hemolysis and agglutination. The DAT may not be strongly positive or may show C3 reactivity only. The clinical clues are C3 reactivity with no cold agglutinins and severe hemolysis, sometimes with an intravascular component. Treatment is the same as for warm AIHA, including the use of rituximab.³⁴

In cold AIHA, the hemolysis is mediated by IgM antibodies directed against red cells.³⁵ As discussed earlier, the term “cold” refers to the fact that the antibody binds maximally at temperatures below 37°C. The most efficient temperature for binding is called the “thermal amplitude,” and, in theory, the higher the thermal amplitude, the more virulent the antibody. An antibody titer can be calculated at each reaction temperature from 4°C to 37°C by serial dilutions of the patient’s serum prior to incubating with reagent red cells. Rarely, the IgM can fix complement rapidly, leading to intravascular hemolysis. In most patients, complement is fixed through C3, and the C3-coated red cells are taken up by macrophages in the mononuclear phagocyte system, primarily in the liver.³

The DAT in patients with cold AIHA will show cells coated with C3. The blood smear will often show ag-glutination of the blood, and if the blood cools before being analyzed, the agglutination will interfere with the analysis. Titers of cold agglutinin can range from 1:1000 to over 1 million. The IgM autoantibodies are most often directed against the I/i antigens on the red blood cell membrane, with 90% against I antigen.³⁵ The I antigen specificity is typical with primary cold agglutinin disease and after Mycoplasma infection. The i antigen specificity is most typical of Epstein-Barr virus and cytomegalovirus infections in children. In young patients, cold AIHA often occurs following an infection, including viral and Mycoplasma infections, and the course is self-limited.^35,36 The hemolysis usually starts 2 to 3 weeks after the illness and will last for 4 to 6 weeks. In older patients, the etiology in over 90% of cases is a B-cell lymphoproliferative disorder, usually with monoclonal kappa B-cells.³⁷ The most common disorders are marginal zone lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma.³

Therapeutic Options

It is important to diagnose cold AIHA because the standard therapy for warm AIHA (steroids) is ineffective in cold AIHA. Because C3-coated red cells are taken up primarily in the liver, removing the spleen is also an ineffective therapy. Simple measures to help with cold AIHA should be employed.³⁷ Patients should be kept in a warm environment and should try to avoid the cold. If transfusions are needed, they should be infused via blood warmers to prevent hemolysis. In rare patients with severe hemolysis, therapeutic plasma exchange (TPE) can be considered.³⁸ Given that the culprit antibody is IgM—mostly intravascular—use of TPE may slow the hemolysis to give time for other therapies to take effect.

Treatment of cold AIHA remains difficult (Table 3). Because most patients with primary AIHA have underlying lymphoproliferative diseases, chlorambucil has been used in the past to treat cold AIHA. However, responses were rare and the drug could worsen the anemia.³⁸ Currently, the drug of choice is rituximab. Response is seen in 45% to 75% of patients, but is almost always a partial response and retreatment is often necessary.^17,37,39 As with other autoimmune hematologic diseases, there can be a delay in response that ranges from 2 weeks to 4 months (median time, 1.5 months).³⁷ Given the lack of robust response (complete and durable) with rituximab, the Berentsen group has explored adding bendamustine to rituximab.⁴⁰ In a prospective trial, 71% of patients responded with a 40% complete response rate. Therapy was well tolerated, with only 29% of patients needing dose reduction Although more toxic, this combination can be considered in patients with aggressive disease. A small study of the use of bortezomib showed a good response in one-third of patients.⁴¹ There is increasing use of the C5 complement inhibitor eculizumab to halt the hemolysis, but further study of this agent is also required.^36,42,43 Blockers of C1s complement, which block hemolysis by preventing complement activation, are currently being studied in clinical trials.⁴⁴

Since most patients with cold AIHA are older, a frequent issue that must be considered is cardiac surgery. The concern is that the hypothermia involved with most heart bypass procedures will lead to agglutination and hemolysis. The development of normothermic bypass has expanded treatment options. A recommended approach in patients who have known cold agglutinins is to measure the thermal amplitude of the antibody preoperatively. If the thermal amplitude is above 18°C, normothermic bypass should be done, if feasible.⁴⁵ If not feasible, preoperative TPE should be considered.

Paroxysmal Cold Hemoglobinuria

A unique cold AIHA is paroxysmal cold hemoglobinuria (PCH).^3,46 This cold hemolytic syndrome most often occurs in children following a viral infection, but in the past it complicated any stage of syphilis.⁴⁷ The mediating antibody in PCH is an IgG antibody directed against the P antigen on the red blood cell. This antibody binds best at temperatures below 37°C, fixing complement at cold temperatures, but then activates the complement cascade at body temperature.⁴⁸ Because this antibody can fix complement, hemolysis can be rapid and severe, leading to extreme anemia. The DAT is often weakly positive but can be negative. The diagnostic test for PCH is the Donath–Landsteiner test. This complex test is performed by incubating 3 blood samples, 1 at 0° to 4°C, another at 37°C, and a third at 0° to 4°C and then at 37°C. The diagnosis of PCH is made if only the third tube shows hemolysis.³⁵ PCH can persist for 1 to 3 months but is almost always self-limiting. In severe case, steroids may be of benefit.

Drug-Induced Hemolytic Anemia

AIHA caused by a drug reaction is rare, with a lower incidence than drug-related ITP. The rate of severe drug-related AIHA is estimated at 1:1,000,000, but less severe cases may be missed.¹ Most patients will have a positive DAT without signs of hemolysis, but in rare cases patients will have relentless hemolysis resulting in death.

Mechanisms

Multiple mechanisms for drug-induced immune hemolysis have been proposed, including drug-absorption (hapten-induced) and immune complex mechanisms.^1,49 The hapten mechanism is most often associated with the use of high-dose penicillin.⁵⁰ High doses of penicillin or similar drugs such as piperacillin lead to incorporation of the drug into the red cell membrane by binding to proteins. Patients will manifest a positive DAT with IgG antibody but not complement.⁵¹ The patient’s plasma will be reactive only with penicillin-coated red cells and not with normal cells. As mentioned, very few patients will have hemolysis, and if they have hemolysis, it will resolve in a few days after discontinuation of the offending drug.⁵²

Binding of a drug-antibody complex to the red cell membrane may cause hemolysis via the immune com-plex mechanism.⁵³ Again, most often the patient will have just a positive DAT, but rarely patients will have life-threatening hemolysis upon exposure or reexposure to the drug. The onset of hemolysis is rapid, with signs of acute illness and intravascular hemolysis. The paradigm drug is quinine, but many other drugs have been implicated. Testing shows a positive Coombs test with anti-complement but not anti-IgG.⁵⁰ This pattern is due to the effectiveness of the tertiary complex at fixing complement. The patient’s plasma reacts with red cells only when the drug is added.

A form of immune complex hemolysis associated with both disseminated intravascular coagulation (DIC) and brisk hemolysis has been recognized. Patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone.^53,54) have developed this syndrome.^50,55-59 The clinical symptoms start 7 to 10 days after the drug is administered; often the patient has only received the antibiotic for surgical prophylaxis. Immune hemolysis with acute hematocrit drop, hypotension, and DIC ensues. The patients are often believed to have sepsis and are often reexposed to the cephalosporin, resulting in worsening of the clinical status. The outcome is often fatal due to massive hemolysis and thrombosis.^56,60,62

Finally, 8% to 36% of patients taking methyldopa will develop a positive DAT after 6 months of therapy, with less than 1% showing hemolysis.^52,63 The hemolysis in these patients is indistinguishable from warm AIHA, consistent with the notion that methyldopa induces an AIHA. The hemolysis often resolves rapidly after the methyldopa is stopped, but the Coombs test may remain positive for months.⁶³ This type of drug-induced hemolytic anemia has been reported with levodopa, procainamide, and chlorpromazine, but fludarabine is the most common cause currently. This form of AIHA is now being seen with increased use of checkpoint inhibitors.⁶⁴

Diagnosis

In many patients, the first clue to the presence of drug AIHA is the finding of a positive DAT. Rarely, patients will have severe hemolysis, but in many patients the hemolytic process is mild and may be wrongly assumed to be part of the underlying illness. Finding the offending drug can be a challenge, unless a patient has recently started a new drug; in a hospitalized patient on multiple agents, identifying the problem drug is difficult. Patients recently started on “suspect drugs,” especially the most common agents cefotetan, ceftriaxone, and piperacillin, should have these agents stopped (Table 4).^1,49,65 Specialty laboratories such as the Blood Center of Wisconsin or the Los Angeles Red Cross can perform in vitro studies of drug interactions that can confirm the clinical diagnosis of drug-induced AIHA.

Treatment

Therapy for patients with positive DAT without signs of hemolysis is uncertain. If the drug is essential, then the patient can be observed. If the patient has hemolysis, the drug needs to be stopped and the patient observed for signs of end-organ damage. It is doubtful that steroids or other autoimmune-directed therapy is effective. For patients with the DIC-hemolysis syndrome, there are anecdotal reports that TPE may be helpful.¹

Summary

AIHA can range from an abnormal laboratory test (positive DAT and signs of hemolysis) to an acute, life-threatening illness. Treatment is guided by the laboratory work-up and evaluation of the patient’s clinical status. While rituximab is promising for many patients, the lack of robust clinical trials hinders the treatment of patients who fail standard therapies.

Autoimmune hemolytic anemia (AIHA) is mediated by antibodies, and in most cases immunoglobulin (Ig) G is the mediating antibody. This type of AIHA is referred to as "warm" AIHA because IgG antibodies bind best at body temperature. "Cold" AIHA is mediated by IgM antibodies, which bind maximally at temperatures below 37°C. AIHA caused by a drug reaction is rare, with an estimated annual incidence of 1:1,000,000 for severe drug-related AIHA.¹ This article reviews the management of the more common types of AIHA, with a focus on warm, cold, and drug-induced AIHA; the evaluation and diagnosis of AIHA is reviewed in a separate article.

Warm Autoimmune Hemolytic Anemia

In AIHA, hemolysis is mediated by antibodies that bind to the surface of red blood cells. AIHA in which IgG antibodies are the offending antibodies is referred to as warm AIHA. “Warm” refers to the fact that the antibody binds best at body temperature (37°C). In warm AIHA, testing will show IgG molecules attached to the surface of the red cells, with 50% of patients also showing C3. Between 50% and 90% of AIHA cases are due to warm antibodies.^2,3 The incidence of warm AIHA varies by series but is approximately 1 case per 100,000 patients per year; this form of hemolysis affects women more frequently than men.^4,5

Therapeutic Options

First Line

Steroids. The goal of therapy in warm AIHA can be hard to define. However, most would agree that a hematocrit above 30% (or higher to prevent symptoms) with a minimal increase in the reticulocyte count—reflective of a significantly slowed hemolytic process—is a reasonable goal. Initial management of warm AIHA is prednisone at a standard dose of 1 mg/kg daily (Table 1).^6,7 Patients should be also started on proton-pump inhibitors to prevent ulcers. It can take up to 3 weeks for patients to respond to prednisone therapy. Once the patient’s hematocrit is above 30%, the prednisone is slowly tapered. Although approximately 80% of patients will respond to steroids, only 30% can be fully tapered off steroids. For patients who can be maintained on a daily steroid dose of 10 mg or less, steroids may be the most reasonable long-term therapy. In addition, because active hemolysis leads to an increased demand for folic acid, patients with warm AIHA are often prescribed folic acid 1 mg daily to prevent megaloblastic anemia due to folic acid deficiency.

Rituximab. Increasingly, rituximab (anti-CD20) therapy is added to the initial steroids. Two clinical trials showed both increased long-term and short-term responses with the use of rituximab.^8,9 An important consideration is that most patients respond gradually to rituximab over weeks, so a rapid response should not be expected. Most studies have used the traditional dosing of 375 mg/m² weekly for 4 weeks. These responses appear to be durable, but as in immune thrombocytopenia (ITP), repeat treatment with rituximab is effective.

The major side effects of rituximab are infusion reactions, which are often worse with the first dose. These reactions can be controlled with antihistamines, steroids, and, for severe rigors, meperidine. Rarely, patients can develop neutropenia (approximately 1:500) that appears to be autoimmune in nature. Infections appear to be only minimally increased with the use of rituximab.¹⁰ One group at risk is chronic carriers of hepatitis B virus, who may experience a reactivation of the virus that can be fatal. Thus, patients being considered for rituximab need to be screened for hepatitis B virus carrier state.¹¹ Patients receiving rituximab are at very slight risk for progressive multifocal leukoencephalopathy, which is more common in patients with cancer and in heavily immunosuppressed patients. The overall risk is unknown but is less than 1:50,000.

Second Line

Splenectomy. For patients who cannot be weaned from steroids or in whom steroid therapy fails, there is no standard therapy. Currently, the 2 main choices are splenectomy or rituximab (anti-CD20) therapy if the patient did not receive it first line. Splenectomy is the classic therapy for warm AIHA. Reported response rates in the literature range from 50% to 80%, with 50% to 60% remaining in remission.^12-16 Timing of the procedure is a balance between allowing time for the steroids to work and the risk of toxicity of steroids. In a patient who has low presurgical risk and has either refractory disease or cannot be weaned from high doses of steroids, splenectomy should be done sooner. Splenectomy can be delayed or other therapy tried first in patients who require lower doses of steroids or have medical risk factors for surgery. Most splenectomies are performed via laparoscopy. The small incisions allow for quicker healing, and the laparoscopic approach provides better visualization of the abdomen to find and remove accessory spleens. When splenectomy is performed by experienced surgeons, the mortality rate is low (< 0.5%).¹⁷

The most concerning complication of splenectomy is overwhelming post-splenectomy infection (OPSI).¹⁸ In adults, the spleen appears to play a minimal role in immunity except for protecting against certain encap-sulated organisms. Splenectomized patients infected with an encapsulated organism (eg, Pneumococcus) will develop overwhelming sepsis within hours. These patients will often have disseminated intravascular coagulation and will rapidly progress to purpura fulminans. Approximately 40% to 50% of patients will die of sepsis even when the infection is detected early. The overall lifetime risk of sepsis may be as high as 1:500. The organism that most commonly causes sepsis in splenectomized patients is Streptococcus pneumoniae, reported in over 50% of cases. Neisseria meningitidis and Haemophilus influenzae have also been implicated in many cases.¹⁹ Overwhelming sepsis after dog bites has been reported due to Capnocytophaga canimorsus infections. Patients are also at increased risk of developing severe malaria and severe babesiosis.¹⁸

Patients who have undergone splenectomy need to be warned about the risk of OPSI and instructed to report to the emergency department readily if they develop a fever greater than 101°F (38.3°C) or shaking chills. Once in the emergency department, blood cultures should be obtained rapidly and the patient started on antibiotic coverage with vancomycin and ceftriaxone (or levofloxacin if allergic to beta-lactams).²⁰ For patients in remote areas, some physicians will prescribe prophylactic antibiotics to take while they are traveling to a health care provider or even recommend a “standby” antibiotic dose to take while traveling to health care.⁵ This usually consists of amoxicillin or a macrolide for penicillin-allergic patients.

Patients in whom splenectomy is being planned or considered should be vaccinated for pneumococcal, meningococcal, and influenza infections (Table 2).¹⁸ If there is a plan to treat with rituximab, patients should first be vaccinated since they will not be able to mount an immune response after being treated with rituximab.

Third Line

The therapeutic options for patients who do not respond to either splenectomy or rituximab are much less certain.^5,6 Although intravenous immune globulin is a standard therapy for ITP, response rates are low in warm AIHA.¹⁷ Numerous therapies have been reported in small series, but no clear approach has emerged. Options include azathioprine, cyclophosphamide, mycophenolate, cyclosporine, danazol, and alemtuzumab. Our approach has been to use mycophenolate for patients requiring high doses of steroids or transfusions. Patients who respond to lower doses of steroids may be good candidates for danazol to help wean them off steroids.

Warm AIHA can complicate several diseases. Patients with systemic lupus erythematosus (SLE) can develop warm AIHA as part of their disease complex. The initial treatment approach is the same, but data suggest that splenectomy may not be as effective.^13,17 Also, many SLE patients have complex medical conditions, making surgeries riskier. For SLE patients who are refractory or cannot be weaned from steroids, rituximab may be the better choice. Babesiosis, particularly in asplenic patients, has been associated with the development of AIHA.^21,22

Of the malignances associated with AIHA, chronic lymphocytic leukemia (CLL) has the strongest association.^4,23 Series show that 5% to 10% of patients with CLL will have warm AIHA. AIHA can appear concurrent with CLL or develop during the course of the disease. The introduction of purine analogs such as fludarabine led to a dramatic increase in the incidence of warm AIHA in treated patients.²⁴ It is speculated that these powerful agents reduce the number and effectiveness of T cells that hold in check the autoantibody response, leading to warm AIHA.²⁵ However, when these purine analogs are used in com-bination with agents such as cyclophosphamide or rituximab (with their immunosuppressive effects), the rates of warm AIHA have been lower.²³

The approach to patients with CLL and warm AIHA depends on the state of their CLL.²³ For patients who have low-stage CLL that does not need treatment, the standard approach to warm AIHA should be steroids, splenectomy, and rituximab.²⁴ For patients with higher-stage CLL, the treatment for the leukemia will often provide therapy for the warm AIHA. The combination of rituximab-cyclophosphamide-dexamethasone has been reported to be effective for both the AIHA and CLL components.²⁶ The use of ibrutinib has also been reported to be effective.²⁷

A rare but important variant of warm AIHA is Evans syndrome.^28,29 This is the combination of AIHA and ITP. Approximately 1% to 3% of AIHA cases are the Evans variant. The ITP can precede, be concurrent with, or develop after the AIHA. The diagnosis of Evans syndrome should raise concern for underlying disorders. In young adults, immunodeficiency disorders such as autoimmune lymphoproliferative disease (ALPS) need to be considered. In older patients, Evans syndrome is often associated with T cell lymphomas. The sparse literature on Evans syndrome suggests that it can be more refractory to standard therapy, with response rates to splenectomy in the 50% range.^28,30 In patients with lymphoma, antineoplastic therapy is crucial. There is increasing data showing that mycophenolate or sirolimus may be effective for patients with ALPS in whom splenectomy or rituximab therapy is unsuccessful.³¹

Warm AIHA with IgA or IgM Antibodies

In rare patients with warm AIHA, IgA or IgM is the implicated antibody. The literature suggests that patients with IgA AIHA may have more severe hemolysis.³² Patients with IgM AIHA often have a severe course with a fatal outcome.³³ In such cases, the patient’s plasma may show spontaneous hemolysis and agglutination. The DAT may not be strongly positive or may show C3 reactivity only. The clinical clues are C3 reactivity with no cold agglutinins and severe hemolysis, sometimes with an intravascular component. Treatment is the same as for warm AIHA, including the use of rituximab.³⁴

In cold AIHA, the hemolysis is mediated by IgM antibodies directed against red cells.³⁵ As discussed earlier, the term “cold” refers to the fact that the antibody binds maximally at temperatures below 37°C. The most efficient temperature for binding is called the “thermal amplitude,” and, in theory, the higher the thermal amplitude, the more virulent the antibody. An antibody titer can be calculated at each reaction temperature from 4°C to 37°C by serial dilutions of the patient’s serum prior to incubating with reagent red cells. Rarely, the IgM can fix complement rapidly, leading to intravascular hemolysis. In most patients, complement is fixed through C3, and the C3-coated red cells are taken up by macrophages in the mononuclear phagocyte system, primarily in the liver.³

The DAT in patients with cold AIHA will show cells coated with C3. The blood smear will often show ag-glutination of the blood, and if the blood cools before being analyzed, the agglutination will interfere with the analysis. Titers of cold agglutinin can range from 1:1000 to over 1 million. The IgM autoantibodies are most often directed against the I/i antigens on the red blood cell membrane, with 90% against I antigen.³⁵ The I antigen specificity is typical with primary cold agglutinin disease and after Mycoplasma infection. The i antigen specificity is most typical of Epstein-Barr virus and cytomegalovirus infections in children. In young patients, cold AIHA often occurs following an infection, including viral and Mycoplasma infections, and the course is self-limited.^35,36 The hemolysis usually starts 2 to 3 weeks after the illness and will last for 4 to 6 weeks. In older patients, the etiology in over 90% of cases is a B-cell lymphoproliferative disorder, usually with monoclonal kappa B-cells.³⁷ The most common disorders are marginal zone lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma.³

Therapeutic Options

It is important to diagnose cold AIHA because the standard therapy for warm AIHA (steroids) is ineffective in cold AIHA. Because C3-coated red cells are taken up primarily in the liver, removing the spleen is also an ineffective therapy. Simple measures to help with cold AIHA should be employed.³⁷ Patients should be kept in a warm environment and should try to avoid the cold. If transfusions are needed, they should be infused via blood warmers to prevent hemolysis. In rare patients with severe hemolysis, therapeutic plasma exchange (TPE) can be considered.³⁸ Given that the culprit antibody is IgM—mostly intravascular—use of TPE may slow the hemolysis to give time for other therapies to take effect.

Treatment of cold AIHA remains difficult (Table 3). Because most patients with primary AIHA have underlying lymphoproliferative diseases, chlorambucil has been used in the past to treat cold AIHA. However, responses were rare and the drug could worsen the anemia.³⁸ Currently, the drug of choice is rituximab. Response is seen in 45% to 75% of patients, but is almost always a partial response and retreatment is often necessary.^17,37,39 As with other autoimmune hematologic diseases, there can be a delay in response that ranges from 2 weeks to 4 months (median time, 1.5 months).³⁷ Given the lack of robust response (complete and durable) with rituximab, the Berentsen group has explored adding bendamustine to rituximab.⁴⁰ In a prospective trial, 71% of patients responded with a 40% complete response rate. Therapy was well tolerated, with only 29% of patients needing dose reduction Although more toxic, this combination can be considered in patients with aggressive disease. A small study of the use of bortezomib showed a good response in one-third of patients.⁴¹ There is increasing use of the C5 complement inhibitor eculizumab to halt the hemolysis, but further study of this agent is also required.^36,42,43 Blockers of C1s complement, which block hemolysis by preventing complement activation, are currently being studied in clinical trials.⁴⁴

Since most patients with cold AIHA are older, a frequent issue that must be considered is cardiac surgery. The concern is that the hypothermia involved with most heart bypass procedures will lead to agglutination and hemolysis. The development of normothermic bypass has expanded treatment options. A recommended approach in patients who have known cold agglutinins is to measure the thermal amplitude of the antibody preoperatively. If the thermal amplitude is above 18°C, normothermic bypass should be done, if feasible.⁴⁵ If not feasible, preoperative TPE should be considered.

Paroxysmal Cold Hemoglobinuria

A unique cold AIHA is paroxysmal cold hemoglobinuria (PCH).^3,46 This cold hemolytic syndrome most often occurs in children following a viral infection, but in the past it complicated any stage of syphilis.⁴⁷ The mediating antibody in PCH is an IgG antibody directed against the P antigen on the red blood cell. This antibody binds best at temperatures below 37°C, fixing complement at cold temperatures, but then activates the complement cascade at body temperature.⁴⁸ Because this antibody can fix complement, hemolysis can be rapid and severe, leading to extreme anemia. The DAT is often weakly positive but can be negative. The diagnostic test for PCH is the Donath–Landsteiner test. This complex test is performed by incubating 3 blood samples, 1 at 0° to 4°C, another at 37°C, and a third at 0° to 4°C and then at 37°C. The diagnosis of PCH is made if only the third tube shows hemolysis.³⁵ PCH can persist for 1 to 3 months but is almost always self-limiting. In severe case, steroids may be of benefit.

Drug-Induced Hemolytic Anemia

AIHA caused by a drug reaction is rare, with a lower incidence than drug-related ITP. The rate of severe drug-related AIHA is estimated at 1:1,000,000, but less severe cases may be missed.¹ Most patients will have a positive DAT without signs of hemolysis, but in rare cases patients will have relentless hemolysis resulting in death.

Mechanisms

Multiple mechanisms for drug-induced immune hemolysis have been proposed, including drug-absorption (hapten-induced) and immune complex mechanisms.^1,49 The hapten mechanism is most often associated with the use of high-dose penicillin.⁵⁰ High doses of penicillin or similar drugs such as piperacillin lead to incorporation of the drug into the red cell membrane by binding to proteins. Patients will manifest a positive DAT with IgG antibody but not complement.⁵¹ The patient’s plasma will be reactive only with penicillin-coated red cells and not with normal cells. As mentioned, very few patients will have hemolysis, and if they have hemolysis, it will resolve in a few days after discontinuation of the offending drug.⁵²

Binding of a drug-antibody complex to the red cell membrane may cause hemolysis via the immune com-plex mechanism.⁵³ Again, most often the patient will have just a positive DAT, but rarely patients will have life-threatening hemolysis upon exposure or reexposure to the drug. The onset of hemolysis is rapid, with signs of acute illness and intravascular hemolysis. The paradigm drug is quinine, but many other drugs have been implicated. Testing shows a positive Coombs test with anti-complement but not anti-IgG.⁵⁰ This pattern is due to the effectiveness of the tertiary complex at fixing complement. The patient’s plasma reacts with red cells only when the drug is added.

A form of immune complex hemolysis associated with both disseminated intravascular coagulation (DIC) and brisk hemolysis has been recognized. Patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone.^53,54) have developed this syndrome.^50,55-59 The clinical symptoms start 7 to 10 days after the drug is administered; often the patient has only received the antibiotic for surgical prophylaxis. Immune hemolysis with acute hematocrit drop, hypotension, and DIC ensues. The patients are often believed to have sepsis and are often reexposed to the cephalosporin, resulting in worsening of the clinical status. The outcome is often fatal due to massive hemolysis and thrombosis.^56,60,62

Finally, 8% to 36% of patients taking methyldopa will develop a positive DAT after 6 months of therapy, with less than 1% showing hemolysis.^52,63 The hemolysis in these patients is indistinguishable from warm AIHA, consistent with the notion that methyldopa induces an AIHA. The hemolysis often resolves rapidly after the methyldopa is stopped, but the Coombs test may remain positive for months.⁶³ This type of drug-induced hemolytic anemia has been reported with levodopa, procainamide, and chlorpromazine, but fludarabine is the most common cause currently. This form of AIHA is now being seen with increased use of checkpoint inhibitors.⁶⁴

Diagnosis

In many patients, the first clue to the presence of drug AIHA is the finding of a positive DAT. Rarely, patients will have severe hemolysis, but in many patients the hemolytic process is mild and may be wrongly assumed to be part of the underlying illness. Finding the offending drug can be a challenge, unless a patient has recently started a new drug; in a hospitalized patient on multiple agents, identifying the problem drug is difficult. Patients recently started on “suspect drugs,” especially the most common agents cefotetan, ceftriaxone, and piperacillin, should have these agents stopped (Table 4).^1,49,65 Specialty laboratories such as the Blood Center of Wisconsin or the Los Angeles Red Cross can perform in vitro studies of drug interactions that can confirm the clinical diagnosis of drug-induced AIHA.

Treatment

Therapy for patients with positive DAT without signs of hemolysis is uncertain. If the drug is essential, then the patient can be observed. If the patient has hemolysis, the drug needs to be stopped and the patient observed for signs of end-organ damage. It is doubtful that steroids or other autoimmune-directed therapy is effective. For patients with the DIC-hemolysis syndrome, there are anecdotal reports that TPE may be helpful.¹

Summary

AIHA can range from an abnormal laboratory test (positive DAT and signs of hemolysis) to an acute, life-threatening illness. Treatment is guided by the laboratory work-up and evaluation of the patient’s clinical status. While rituximab is promising for many patients, the lack of robust clinical trials hinders the treatment of patients who fail standard therapies.

The autoimmune hemolytic anemias (AIHA) are rare but important hematologic diseases. They can range in severity from mildly symptomatic illness to a rapidly fatal syndrome. The incidence of AIHA is estimated to be between 0.6 and 3 cases per 100,000 persons.^1,2 AIHA is mediated by antibodies, and in the majority of cases immunoglobulin (Ig) G is the mediating antibody. This type of AIHA is referred to as "warm" AIHA because IgG antibodies bind best at body temperature. "Cold" AIHA is mediated by IgM antibodies, which bind maximally at temperatures below 37°C (Table 1). This article series reviews the most common types of AIHA, with an overview of evaluation and diagnosis presented in this article and management of warm, cold, and drug-induced AIHA reviewed in a separate article.

Pathogenesis

In most cases, the ultimate etiology of AIHA is unknown. In warm AIHA, the target epitopes in most cases are Rh proteins.² What leads the immune system to target these proteins is unidentified, but one theory is that an initial immune response to a foreign antigen starts to cross-react with the Rh proteins and the immune system fails to suppress this autoreactive response, leading to hemolysis. In IgG-mediated (warm) hemolysis, the red cells become coated with IgG molecules, which mark the cells for uptake and destruction by splenic macrophages.³ In "cold" AIHA, IgM molecules fix complement to the surface of red blood cells. Rarely, this can lead to activation of the full complement cascade, resulting in red cell lysis, but more often it is stopped at the C3 stage, leading to C3-coated red cells which are then taken up by hepatic macrophages.⁴

Suspecting the Diagnosis

In many patients, it is the symptoms and signs of anemia that lead to suspicion of hemolysis. Older patients often present earlier in the course of the disease due to lack of tolerance of anemia, especially if there is a sudden drop in the red blood cell count. Dark, cola-colored urine resulting from the presence of free hemoglobin may be noted by some patients. Patients with rapid-onset hemolysis may note lumbar back pain, and those with cold agglutinins often note symptoms related to agglutination of red cells in the peripheral circulation, such as the development of acrocyanosis in cold weather.⁵ In rare cases, patients will have abdominal pain when eating cold food due to ischemia related to agglutination of red cells in the viscera. Some patients with cold agglutinins can have an exacerbation of their hemolysis with cold exposure.

Unlike patients with immune thrombocytopenia, those with AIHA may have mild splenomegaly on exam. The presence of enlarged lymph nodes or massive splenomegaly should raise concern about concomitant lymphoma or chronic lymphocytic leukemia.

Making the Diagnosis

The 2 key steps in diagnosis are (1) demonstrating hemolysis and (2) demonstrating the autoimmune component.

Laboratory Evaluation for Hemolysis

Hemolysis is proven by finding evidence of both red cell breakdown and the compensatory increase in red cell production this stimulates (Table 2). The following sections discuss the laboratory tests that are performed to investigate hemolysis.

Lactate Dehydrogenase

When red cells undergo hemolysis, they release their contents, which are mostly comprised of hemoglobin but also include lactate dehydrogenase (LDH), an enzyme found in high concentration in red cells. Most patients with hemolysis will have an elevated LDH level, making this a sensitive test. However, because many other processes, including liver disease and pneumonia, also raise the serum LDH level, this finding is not specific for hemolysis.

Hemoglobin is salvaged by haptoglobin, and the heme moiety is broken down first to bilirubin and then to urobilinogen, which is excreted in the urine.² Bilirubin produced from the breakdown of heme is not conjugated, but rather is delivered to the liver, where it is conjugated and excreted into the bile. In hemolysis, the concentration of unconjugated bilirubin (indirect bilirubin) is increased, while in liver disease the level of conjugated bilirubin (direct bilirubin) is increased. However, if the patient has concomitant liver disease with an increased direct bilirubin level, the serum bilirubin test is not reliable.

Serum Haptoglobin

Haptoglobin binds free serum hemoglobin and is taken up by the liver. Haptoglobin usually falls to very low levels in hemolysis. A confounder is that haptoglobin is an acute phase reactant and can rise with systemic disease or inflammation. However, patients with advanced liver disease will have low haptoglobin levels due to lack of synthesis, and up to 2% of the population may congenitally lack haptoglobin.¹

Serum Hemoglobin

If the hemolysis is very rapid, the amount of free hemoglobin released will overwhelm the binding capacity of haptoglobin and lead to free hemoglobin in the plasma. This can be crudely quantified by examining the plasma color. Even minute amounts of free hemoglobin will turn the plasma pink. In fulminant hemolysis, the plasma will be cola-colored.

Reticulocyte Count

In most patients with hemolysis, the destruction of red cells is accompanied by an increase in the reticulocyte count. Reticulocytes are red cells that still contain RNA and are a marker of red cells that are approximately 24 hours old or less. Traditionally, reticulocytes were measured manually by staining the blood smear with vital blue and counting the percentage of cells that absorb the stain; this percentage needs to be adjusted for the hematocrit. Usually a percentage above 1.5% is considered indicative of an elevated reticulocyte count. Recently, automated complete blood count machines have taken advantage of the fact that reticulocytes will absorb certain stains; these machines can directly measure the reticulocyte count via flow cytometry, which results in an “absolute” reticulocyte count. The reticulocyte count obtained using this method does not have to be corrected for hematocrit, and levels of approximately 90,000/μL are considered raised. However, the reticulocyte count can also be raised in blood loss or in patients who have other causes of anemia (eg, iron deficiency) under treatment. In addition, as many as 25% of patients with AIHA will never have raised counts for various reasons, such as nutritional deficiency, autoimmune destruction of red cell precursors, or lack of erythropoietin.

Blood Smear

The blood smear provides vital information. The hallmark laboratory parameter of AIHA is spherocytes seen on the blood smear. In AIHA, antibodies and/or complement attach to the red cells, and when the antibodies or complement are taken up by macrophages in the spleen some of the red blood cell mem-brane is removed as well, decreasing the surface area of the cell. As the surface area of the red cell decreases with each pass through the spleen, the cell's shape changes from a biconcave disk to a sphere before the cell is destroyed, reflecting the fact that a sphere has the smallest surface area for a given volume. The vast majority of patients with AIHA will have spherocytes on the blood smear. However, spherocytes are not specific to AIHA, as they can be seen in hereditary spherocytosis, Wilson’s disease, clostridial sepsis, and severe burns.

Patients with cold agglutinins will often have red cell agglutination on the blood smear. In addition, patients with AIHA will often have a raised mean corpuscular volume (MCV) for 2 reasons. In patients with brisk reticulocytosis, the MCV will be raised due to the large size of the reticulocyte. In patients with cold agglutinin disease, the MCV may be falsely raised due to clumping of the red blood cells.

Urinary Hemosiderin

When hemoglobin is excreted by the kidney, the iron is deposited in the tubules. When the tubule cells are sloughed off, they appear in the urine. The urine can be stained for iron, and a positive result is another sign of hemolysis. Hemosiderinuria is a later sign of hemolysis, as it takes 1 week for iron-laden tubule cells to be excreted in sufficient quantities to be detected in the urine.

Urinary Hemoglobin

One other sign of hemolysis is the presence of hemoglobin in the urine. A quick way to demonstrate hemoglobinuria is to check the urine with a dipstick followed by a microscopic exam. In hemolysis, the dipstick will detect “blood,” while the microscopic exam will be negative for red cells.

Laboratory Evaluation for Autoimmune Component

The autoimmune component is shown by demonstrating the presence of either IgG molecules or complement on the surface of red blood cells.^4,6 This can be done by performing the direct antiglobulin test (DAT) or Coombs test. IgG bound to red cells will not agglutinate them, but if IgM that is directed against IgG or C3 is added, the red cells will agglutinate, proving that there is IgG and/or C3 on the red cell membrane. The finding of a positive DAT in the setting of a hemolytic anemia is diagnostic of AIHA. Beware of individuals with concomitant weak positive DAT and other causes of hemolysis. The strength of the DAT result and the degree of hemolysis must match in order to conclude that the hemolysis is immune-mediated.

There are several pitfalls to the DAT. One is that a positive DAT is found in 1:1000 patients in the normal population and in up to several percent of ill patients, especially those with elevated gamma globulin, such as patients with liver disease or HIV infection.⁶ Administration of intravenous immunoglobulin (IVIG) can also create a positive DAT. Conversely, patients can have AIHA with a negative DAT.^7-9 For some patients, the number of IgG molecules bound to the red cell is below the detection limit of the DAT reagents. Other patients can have IgA or “warm” IgM as the cause of the AIHA.¹⁰ Specialty laboratories can test for these possibilities. The diagnosis of DAT-negative AIHA should be made with caution, and other causes of hemolysis, such as hereditary spherocytosis or paroxysmal hematuria, should be excluded.

Performing transfusions can be very difficult in patients with AIHA.² The presence of the autoantibody can interfere with typing of the blood and almost always interferes with the crossmatch, since this final step consists of mixing the patient’s serum or plasma with donor red cells. In most patients with AIHA, the autoantibodies will react with any donor cells, rendering a negative crossmatch impossible. Without the crossmatch, the concern is that underlying alloantibodies can be missed. Studies indicate that 15% to 32% of patients will have underlying alloantibodies, which can lead to transfusion reactions.² However, there are 2 considerations that may mitigate these concerns.^11,12 First, patients who have never been transfused or pregnant will rarely have alloantibodies. Second, a patient who has been transfused in the remote past may have an anamnestic antibody response but not an immediate hemolytic reaction.

The transfusion service can take several steps to identify alloantibodies. Occasionally, if the autoantibody is weakly reacting when the patient’s serum is tested against a panel of reagent red cells, the alloantibodies can be identified by their stronger reactions as compared with the weakly reactive autoantibody. The most common technique for identifying alloantibodies is the autoadsorption technique.^4,13 This involves incu-bating the patient’s red cells with the patient’s serum to adsorb the autoantibody. After a period of incubation, the cells are pelleted and the serum is collected as the supernatant. The adsorbed serum may be incubated with another sample of the patient’s cells for a second adsorption if the initial agglutination reactions of the patient’s serum with the reagent cells were strong. After 1 to 3 adsorptions, the adsorbed serum is tested with a red cell panel in order to check for “leftover” alloantibodies.

When a patient is first suspected of having AIHA, a generous sample of blood should be given to the transfusion service to allow for adequate testing. Many centers will test the blood not only for blood groups ABO and D but also perform full Rh typing plus check for Kidd, Duffy and Kell status.¹⁴ Increasingly, this is performed by direct genetic sequencing for the appropriate genotypes. This can allow transfusion of phenotypically matched red blood cells to lessen the risk of alloantibody formation.

One difficult issue is timing of transfusion. Clinicians are often hesitant to transfuse patients with AIHA due to fear of reactions, but in patients with severe anemia, especially elderly patients or those with heart disease, transfusion can be lifesaving. Since in some cases it may take hours to screen for alloantibodies, it is often preferable to transfuse patients with severe anemia and observe carefully for reaction.

The autoimmune hemolytic anemias (AIHA) are rare but important hematologic diseases. They can range in severity from mildly symptomatic illness to a rapidly fatal syndrome. The incidence of AIHA is estimated to be between 0.6 and 3 cases per 100,000 persons.^1,2 AIHA is mediated by antibodies, and in the majority of cases immunoglobulin (Ig) G is the mediating antibody. This type of AIHA is referred to as "warm" AIHA because IgG antibodies bind best at body temperature. "Cold" AIHA is mediated by IgM antibodies, which bind maximally at temperatures below 37°C (Table 1). This article series reviews the most common types of AIHA, with an overview of evaluation and diagnosis presented in this article and management of warm, cold, and drug-induced AIHA reviewed in a separate article.

Pathogenesis

In most cases, the ultimate etiology of AIHA is unknown. In warm AIHA, the target epitopes in most cases are Rh proteins.² What leads the immune system to target these proteins is unidentified, but one theory is that an initial immune response to a foreign antigen starts to cross-react with the Rh proteins and the immune system fails to suppress this autoreactive response, leading to hemolysis. In IgG-mediated (warm) hemolysis, the red cells become coated with IgG molecules, which mark the cells for uptake and destruction by splenic macrophages.³ In "cold" AIHA, IgM molecules fix complement to the surface of red blood cells. Rarely, this can lead to activation of the full complement cascade, resulting in red cell lysis, but more often it is stopped at the C3 stage, leading to C3-coated red cells which are then taken up by hepatic macrophages.⁴

Suspecting the Diagnosis

In many patients, it is the symptoms and signs of anemia that lead to suspicion of hemolysis. Older patients often present earlier in the course of the disease due to lack of tolerance of anemia, especially if there is a sudden drop in the red blood cell count. Dark, cola-colored urine resulting from the presence of free hemoglobin may be noted by some patients. Patients with rapid-onset hemolysis may note lumbar back pain, and those with cold agglutinins often note symptoms related to agglutination of red cells in the peripheral circulation, such as the development of acrocyanosis in cold weather.⁵ In rare cases, patients will have abdominal pain when eating cold food due to ischemia related to agglutination of red cells in the viscera. Some patients with cold agglutinins can have an exacerbation of their hemolysis with cold exposure.

Unlike patients with immune thrombocytopenia, those with AIHA may have mild splenomegaly on exam. The presence of enlarged lymph nodes or massive splenomegaly should raise concern about concomitant lymphoma or chronic lymphocytic leukemia.

Making the Diagnosis

The 2 key steps in diagnosis are (1) demonstrating hemolysis and (2) demonstrating the autoimmune component.

Laboratory Evaluation for Hemolysis

Hemolysis is proven by finding evidence of both red cell breakdown and the compensatory increase in red cell production this stimulates (Table 2). The following sections discuss the laboratory tests that are performed to investigate hemolysis.

Lactate Dehydrogenase

When red cells undergo hemolysis, they release their contents, which are mostly comprised of hemoglobin but also include lactate dehydrogenase (LDH), an enzyme found in high concentration in red cells. Most patients with hemolysis will have an elevated LDH level, making this a sensitive test. However, because many other processes, including liver disease and pneumonia, also raise the serum LDH level, this finding is not specific for hemolysis.

Hemoglobin is salvaged by haptoglobin, and the heme moiety is broken down first to bilirubin and then to urobilinogen, which is excreted in the urine.² Bilirubin produced from the breakdown of heme is not conjugated, but rather is delivered to the liver, where it is conjugated and excreted into the bile. In hemolysis, the concentration of unconjugated bilirubin (indirect bilirubin) is increased, while in liver disease the level of conjugated bilirubin (direct bilirubin) is increased. However, if the patient has concomitant liver disease with an increased direct bilirubin level, the serum bilirubin test is not reliable.

Serum Haptoglobin

Haptoglobin binds free serum hemoglobin and is taken up by the liver. Haptoglobin usually falls to very low levels in hemolysis. A confounder is that haptoglobin is an acute phase reactant and can rise with systemic disease or inflammation. However, patients with advanced liver disease will have low haptoglobin levels due to lack of synthesis, and up to 2% of the population may congenitally lack haptoglobin.¹

Serum Hemoglobin

If the hemolysis is very rapid, the amount of free hemoglobin released will overwhelm the binding capacity of haptoglobin and lead to free hemoglobin in the plasma. This can be crudely quantified by examining the plasma color. Even minute amounts of free hemoglobin will turn the plasma pink. In fulminant hemolysis, the plasma will be cola-colored.

Reticulocyte Count

In most patients with hemolysis, the destruction of red cells is accompanied by an increase in the reticulocyte count. Reticulocytes are red cells that still contain RNA and are a marker of red cells that are approximately 24 hours old or less. Traditionally, reticulocytes were measured manually by staining the blood smear with vital blue and counting the percentage of cells that absorb the stain; this percentage needs to be adjusted for the hematocrit. Usually a percentage above 1.5% is considered indicative of an elevated reticulocyte count. Recently, automated complete blood count machines have taken advantage of the fact that reticulocytes will absorb certain stains; these machines can directly measure the reticulocyte count via flow cytometry, which results in an “absolute” reticulocyte count. The reticulocyte count obtained using this method does not have to be corrected for hematocrit, and levels of approximately 90,000/μL are considered raised. However, the reticulocyte count can also be raised in blood loss or in patients who have other causes of anemia (eg, iron deficiency) under treatment. In addition, as many as 25% of patients with AIHA will never have raised counts for various reasons, such as nutritional deficiency, autoimmune destruction of red cell precursors, or lack of erythropoietin.

Blood Smear

The blood smear provides vital information. The hallmark laboratory parameter of AIHA is spherocytes seen on the blood smear. In AIHA, antibodies and/or complement attach to the red cells, and when the antibodies or complement are taken up by macrophages in the spleen some of the red blood cell mem-brane is removed as well, decreasing the surface area of the cell. As the surface area of the red cell decreases with each pass through the spleen, the cell's shape changes from a biconcave disk to a sphere before the cell is destroyed, reflecting the fact that a sphere has the smallest surface area for a given volume. The vast majority of patients with AIHA will have spherocytes on the blood smear. However, spherocytes are not specific to AIHA, as they can be seen in hereditary spherocytosis, Wilson’s disease, clostridial sepsis, and severe burns.

Patients with cold agglutinins will often have red cell agglutination on the blood smear. In addition, patients with AIHA will often have a raised mean corpuscular volume (MCV) for 2 reasons. In patients with brisk reticulocytosis, the MCV will be raised due to the large size of the reticulocyte. In patients with cold agglutinin disease, the MCV may be falsely raised due to clumping of the red blood cells.

Urinary Hemosiderin

When hemoglobin is excreted by the kidney, the iron is deposited in the tubules. When the tubule cells are sloughed off, they appear in the urine. The urine can be stained for iron, and a positive result is another sign of hemolysis. Hemosiderinuria is a later sign of hemolysis, as it takes 1 week for iron-laden tubule cells to be excreted in sufficient quantities to be detected in the urine.

Urinary Hemoglobin

One other sign of hemolysis is the presence of hemoglobin in the urine. A quick way to demonstrate hemoglobinuria is to check the urine with a dipstick followed by a microscopic exam. In hemolysis, the dipstick will detect “blood,” while the microscopic exam will be negative for red cells.

Laboratory Evaluation for Autoimmune Component

The autoimmune component is shown by demonstrating the presence of either IgG molecules or complement on the surface of red blood cells.^4,6 This can be done by performing the direct antiglobulin test (DAT) or Coombs test. IgG bound to red cells will not agglutinate them, but if IgM that is directed against IgG or C3 is added, the red cells will agglutinate, proving that there is IgG and/or C3 on the red cell membrane. The finding of a positive DAT in the setting of a hemolytic anemia is diagnostic of AIHA. Beware of individuals with concomitant weak positive DAT and other causes of hemolysis. The strength of the DAT result and the degree of hemolysis must match in order to conclude that the hemolysis is immune-mediated.

There are several pitfalls to the DAT. One is that a positive DAT is found in 1:1000 patients in the normal population and in up to several percent of ill patients, especially those with elevated gamma globulin, such as patients with liver disease or HIV infection.⁶ Administration of intravenous immunoglobulin (IVIG) can also create a positive DAT. Conversely, patients can have AIHA with a negative DAT.^7-9 For some patients, the number of IgG molecules bound to the red cell is below the detection limit of the DAT reagents. Other patients can have IgA or “warm” IgM as the cause of the AIHA.¹⁰ Specialty laboratories can test for these possibilities. The diagnosis of DAT-negative AIHA should be made with caution, and other causes of hemolysis, such as hereditary spherocytosis or paroxysmal hematuria, should be excluded.

Performing transfusions can be very difficult in patients with AIHA.² The presence of the autoantibody can interfere with typing of the blood and almost always interferes with the crossmatch, since this final step consists of mixing the patient’s serum or plasma with donor red cells. In most patients with AIHA, the autoantibodies will react with any donor cells, rendering a negative crossmatch impossible. Without the crossmatch, the concern is that underlying alloantibodies can be missed. Studies indicate that 15% to 32% of patients will have underlying alloantibodies, which can lead to transfusion reactions.² However, there are 2 considerations that may mitigate these concerns.^11,12 First, patients who have never been transfused or pregnant will rarely have alloantibodies. Second, a patient who has been transfused in the remote past may have an anamnestic antibody response but not an immediate hemolytic reaction.

The transfusion service can take several steps to identify alloantibodies. Occasionally, if the autoantibody is weakly reacting when the patient’s serum is tested against a panel of reagent red cells, the alloantibodies can be identified by their stronger reactions as compared with the weakly reactive autoantibody. The most common technique for identifying alloantibodies is the autoadsorption technique.^4,13 This involves incu-bating the patient’s red cells with the patient’s serum to adsorb the autoantibody. After a period of incubation, the cells are pelleted and the serum is collected as the supernatant. The adsorbed serum may be incubated with another sample of the patient’s cells for a second adsorption if the initial agglutination reactions of the patient’s serum with the reagent cells were strong. After 1 to 3 adsorptions, the adsorbed serum is tested with a red cell panel in order to check for “leftover” alloantibodies.

When a patient is first suspected of having AIHA, a generous sample of blood should be given to the transfusion service to allow for adequate testing. Many centers will test the blood not only for blood groups ABO and D but also perform full Rh typing plus check for Kidd, Duffy and Kell status.¹⁴ Increasingly, this is performed by direct genetic sequencing for the appropriate genotypes. This can allow transfusion of phenotypically matched red blood cells to lessen the risk of alloantibody formation.

One difficult issue is timing of transfusion. Clinicians are often hesitant to transfuse patients with AIHA due to fear of reactions, but in patients with severe anemia, especially elderly patients or those with heart disease, transfusion can be lifesaving. Since in some cases it may take hours to screen for alloantibodies, it is often preferable to transfuse patients with severe anemia and observe carefully for reaction.

The autoimmune hemolytic anemias (AIHA) are rare but important hematologic diseases. They can range in severity from mildly symptomatic illness to a rapidly fatal syndrome. The incidence of AIHA is estimated to be between 0.6 and 3 cases per 100,000 persons.^1,2 AIHA is mediated by antibodies, and in the majority of cases immunoglobulin (Ig) G is the mediating antibody. This type of AIHA is referred to as "warm" AIHA because IgG antibodies bind best at body temperature. "Cold" AIHA is mediated by IgM antibodies, which bind maximally at temperatures below 37°C (Table 1). This article series reviews the most common types of AIHA, with an overview of evaluation and diagnosis presented in this article and management of warm, cold, and drug-induced AIHA reviewed in a separate article.

Pathogenesis

In most cases, the ultimate etiology of AIHA is unknown. In warm AIHA, the target epitopes in most cases are Rh proteins.² What leads the immune system to target these proteins is unidentified, but one theory is that an initial immune response to a foreign antigen starts to cross-react with the Rh proteins and the immune system fails to suppress this autoreactive response, leading to hemolysis. In IgG-mediated (warm) hemolysis, the red cells become coated with IgG molecules, which mark the cells for uptake and destruction by splenic macrophages.³ In "cold" AIHA, IgM molecules fix complement to the surface of red blood cells. Rarely, this can lead to activation of the full complement cascade, resulting in red cell lysis, but more often it is stopped at the C3 stage, leading to C3-coated red cells which are then taken up by hepatic macrophages.⁴

Suspecting the Diagnosis

In many patients, it is the symptoms and signs of anemia that lead to suspicion of hemolysis. Older patients often present earlier in the course of the disease due to lack of tolerance of anemia, especially if there is a sudden drop in the red blood cell count. Dark, cola-colored urine resulting from the presence of free hemoglobin may be noted by some patients. Patients with rapid-onset hemolysis may note lumbar back pain, and those with cold agglutinins often note symptoms related to agglutination of red cells in the peripheral circulation, such as the development of acrocyanosis in cold weather.⁵ In rare cases, patients will have abdominal pain when eating cold food due to ischemia related to agglutination of red cells in the viscera. Some patients with cold agglutinins can have an exacerbation of their hemolysis with cold exposure.

Unlike patients with immune thrombocytopenia, those with AIHA may have mild splenomegaly on exam. The presence of enlarged lymph nodes or massive splenomegaly should raise concern about concomitant lymphoma or chronic lymphocytic leukemia.

Making the Diagnosis

The 2 key steps in diagnosis are (1) demonstrating hemolysis and (2) demonstrating the autoimmune component.

Laboratory Evaluation for Hemolysis

Hemolysis is proven by finding evidence of both red cell breakdown and the compensatory increase in red cell production this stimulates (Table 2). The following sections discuss the laboratory tests that are performed to investigate hemolysis.

Lactate Dehydrogenase

When red cells undergo hemolysis, they release their contents, which are mostly comprised of hemoglobin but also include lactate dehydrogenase (LDH), an enzyme found in high concentration in red cells. Most patients with hemolysis will have an elevated LDH level, making this a sensitive test. However, because many other processes, including liver disease and pneumonia, also raise the serum LDH level, this finding is not specific for hemolysis.

Hemoglobin is salvaged by haptoglobin, and the heme moiety is broken down first to bilirubin and then to urobilinogen, which is excreted in the urine.² Bilirubin produced from the breakdown of heme is not conjugated, but rather is delivered to the liver, where it is conjugated and excreted into the bile. In hemolysis, the concentration of unconjugated bilirubin (indirect bilirubin) is increased, while in liver disease the level of conjugated bilirubin (direct bilirubin) is increased. However, if the patient has concomitant liver disease with an increased direct bilirubin level, the serum bilirubin test is not reliable.

Serum Haptoglobin

Haptoglobin binds free serum hemoglobin and is taken up by the liver. Haptoglobin usually falls to very low levels in hemolysis. A confounder is that haptoglobin is an acute phase reactant and can rise with systemic disease or inflammation. However, patients with advanced liver disease will have low haptoglobin levels due to lack of synthesis, and up to 2% of the population may congenitally lack haptoglobin.¹

Serum Hemoglobin

If the hemolysis is very rapid, the amount of free hemoglobin released will overwhelm the binding capacity of haptoglobin and lead to free hemoglobin in the plasma. This can be crudely quantified by examining the plasma color. Even minute amounts of free hemoglobin will turn the plasma pink. In fulminant hemolysis, the plasma will be cola-colored.

Reticulocyte Count

In most patients with hemolysis, the destruction of red cells is accompanied by an increase in the reticulocyte count. Reticulocytes are red cells that still contain RNA and are a marker of red cells that are approximately 24 hours old or less. Traditionally, reticulocytes were measured manually by staining the blood smear with vital blue and counting the percentage of cells that absorb the stain; this percentage needs to be adjusted for the hematocrit. Usually a percentage above 1.5% is considered indicative of an elevated reticulocyte count. Recently, automated complete blood count machines have taken advantage of the fact that reticulocytes will absorb certain stains; these machines can directly measure the reticulocyte count via flow cytometry, which results in an “absolute” reticulocyte count. The reticulocyte count obtained using this method does not have to be corrected for hematocrit, and levels of approximately 90,000/μL are considered raised. However, the reticulocyte count can also be raised in blood loss or in patients who have other causes of anemia (eg, iron deficiency) under treatment. In addition, as many as 25% of patients with AIHA will never have raised counts for various reasons, such as nutritional deficiency, autoimmune destruction of red cell precursors, or lack of erythropoietin.

Blood Smear

The blood smear provides vital information. The hallmark laboratory parameter of AIHA is spherocytes seen on the blood smear. In AIHA, antibodies and/or complement attach to the red cells, and when the antibodies or complement are taken up by macrophages in the spleen some of the red blood cell mem-brane is removed as well, decreasing the surface area of the cell. As the surface area of the red cell decreases with each pass through the spleen, the cell's shape changes from a biconcave disk to a sphere before the cell is destroyed, reflecting the fact that a sphere has the smallest surface area for a given volume. The vast majority of patients with AIHA will have spherocytes on the blood smear. However, spherocytes are not specific to AIHA, as they can be seen in hereditary spherocytosis, Wilson’s disease, clostridial sepsis, and severe burns.

Patients with cold agglutinins will often have red cell agglutination on the blood smear. In addition, patients with AIHA will often have a raised mean corpuscular volume (MCV) for 2 reasons. In patients with brisk reticulocytosis, the MCV will be raised due to the large size of the reticulocyte. In patients with cold agglutinin disease, the MCV may be falsely raised due to clumping of the red blood cells.

Urinary Hemosiderin

When hemoglobin is excreted by the kidney, the iron is deposited in the tubules. When the tubule cells are sloughed off, they appear in the urine. The urine can be stained for iron, and a positive result is another sign of hemolysis. Hemosiderinuria is a later sign of hemolysis, as it takes 1 week for iron-laden tubule cells to be excreted in sufficient quantities to be detected in the urine.

Urinary Hemoglobin

One other sign of hemolysis is the presence of hemoglobin in the urine. A quick way to demonstrate hemoglobinuria is to check the urine with a dipstick followed by a microscopic exam. In hemolysis, the dipstick will detect “blood,” while the microscopic exam will be negative for red cells.

Laboratory Evaluation for Autoimmune Component

The autoimmune component is shown by demonstrating the presence of either IgG molecules or complement on the surface of red blood cells.^4,6 This can be done by performing the direct antiglobulin test (DAT) or Coombs test. IgG bound to red cells will not agglutinate them, but if IgM that is directed against IgG or C3 is added, the red cells will agglutinate, proving that there is IgG and/or C3 on the red cell membrane. The finding of a positive DAT in the setting of a hemolytic anemia is diagnostic of AIHA. Beware of individuals with concomitant weak positive DAT and other causes of hemolysis. The strength of the DAT result and the degree of hemolysis must match in order to conclude that the hemolysis is immune-mediated.

There are several pitfalls to the DAT. One is that a positive DAT is found in 1:1000 patients in the normal population and in up to several percent of ill patients, especially those with elevated gamma globulin, such as patients with liver disease or HIV infection.⁶ Administration of intravenous immunoglobulin (IVIG) can also create a positive DAT. Conversely, patients can have AIHA with a negative DAT.^7-9 For some patients, the number of IgG molecules bound to the red cell is below the detection limit of the DAT reagents. Other patients can have IgA or “warm” IgM as the cause of the AIHA.¹⁰ Specialty laboratories can test for these possibilities. The diagnosis of DAT-negative AIHA should be made with caution, and other causes of hemolysis, such as hereditary spherocytosis or paroxysmal hematuria, should be excluded.

Performing transfusions can be very difficult in patients with AIHA.² The presence of the autoantibody can interfere with typing of the blood and almost always interferes with the crossmatch, since this final step consists of mixing the patient’s serum or plasma with donor red cells. In most patients with AIHA, the autoantibodies will react with any donor cells, rendering a negative crossmatch impossible. Without the crossmatch, the concern is that underlying alloantibodies can be missed. Studies indicate that 15% to 32% of patients will have underlying alloantibodies, which can lead to transfusion reactions.² However, there are 2 considerations that may mitigate these concerns.^11,12 First, patients who have never been transfused or pregnant will rarely have alloantibodies. Second, a patient who has been transfused in the remote past may have an anamnestic antibody response but not an immediate hemolytic reaction.

The transfusion service can take several steps to identify alloantibodies. Occasionally, if the autoantibody is weakly reacting when the patient’s serum is tested against a panel of reagent red cells, the alloantibodies can be identified by their stronger reactions as compared with the weakly reactive autoantibody. The most common technique for identifying alloantibodies is the autoadsorption technique.^4,13 This involves incu-bating the patient’s red cells with the patient’s serum to adsorb the autoantibody. After a period of incubation, the cells are pelleted and the serum is collected as the supernatant. The adsorbed serum may be incubated with another sample of the patient’s cells for a second adsorption if the initial agglutination reactions of the patient’s serum with the reagent cells were strong. After 1 to 3 adsorptions, the adsorbed serum is tested with a red cell panel in order to check for “leftover” alloantibodies.

When a patient is first suspected of having AIHA, a generous sample of blood should be given to the transfusion service to allow for adequate testing. Many centers will test the blood not only for blood groups ABO and D but also perform full Rh typing plus check for Kidd, Duffy and Kell status.¹⁴ Increasingly, this is performed by direct genetic sequencing for the appropriate genotypes. This can allow transfusion of phenotypically matched red blood cells to lessen the risk of alloantibody formation.

One difficult issue is timing of transfusion. Clinicians are often hesitant to transfuse patients with AIHA due to fear of reactions, but in patients with severe anemia, especially elderly patients or those with heart disease, transfusion can be lifesaving. Since in some cases it may take hours to screen for alloantibodies, it is often preferable to transfuse patients with severe anemia and observe carefully for reaction.

From the Oregon Health and Science University, Portland, OR.

Abstract

• Objective: To describe the current approach to diagnosis and treatment of aplastic anemia.
• Methods: Review of the literature.
• Results: Aplastic anemia can be acquired or associated with an inherited marrow failure syndrome (IMFS), and the treatment and prognosis vary dramatically between these 2 etiologies. Patients may present along a spectrum, ranging from being asymptomatic with incidental findings on peripheral blood testing to life-threatening neutropenic infections or bleeding. Workup and diagnosis involves investigating IMFSs and ruling out malignant or infectious etiologies for pancytopenia.
• Conclusion: Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care for aplastic anemia.

Keywords: inherited marrow failure syndrome; Fanconi anemia; immunosuppression; transplant; stem cell.

Aplastic anemia is a clinical and pathological entity of bone marrow failure that causes progressive loss of hematopoietic progenitor stem cells (HPSC), resulting in pancytopenia.¹ Patients may present along a spectrum, ranging from being asymptomatic with incidental findings on peripheral blood testing to having life-threatening neutropenic infections or bleeding. Aplastic anemia results from either inherited or acquired causes, and the pathophysiology and treatment approach vary significantly between these 2 causes. Therefore, recognition of inherited marrow failure diseases, such as Fanconi anemia and telomere biology disorders, is critical to establishing the management plan. 

Epidemiology

Aplastic anemia is a rare disorder, with an incidence of approximately 1.5 to 7 cases per million individuals per year.^2,3 A recent Scandinavian study reported that the incidence of aplastic anemia among the Swedish population is 2.3 cases per million individuals per year, with a median age at diagnosis of 60 years and a slight female predominance (52% versus 48%, respectively).² This data is congruent with prior observations made in Barcelona, where the incidence was 2.34 cases per million individuals per year, albeit with a slightly higher incidence in males compared to females (2.54 versus 2.16, respectively).⁴ The incidence of aplastic anemia varies globally, with a disproportionate increase in incidence seen among Asian populations, with rates as high as 8.8 per million individuals per year.^3-5 This variation in incidence in Asia versus other countries has not been well explained. There appears to be a bimodal distribution, with incidence peaks seen in young adults and in older adults.^2,3,6

Pathophysiology

Acquired Aplastic Anemia

The leading hypothesis as to the cause of most cases of acquired aplastic anemia is that a dysregulated immune system destroys HPSCs. Inciting etiologies implicated in the development of acquired aplastic anemia include pregnancy, infection, medications, and exposure to certain chemicals, such as benzene.^1,7 The historical understanding of acquired aplastic anemia implicates cytotoxic T-lymphocyte–mediated destruction of CD34+ hematopoietic stem cells.^1,8,9 This hypothesis served as the basis for treatment of acquired aplastic anemia with immunosuppressive therapy, predominantly anti-thymocyte globulin (ATG) combined with cyclosporine A.^1,8 More recent work has focused on cytokine interactions, particularly the suppressive role of interferon (IFN)-γ on hematopoietic stem cells independent of T-lymphocyte–mediated destruction, which has been demonstrated in a murine model.⁸ The interaction of IFN-γ with the hematopoietic stem cell pool is dynamic. IFN-γ levels are elevated during an acute inflammatory response, such as a viral infection, providing further basis for the immune-mediated nature of the acquired disease.¹⁰ Specifically, in vitro studies suggest the effects of IFN-γ on HPSC may be secondary to interruption of thrombopoietin and its respective signaling pathways, which play a key role in hematopoietic stem cell renewal.¹¹ Eltrombopag, a thrombopoietin receptor antagonist, has shown promise in the treatment of refractory aplastic anemia, with studies indicating that its effectiveness is independent of IFN-γ levels.^11,12

Inherited Aplastic Anemia

The inherited marrow failure syndromes (IMFSs) are a group of disorders characterized by cellular maintenance and repair defects, leading to cytopenias, increased cancer risk, structural defects, and risk of end organ damage, such as liver cirrhosis and pulmonary fibrosis.^13-15 The most common diseases include Fanconi anemia, dyskeratosis congenita/telomere biology disorders, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, but with the advent of whole exome sequencing, new syndromes continue to be discovered. While classically these disorders present in children, adult presentations are now commonplace. Broadly, the pathophysiology of inherited aplastic anemia relates to the defective HPSCs and an accelerated decline of the hematopoietic stem cell compartment.

The most common IMFSs, Fanconi anemia and telomere biology disorders, are associated with numerous mutations in DNA damage repair pathways and telomere maintenance pathways. TERT, DKC, and TERC mutations are most commonly associated with dyskeratosis congenita, but may also be found infrequently in patients with aplastic anemia presenting at an older age in the absence of the classic phenotypical features.^1,16,17 The recognition of an underlying genetic disorder or telomere biology disorder leading to constitutional aplastic anemia is significant, as these conditions are associated not only with marrow failure, but also with endocrinopathies, organ fibrosis, and and hematopoietic and solid organ malignancies.^13-15 In particular, TERT and TERC gene mutations have been associated with dyskeratosis congenita as well as pulmonary fibrosis and cirrhosis.^18,19 The implications of early diagnosis of an IMFS lie in the approach to treatment and prognosis.

Clonal Disorders and Secondary Malignancies

Myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) are 2 clonal disorders that may arise from a background of aplastic anemia.^9,20,21 Hypoplastic MDS can be difficult to differentiate from aplastic anemia at diagnosis based on morphology alone, although recent work has demonstrated that molecular testing for somatic mutations in ASXL1, DNMT3A, and BCOR can aid in differentiating a subset of aplastic anemia patients who are more likely to progress to MDS.²¹ Clonal populations of cells harboring 6p uniparental disomy are seen in more than 10% of patients with aplastic anemia on cytogenetic analysis, which can help differentiate the diseases.⁹ Yoshizato and colleagues found lower rates of ASXL1 and DNMT3A mutations in patients with aplastic anemia as compared with patients with MDS or AML. In this study, patients with aplastic anemia had higher rates of mutations in PIGA (reflecting the increased paroxysmal nocturnal hemoglobinuria [PNH] clonality seen in aplastic anemia) and BCOR.⁹ Mutations were also found in genes commonly mutated in MDS and AML, including TET2, RUNX1, TP53, and JAK2, albeit at lower frequencies.⁹ These mutations as a whole have not predicted response to therapy or prognosis. However, when performing survival analysis in patients with specific mutations, those commonly encountered in MDS/AML (ASXL1, DNMT3A, TP53, RUNX1, CSMD1) are associated with faster progression to overt MDS/AML and decreased overall survival (OS),^20,21 suggesting these mutations may represent early clonality that can lead to clonal evolution and the development of secondary malignancies. Conversely, mutations in BCOR and BCORL appear to identify patients who may have a favorable outcome in response to immunosuppressive therapy and, similar to patients with PIGA mutations, improved OS.⁹

Paroxysmal Nocturnal Hemoglobinuria

In addition to having an increased risk of myelodysplasia and malignancy due to the development of a dominant pre-malignant clone, patients with aplastic anemia often harbor progenitor cell clones associated with PNH.^1,17 PNH clones have been identified in more than 50% of patients with aplastic anemia.^22,23 PNH represents a clonal disorder of hematopoiesis in which cells harbor X-linked somatic mutations in the PIGA gene; this gene encodes a protein responsible for the synthesis of glycosylphosphatidylinositol anchors on the cell surface.^22,24 The lack of these cell surface proteins, specifically CD55 (also known as decay accelerating factor) and CD59 (also known as membrane inhibitor of reactive lysis), predisposes red cells to increased complement-mediated lysis.²⁵ The exact mechanism for the development of these clones in patients with aplastic anemia is not fully understood. Current theories hypothesize that the clones are protected from the immune-mediated destruction of normal hematopoietic stem cells due to the absence of the cell surface proteins.^1,20 The role of these clones over time in patients with aplastic anemia is less clear, though recent work demonstrated that despite differences in clonality over the disease course, aplastic anemia patients with small PNH clones are less likely to develop overt hemolysis and larger PNH clones compared to patients harboring larger (≥ 50%) PNH clones at diagnosis.^23,26,27 Additionally, PNH clones in patients with aplastic anemia infrequently become clinically significant.²⁷ It should be noted that these conditions exist along a continuum; that is, patients with aplastic anemia may develop PNH clones, while conversely patients with PNH may develop aplastic anemia.²⁰ Patients with PNH clones should be followed via peripheral blood flow cytometry and complete blood count to track clonal stability and identify clinically significant PNH among aplastic anemia patients.²⁸

Clinical Presentation

Patients with aplastic anemia typically are diagnosed either due to asymptomatic cytopenias found on peripheral blood sampling, symptomatic anemia, bleeding secondary to thrombocytopenia, or wound healing and infectious complications related to neutropenia.²⁹ A thorough history to understand the timing of symptoms, recent infectious symptoms/exposure, habits, and chemical or toxin exposures (including medications, travel, and supplements) helps guide diagnostic testing. Family history is also critical, with attention given to premature graying; pulmonary, renal, and liver disease; and blood disorders.

Patients with an IMFS (eg, Fanconi anemia or dyskeratosis congenita) may have associated phenotypical findings such as urogenital abnormalities or short stature; in addition, those with dyskeratosis congenita may present with the classic triad of oral leukoplakia, lacy skin pigmentation, and dystrophic nails.⁷ However, classic phenotypical findings may be lacking in up to 30% to 40% of patients with an IMFS.⁷ As described previously, while congenital malformations are common in Fanconi anemia and dyskeratosis congenita, a third of patients may have no or only subtle phenotypical abnormalities, including alterations in skin or hair pigmentation, skeletal and growth abnormalities, and endocrine disorders.³⁰ The International Fanconi Anemia Registry identified central nervous system, genitourinary, skin and musculoskeletal, ophthalmic, and gastrointestinal system malformations among children with Fanconi anemia.^31,32 Patients with dyskeratosis congenita may present with pulmonary fibrosis, hepatic cirrhosis, or premature graying, as highlighted in a recent study by DiNardo and colleagues.³³ Therefore, physicians must have a heightened index of suspicion in patients with subtle phenotypical findings and associated cytopenias.

The diagnosis of aplastic anemia should be suspected in any patient presenting with pancytopenia. Aplastic anemia is a diagnosis of exclusion.³⁴ Other conditions associated with peripheral blood pancytopenia should be considered, including infections (HIV, hepatitis, parvovirus B19, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus), nutritional deficiencies (vitamin B12, folate, copper, zinc), autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, hemophagocytic lymphohistiocytosis), hypersplenism, marrow-occupying diseases (eg, leukemia, lymphoma, MDS), solid malignancies, and fibrosis (Table).⁷

Diagnostic Evaluation

The workup for aplastic anemia should include a thorough history and physical exam to search simultaneously for alternative diagnoses and clues pointing to potential etiologic agents.⁷ Diagnostic tests to be performed include a complete blood count with differential, reticulocyte count, immature platelet fraction, flow cytometry (to rule out lymphoproliferative disorders and atypical myeloid cells and to evaluate for PNH), and bone marrow biopsy with subsequent cytogenetic, immunohistochemical, and molecular testing.³⁵ Typical findings in aplastic anemia include peripheral blood pancytopenia without dysplastic features and bone marrow biopsy demonstrating a hypocellular marrow.⁷ A relative lymphocytosis in the peripheral blood is common.⁷ In patients with a significant PNH clone, a macrocytosis along with elevated lactate dehydrogenase and elevated reticulocyte and granulocyte counts may be present.³⁶

The diagnosis (based on the Camitta criteria³⁷ and modified Camitta criteria³⁸ for severe aplastic anemia) requires 2 of the following findings on peripheral blood samples:

• Absolute neutrophil count (ANC) < 500 cells/µL
• Platelet count < 20,000 cells/µL
• Reticulocyte count < 1% corrected or < 20,000 cells/µL.³⁵

In addition to peripheral blood findings, bone marrow biopsy is essential for the diagnosis, and should demonstrate a markedly hypocellular marrow (cellularity < 25%), occasionally with an increase in T lymphocytes.^7,39 Because marrow cellularity varies with age and can be challenging to assess, additional biopsies may be needed to confirm the diagnosis.²⁹ A 1- to 2-cm core biopsy is necessary to confirm hypocellularity, as small areas of residual hematopoiesis may be present and obscure the diagnosis.³⁵

Excluding Hypocellular MDS and IMFS

Excluding hypocellular MDS is challenging, especially in the older adult presenting with aplastic anemia, as patients with aplastic anemia may have some degree of erythroid dysplasia on bone marrow morphology.³⁶ The presence of a PNH clone on flow cytometry can aid in diagnosing aplastic anemia and excluding MDS,³⁴ although PNH clones can be present in refractory anemia MDS. Patients with aplastic anemia have a lower ratio of CD34+ cells compared to those with hypoplastic MDS, with 1 study demonstrating a mean CD34+ percentage of < 0.5% in aplastic anemia versus 3.7% in hypoplastic MDS.⁴⁰ Cytogenetic and molecular testing can also aid in making this distinction by identifying mutations commonly implicated in MDS.⁷ The presence of monosomy 7 (-7) in aplastic anemia patients is associated with a poor overall prognosis.^34,41

Peripheral blood screening using chromosome breakage analysis (done using either mitomycin C or diepoxybutane as in vitro DNA-crosslinking agents)⁴² and telomere length testing (of peripheral blood leukocytes) is necessary to exclude the main IMFSs, Fanconi anemia and telomere biology disorders, respectively. Ruling out these conditions is imperative, as the approach to treatment varies significantly between IMFS and aplastic anemia. Patients with shortened telomeres should undergo genetic screening for mutations in the telomere maintenance genes to evaluate the underlying defect leading to shortened telomeres. Patients with increased peripheral blood breakage should have genetic testing to detect mutations associated with Fanconi anemia.

Classification

Once the diagnosis of aplastic anemia has been made, the patient should be classified according to the severity of their disease. Disease severity is determined based on peripheral blood ANC: non-severe aplastic anemia (NSAA), ANC > 500 polymorphonuclear neutrophils (PMNs)/µL; severe aplastic anemia (SAA), 200–500 PMNs/µL; and very severe aplastic anemia (VSAA), 0–200 PMNs/µL.^4,34 Disease classification is important, as VSAA is associated with a decreased OS compared to SAA.² Disease classification may affect treatment decisions, as patients with NSAA may be observed for a short period of time, while, conversely, patients with SAA have a worse prognosis with delays in therapy.^43-45

Treatment of Inherited Aplastic Anemia

First-line treatment options for patients with IMFS are androgen therapy and hematopoietic stem cell transplant (HSCT). When evaluating patients for HSCT, it is critical to identify the presence of an IMFS, as the risk and mortality associated with the conditioning regimen, stem cell source, graft-versus-host disease (GVHD), and secondary malignancies differ between patients with IMFS and those with acquired marrow failure syndromes or hematologic malignancies.

Potential sibling donors need to be screened for donor candidacy as well as for the inherited defect. Among patients with Fanconi anemia or a telomere biology disorder, the stem cell source must be considered, with multiple studies in IMFSs and SAA showing superior outcomes with a bone marrow product compared to peripheral blood stem cells.^46-48 In IMFS patients, the donor cell type may affect the choice of conditioning regimen.^5,6 Reduced-intensity conditioning in lieu of myeloablative conditioning without total body irradiation has proved feasible in patients with Fanconi anemia, and is associated with a reduced risk of secondary malignancies.^49,50 Incorporation of fludarabine in the conditioning regimen of patients without a matched sibling donor is associated with superior engraftment and survival^46,49,51 compared to cyclophosphamide conditioning, which was historically used in matched related donors.^50,52  Adding fludarabine appears to be especially beneficial in older patients, in whom its use is associated with lower rates of graft failure, likely due to increased immunosuppression at the time of engraftment.^51,53 Fludarabine has also been incorporated into conditioning regimens for patients with a telomere biology disorder, but outcomes data are limited.⁵

For patients presenting with AML or a high-risk MDS who are subsequently diagnosed with an IMFS, treatment can be more complex, as these patients are at high risk for toxicity from standard chemotherapy. Limited data suggest that induction therapy and transplantation are feasible in this group of patients, and this approach is associated with increased OS, despite lower OS rates than those of IMFS patients who present prior to the development of MDS or AML.^54,55 Further work is needed to determine the optimal induction regimen that balances the risks of treatment-related mortality and complications associated with conditioning regimens, risk of relapse, and risk of secondary malignancies, especially in the cohort of patients diagnosed at an older age.

Treatment of Acquired Aplastic Anemia

Supportive Care

While the workup and treatment plan are being established, attention should be directed at supportive care for prevention of complications. The most common complications leading to death in patients with significant pancytopenia and neutropenia are opportunistic infections and hemorrhagic complications.²

Transfusion support is critical to avoid symptomatic anemia and hemorrhagic complications related to thrombocytopenia, which typically occur with platelet counts lower than 10,000 cells/µL. However, transfusion carries the risk of alloimmunization (which may persist for years following transfusion) and transfusion-related graft versus host disease (trGVHD), and thus use of transfusion should be minimized when possible.^56,57 All blood products given to patients with aplastic anemia should be irradiated and leukoreduced to reduce the risk of both alloimmunization and trGVHD. Guidelines from the British Society for Haematology recommend routine screening for Rh and Kell antibodies to reduce the risk of alloimmunization.⁵⁸ Infectious complications remain a common cause of morbidity and mortality in patients with aplastic anemia who have prolonged neutropenia (defined as an ANC < 500 cells/µL).^59-62 Therefore, patients should receive broad-spectrum antibiotics with antipseudomonal coverage. In a study evaluating the role of granulocyte-colony stimulating factor (G-CSF) in patients with SAA receiving immunosuppressive therapy, 55% of all patient deaths were secondary to infection.⁶³ There was no OS benefit seen in patients who received G-CSF, though a significantly lower rate of infection was observed in the G-CSF arm compared to those not receiving G-CSF (56% versus 81%, P = 0.006). This difference was largely driven by a decrease in infectious episodes in patients with VSAA treated with G-CSF as compared to those who did not receive this therapy (22% versus 48%, P = 0.014).⁶³

Angio-invasive pulmonary aspergillosis and Zygomycetes (eg, Rhizopus, Mucor species) remain major causes of mortality related to opportunistic mycotic infections in patients with aplastic anemia.¹⁸ The infectious risk is directly related to the duration and severity of neutropenia, with one study demonstrating a significant increase in risk in AML patients with neutropenia lasting longer than 3 weeks.⁶⁴ Invasive fungal infections carry a high mortality in patients with severe neutropenia, though due to earlier recognition and empiric antifungal therapy with extended-spectrum azoles, overall mortality secondary to invasive fungal infections is declining.^62,65

While neutropenia related to cytotoxic chemotherapy is commonly associated with gram-negative bacteria due to disruption of mucosal barriers, patients with aplastic anemia have an increased incidence of gram-positive bacteremia with staphylococcal species compared to other neutropenic populations.^61,62 This appears to be changing with time. Valdez et al demonstrated a decrease in prevalence of coagulase-negative staphylococcal infections, increased prevalence of gram-positive bacilli bacteremia, and no change in prevalence of gram-negative bacteremia in patients with aplastic anemia treated between 1989 and 2008.⁶⁵ Gram-negative bacteremia caused by Stenotrophomonas maltophila, Escherichia coli, Klebsiella pneumoniae, Citrobacter, and Proteus has also been reported.⁶² Despite a lack of clinical trials investigating the role of antifungal and antibacterial prophylaxis for patients with aplastic anemia, most centers initiate antifungal prophylaxis in patients with SAA or VSAA with an anti-mold agent such as voriconazole or posaconazole (which has the additional benefit compared to voriconazole of covering Mucor species).^60,66 This is especially true for patients who have received ATG or undergone HSCT. For antimicrobial prophylaxis, a fluoroquinolone antibiotic with a spectrum of activity against Pseudomonas should be considered for patients with an ANC < 500 cells/µL.⁶⁰ Acyclovir or valacyclovir prophylaxis is recommended for varicella-zoster virus and herpes simplex virus. Cytomegalovirus reactivation is minimal in patients with aplastic anemia, unless multiple courses of ATG are used.

Iron overload is another complication the provider must be aware of in the setting of increased transfusions in aplastic anemia patients. Lee and colleagues showed that iron chelation therapy using deferasirox is effective at reducing serum ferritin levels in patients with aplastic anemia (median ferritin level of 3254 ng/mL prior to therapy, 1854 ng/mL following), and is associated with no serious adverse events (most common adverse events included nausea, diarrhea, vomiting, and rash).⁶⁷ Approximately 25% of patients in this trial had an increase in creatinine, with patients taking concomitant cyclosporine affected to a greater degree than those on chelation therapy alone. For patients following HSCT or with improved hematopoiesis following immunosuppressive therapy, phlebotomy can be used to treat iron overload in lieu of chelation therapy.⁵⁸

Approach to Therapy

The main treatment options for SAA and VSAA include allogeneic bone marrow transplant and immunosuppression. The deciding factors as to which treatment is best initially depends on the availability of HLA-matched related donors and age (Figure 1 and Figure 2). Survival is decreased in patients with SAA or VSAA who delay initiation of therapy, and therefore prompt referral for HLA typing and evaluation for bone marrow transplant is a very important first step in managing aplastic anemia.

Matched Sibling Donor Transplant. Current standards of care recommend HLA-matched sibling donor transplant for patients with SAA or VSAA who are younger than 50 years, with the caveat that integration of fludarabine and reduced cyclophosphamide dosing along with ATG shows the best overall outcomes. Locasciulli and colleagues examined outcomes in patients given either immunosuppressive therapy or sibling HSCT between 1991-1996 and 1997-2002, respectively, and found that sibling HSCT was associated with a superior 10-year OS compared to immunosuppressive therapy (73% versus 68%).⁴³ Interestingly in this study, there was no OS improvement seen with immunosuppressive therapy alone (69% versus 73%) between the 2 time periods, despite increased OS in both sibling HSCT (74% and 80%) and MUD HSCT (38% and 65%).⁴³ Though total body irradiation has been used in the past, it is typically not included in current conditioning regimens for matched related donor transplants.⁶⁸

Current conditioning regimens typically use a combination of cyclophosphamide and ATG,^69,70 with or without fludarabine. Fludarabine-based conditioning regimens have shown promise in patients undergoing sibling HSCT. Maury and colleagues evaluated the role of fludarabine in addition to low-dose cyclophosphamide and ATG compared to cyclophosphamide alone or in combination with ATG in patients over age 30 undergoing sibling HSCT.⁵³ There was a nonsignificant improvement in 5-year OS in the fludarabine arm compared to controls (77% ± 8% versus 60% ± 3%, P = 0.14) in the pooled analysis, but when adjusted for age the fludarabine arm had a significantly lower relative risk (RR) of death (0.44; P = 0.04) compared to the control arm. Shin et al reported outcomes with fludarabine/cyclophosphamide/ATG, with excellent overall outcomes and no difference in patients older or younger than 40 years.⁷¹

Kim et al evaluated their experience with patients older than 40 years receiving matched related donors, finding comparable outcomes in those ages 41 to 50 years compared to younger patients. Outcomes declined in those over the age of 50 years.⁷² Long-term data for matched related donor transplant for aplastic anemia show excellent long-term outcomes, with minimal chronic GVHD and good performance status.⁷³ Hence, these factors support the role of matched related donor transplant as the initial treatment in SAA and VSAA.

Regarding the role of transplant for patients who lack a matched related donor, a growing body of literature demonstrating identical outcomes between matched related and MUD transplants for pediatric patients^74,75 supports recent recommendations for upfront unrelated donor transplantation for aplastic anemia.^76,77

Immunosuppressive Therapy. For patients without an HLA-matched sibling donor or those who are older than 50 years of age, immunosuppressive therapy is the first-line therapy. ATG and cyclosporine A are the treatments of choice.⁷⁸ The potential effectiveness of immunosuppressive therapy in treating aplastic anemia was initially observed in patients in whom autologous transplant failed but who still experienced hematopoietic reconstitution despite the failed graft; this observation led to the hypothesis that the conditioning regimen may have an effect on hematopoiesis.^59,78,79

Immunosuppressive therapy with ATG has been used for the treatment of aplastic anemia since the 1980s.⁸⁰ Historically, rabbit ATG had been used, but a 2011 study of horse ATG demonstrated superior hematological response at 6 months compared to rabbit ATG (68% versus 37%).⁵⁹ Superior survival was also seen with horse ATG compared to rabbit ATG (3-year OS, 96% versus 76%). Due to these results, horse ATG is preferred over rabbit ATG. ATG should be used in combination with cyclosporine A to optimize outcomes.

Early studies also demonstrated the efficacy of cyclosporine A in the treatment of aplastic anemia, with response rates equivalent to that of ATG monotherapy.⁸¹ Recent publications still note the efficacy of cyclosporine A in the treatment of aplastic anemia. Its role as an affordable option for single-agent therapy in developing countries is intriguing.⁸¹ The combination of ATG and cyclosporine A was proven superior to either agent alone in a study by Frickhofen et al.⁷⁹ In this study, patients were randomly assigned to a control arm that received ATG plus methylprednisolone or to an arm that received ATG plus cyclosporine A and methylprednisolone. At 6 months, 70% of patients in the cyclosporine A arm had a complete remission (CR) or partial remission compared to 46% in the control arm.⁸² Further work confirmed the long-term efficacy of this regimen, reporting a 7-year OS of 55%.⁸³ Among a pediatric population, immunosuppressive therapy was associated with an 83% 10-year OS.⁸⁴

It is recommended that patients remain on cyclosporine therapy for a minimum of 6 months, after which a gradual taper may be considered, although there is variation among practitioners, with some continuing immunosuppressive therapy for a minimum of 12 months due to a proportion of patients being cyclosporine dependent.^34,84 A study found that within a population of patients who responded to immunosuppressive therapy, 18% became cyclosporine dependent.⁸⁴ The median duration of cyclosporine A treatment at full dose was 12 months, with tapering completed over a median of 19 months after patients had been in a stable CR for a minimum of 3 months. Relapse occurred more often when patients were tapered quickly (decrease ≥ 0.8 mg/kg/month) compared to slowly (0.4-0.7 mg/kg/month) or very slowly (< 0.3 mg/kg/month).

Townsley and colleagues recently investigated incorporating the use of the thrombopoietin receptor agonist eltrombopag with immunosuppressive therapy as first-line therapy in aplastic anemia.⁸⁵ When given at a dose of 150 mg daily in patients ages 12 years and older or 75 mg daily in patients younger than 12 years, in conjunction with cyclosporine A and ATG, patients demonstrated markedly improved hematological response compared to historical treatment with standard immunosuppressive therapy alone.⁴⁵ In the patient cohort administered eltrombopag starting on day 1 and continuing for 6 months, the complete response rate was 58%. Eltrombopag led to improvement in all cell lines among all treatment subgroups, and OS (censored for patients who proceeded to transplant) was 99% at 2 years.¹² Overall, toxicities associated with this therapy were low, with liver enzyme elevations most commonly observed.⁸⁵ Recently, a phase 2 trial of immunosuppressive therapy with or without eltrombopag was reported. Of the 38 patients enrolled, overall response, complete response, and time to response were not statistically different.⁸⁶ With this recent finding, the role of eltrombopag in addition to immunosuppressive therapy is not clearly defined, and further studies are warranted.

OS for patients who do not respond to immunosuppressive therapy is approximately 57% at 5 years, largely due to improved supportive measures among this patient population.^48,65 Therefore, it is important to recognize those patients who have a low chance of response so that second-line therapy can be pursued to improve outcomes.

Matched Unrelated Donor Transplant. For patients with refractory disease following immunosuppressive therapy who lack a matched sibling donor, MUD HSCT is considered standard therapy given the marked improvement in overall outcomes with modulating conditioning regimens and high-resolution HLA typing. A European Society for Blood and Marrow Transplantation (EBMT) analysis comparing matched sibling HSCT to MUD HSCT noted significantly higher rates of acute grade II-IV and grade III-IV GVHD (grade II-IV 13% versus 25%, grade III-IV 5% versus 10%) among patients undergoing MUD transplant.⁴⁷ Chronic GVHD rates were 14% in the sibling group, as compared to 26% in the MUD group. Factors associated with improved survival in this analysis include transplant under age 20 years (84% versus 72%), transplant within 6 months of diagnosis (85% versus 72%), the use of ATG in the conditioning regimen (81% versus 73%), and cytomegalovirus-negative donor and recipient as compared to other combinations (82% versus 76%).⁸⁷ Interestingly, this study demonstrated that OS was not significantly increased when using a sibling HSCT compared to a MUD HSCT, likely as a result of improved understanding of conditioning regimens, GVHD prophylaxis, and supportive care.

Additional studies of MUD HSCT have shown outcomes similar to those seen in sibling HSCT.^34,48 A French study found a significant increase in survival in patients undergoing MUD HSCT compared to historical cohorts (2000-2005: OS 52%; 2006-2012: OS 74%).⁷⁵ The majority of patients underwent conditioning with cyclophosphamide or a combination of busulfan and cyclophosphamide, with or without fludarabine; 81% of patients underwent in vivo T-cell depletion, and a bone marrow donor source was utilized. OS was significantly lower in patients over age 30 years undergoing MUD HSCT (57%) compared to those under age 30 years (70%). Improved OS was also seen when patients underwent transplant within 1 year of diagnosis and when a 10/10 matched donor (compared to a 9/10 mismatched donor) was utilized.⁴⁸

A 2015 study investigated the role of MUD HSCT as frontline therapy instead of immunosuppressive therapy in patients without a matched sibling donor.⁷⁵ The 2-year OS was 96% in the MUD HSCT cohort compared to 91%, 94%, and 74% in historical cohorts of sibling HSCT, frontline immunosuppressive therapy, and second-line MUD HSCT following failed immunosuppressive therapy, respectively. Additionally, event-free survival in the MUD HSCT cohort (defined by the authors as death, lack of response, relapse, occurrence of clonal evolution/clinical PNH, malignancies developing over follow‐up, and transplant for patients receiving immunosuppressive therapy frontline) was similar compared to sibling HSCT and superior to frontline immunosuppressive therapy and second-line MUD HSCT. Furthermore, Samarasinghe et al highlighted the importance of in vivo T-cell depletion with either ATG or alemtuzumab (anti-CD52 monoclonal antibody) in the prevention of acute and chronic GVHD in both sibling HSCT and MUD HSCT.⁸⁸

With continued improvement of less toxic and more immunomodulating conditioning regimens,utilization of bone marrow as a donor cell source, in vivo T-cell depletion, and use of GVHD and antimicrobial prophylaxis, more clinical evidence supports elevating MUD HSCT in the treatment plan for patients without a matched sibling donor.⁸⁹ However, there is still a large population of patients without matched sibling or unrelated donor options. Given the need to expand the transplant pool and thus avoid clonal hematopoiesis, clinically significant PNH, and relapsed aplastic anemia, more work continues to recognize the expanding role of alternative donor transplants (cord blood and haploidentical) as another viable treatment strategy for aplastic anemia after immunosuppressive therapy failure.⁹⁰

Summary

Aplastic anemia is a rare but potentially life-threatening disorder with pancytopenia and a marked reduction in the HSC compartment. It can be acquired or associated with an IMFS, and the treatment and prognosis vary dramatically between these 2 etiologies. Workup and diagnosis involves investigating IMFSs and ruling out malignant or infectious etiologies for pancytopenia. Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care.

Corresponding author: Gabrielle Meyers, MD, 3181 SW Sam Jackson Park Road, Mail Code UHN73C, Portland, OR 97239.

Financial disclosures: None.

From the Oregon Health and Science University, Portland, OR.

Abstract

• Objective: To describe the current approach to diagnosis and treatment of aplastic anemia.
• Methods: Review of the literature.
• Results: Aplastic anemia can be acquired or associated with an inherited marrow failure syndrome (IMFS), and the treatment and prognosis vary dramatically between these 2 etiologies. Patients may present along a spectrum, ranging from being asymptomatic with incidental findings on peripheral blood testing to life-threatening neutropenic infections or bleeding. Workup and diagnosis involves investigating IMFSs and ruling out malignant or infectious etiologies for pancytopenia.
• Conclusion: Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care for aplastic anemia.

Keywords: inherited marrow failure syndrome; Fanconi anemia; immunosuppression; transplant; stem cell.

Aplastic anemia is a clinical and pathological entity of bone marrow failure that causes progressive loss of hematopoietic progenitor stem cells (HPSC), resulting in pancytopenia.¹ Patients may present along a spectrum, ranging from being asymptomatic with incidental findings on peripheral blood testing to having life-threatening neutropenic infections or bleeding. Aplastic anemia results from either inherited or acquired causes, and the pathophysiology and treatment approach vary significantly between these 2 causes. Therefore, recognition of inherited marrow failure diseases, such as Fanconi anemia and telomere biology disorders, is critical to establishing the management plan. 

Epidemiology

Aplastic anemia is a rare disorder, with an incidence of approximately 1.5 to 7 cases per million individuals per year.^2,3 A recent Scandinavian study reported that the incidence of aplastic anemia among the Swedish population is 2.3 cases per million individuals per year, with a median age at diagnosis of 60 years and a slight female predominance (52% versus 48%, respectively).² This data is congruent with prior observations made in Barcelona, where the incidence was 2.34 cases per million individuals per year, albeit with a slightly higher incidence in males compared to females (2.54 versus 2.16, respectively).⁴ The incidence of aplastic anemia varies globally, with a disproportionate increase in incidence seen among Asian populations, with rates as high as 8.8 per million individuals per year.^3-5 This variation in incidence in Asia versus other countries has not been well explained. There appears to be a bimodal distribution, with incidence peaks seen in young adults and in older adults.^2,3,6

Pathophysiology

Acquired Aplastic Anemia

The leading hypothesis as to the cause of most cases of acquired aplastic anemia is that a dysregulated immune system destroys HPSCs. Inciting etiologies implicated in the development of acquired aplastic anemia include pregnancy, infection, medications, and exposure to certain chemicals, such as benzene.^1,7 The historical understanding of acquired aplastic anemia implicates cytotoxic T-lymphocyte–mediated destruction of CD34+ hematopoietic stem cells.^1,8,9 This hypothesis served as the basis for treatment of acquired aplastic anemia with immunosuppressive therapy, predominantly anti-thymocyte globulin (ATG) combined with cyclosporine A.^1,8 More recent work has focused on cytokine interactions, particularly the suppressive role of interferon (IFN)-γ on hematopoietic stem cells independent of T-lymphocyte–mediated destruction, which has been demonstrated in a murine model.⁸ The interaction of IFN-γ with the hematopoietic stem cell pool is dynamic. IFN-γ levels are elevated during an acute inflammatory response, such as a viral infection, providing further basis for the immune-mediated nature of the acquired disease.¹⁰ Specifically, in vitro studies suggest the effects of IFN-γ on HPSC may be secondary to interruption of thrombopoietin and its respective signaling pathways, which play a key role in hematopoietic stem cell renewal.¹¹ Eltrombopag, a thrombopoietin receptor antagonist, has shown promise in the treatment of refractory aplastic anemia, with studies indicating that its effectiveness is independent of IFN-γ levels.^11,12

Inherited Aplastic Anemia

The inherited marrow failure syndromes (IMFSs) are a group of disorders characterized by cellular maintenance and repair defects, leading to cytopenias, increased cancer risk, structural defects, and risk of end organ damage, such as liver cirrhosis and pulmonary fibrosis.^13-15 The most common diseases include Fanconi anemia, dyskeratosis congenita/telomere biology disorders, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, but with the advent of whole exome sequencing, new syndromes continue to be discovered. While classically these disorders present in children, adult presentations are now commonplace. Broadly, the pathophysiology of inherited aplastic anemia relates to the defective HPSCs and an accelerated decline of the hematopoietic stem cell compartment.

The most common IMFSs, Fanconi anemia and telomere biology disorders, are associated with numerous mutations in DNA damage repair pathways and telomere maintenance pathways. TERT, DKC, and TERC mutations are most commonly associated with dyskeratosis congenita, but may also be found infrequently in patients with aplastic anemia presenting at an older age in the absence of the classic phenotypical features.^1,16,17 The recognition of an underlying genetic disorder or telomere biology disorder leading to constitutional aplastic anemia is significant, as these conditions are associated not only with marrow failure, but also with endocrinopathies, organ fibrosis, and and hematopoietic and solid organ malignancies.^13-15 In particular, TERT and TERC gene mutations have been associated with dyskeratosis congenita as well as pulmonary fibrosis and cirrhosis.^18,19 The implications of early diagnosis of an IMFS lie in the approach to treatment and prognosis.

Clonal Disorders and Secondary Malignancies

Myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) are 2 clonal disorders that may arise from a background of aplastic anemia.^9,20,21 Hypoplastic MDS can be difficult to differentiate from aplastic anemia at diagnosis based on morphology alone, although recent work has demonstrated that molecular testing for somatic mutations in ASXL1, DNMT3A, and BCOR can aid in differentiating a subset of aplastic anemia patients who are more likely to progress to MDS.²¹ Clonal populations of cells harboring 6p uniparental disomy are seen in more than 10% of patients with aplastic anemia on cytogenetic analysis, which can help differentiate the diseases.⁹ Yoshizato and colleagues found lower rates of ASXL1 and DNMT3A mutations in patients with aplastic anemia as compared with patients with MDS or AML. In this study, patients with aplastic anemia had higher rates of mutations in PIGA (reflecting the increased paroxysmal nocturnal hemoglobinuria [PNH] clonality seen in aplastic anemia) and BCOR.⁹ Mutations were also found in genes commonly mutated in MDS and AML, including TET2, RUNX1, TP53, and JAK2, albeit at lower frequencies.⁹ These mutations as a whole have not predicted response to therapy or prognosis. However, when performing survival analysis in patients with specific mutations, those commonly encountered in MDS/AML (ASXL1, DNMT3A, TP53, RUNX1, CSMD1) are associated with faster progression to overt MDS/AML and decreased overall survival (OS),^20,21 suggesting these mutations may represent early clonality that can lead to clonal evolution and the development of secondary malignancies. Conversely, mutations in BCOR and BCORL appear to identify patients who may have a favorable outcome in response to immunosuppressive therapy and, similar to patients with PIGA mutations, improved OS.⁹

Paroxysmal Nocturnal Hemoglobinuria

In addition to having an increased risk of myelodysplasia and malignancy due to the development of a dominant pre-malignant clone, patients with aplastic anemia often harbor progenitor cell clones associated with PNH.^1,17 PNH clones have been identified in more than 50% of patients with aplastic anemia.^22,23 PNH represents a clonal disorder of hematopoiesis in which cells harbor X-linked somatic mutations in the PIGA gene; this gene encodes a protein responsible for the synthesis of glycosylphosphatidylinositol anchors on the cell surface.^22,24 The lack of these cell surface proteins, specifically CD55 (also known as decay accelerating factor) and CD59 (also known as membrane inhibitor of reactive lysis), predisposes red cells to increased complement-mediated lysis.²⁵ The exact mechanism for the development of these clones in patients with aplastic anemia is not fully understood. Current theories hypothesize that the clones are protected from the immune-mediated destruction of normal hematopoietic stem cells due to the absence of the cell surface proteins.^1,20 The role of these clones over time in patients with aplastic anemia is less clear, though recent work demonstrated that despite differences in clonality over the disease course, aplastic anemia patients with small PNH clones are less likely to develop overt hemolysis and larger PNH clones compared to patients harboring larger (≥ 50%) PNH clones at diagnosis.^23,26,27 Additionally, PNH clones in patients with aplastic anemia infrequently become clinically significant.²⁷ It should be noted that these conditions exist along a continuum; that is, patients with aplastic anemia may develop PNH clones, while conversely patients with PNH may develop aplastic anemia.²⁰ Patients with PNH clones should be followed via peripheral blood flow cytometry and complete blood count to track clonal stability and identify clinically significant PNH among aplastic anemia patients.²⁸

Clinical Presentation

Patients with aplastic anemia typically are diagnosed either due to asymptomatic cytopenias found on peripheral blood sampling, symptomatic anemia, bleeding secondary to thrombocytopenia, or wound healing and infectious complications related to neutropenia.²⁹ A thorough history to understand the timing of symptoms, recent infectious symptoms/exposure, habits, and chemical or toxin exposures (including medications, travel, and supplements) helps guide diagnostic testing. Family history is also critical, with attention given to premature graying; pulmonary, renal, and liver disease; and blood disorders.

Patients with an IMFS (eg, Fanconi anemia or dyskeratosis congenita) may have associated phenotypical findings such as urogenital abnormalities or short stature; in addition, those with dyskeratosis congenita may present with the classic triad of oral leukoplakia, lacy skin pigmentation, and dystrophic nails.⁷ However, classic phenotypical findings may be lacking in up to 30% to 40% of patients with an IMFS.⁷ As described previously, while congenital malformations are common in Fanconi anemia and dyskeratosis congenita, a third of patients may have no or only subtle phenotypical abnormalities, including alterations in skin or hair pigmentation, skeletal and growth abnormalities, and endocrine disorders.³⁰ The International Fanconi Anemia Registry identified central nervous system, genitourinary, skin and musculoskeletal, ophthalmic, and gastrointestinal system malformations among children with Fanconi anemia.^31,32 Patients with dyskeratosis congenita may present with pulmonary fibrosis, hepatic cirrhosis, or premature graying, as highlighted in a recent study by DiNardo and colleagues.³³ Therefore, physicians must have a heightened index of suspicion in patients with subtle phenotypical findings and associated cytopenias.

The diagnosis of aplastic anemia should be suspected in any patient presenting with pancytopenia. Aplastic anemia is a diagnosis of exclusion.³⁴ Other conditions associated with peripheral blood pancytopenia should be considered, including infections (HIV, hepatitis, parvovirus B19, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus), nutritional deficiencies (vitamin B12, folate, copper, zinc), autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, hemophagocytic lymphohistiocytosis), hypersplenism, marrow-occupying diseases (eg, leukemia, lymphoma, MDS), solid malignancies, and fibrosis (Table).⁷

Diagnostic Evaluation

The workup for aplastic anemia should include a thorough history and physical exam to search simultaneously for alternative diagnoses and clues pointing to potential etiologic agents.⁷ Diagnostic tests to be performed include a complete blood count with differential, reticulocyte count, immature platelet fraction, flow cytometry (to rule out lymphoproliferative disorders and atypical myeloid cells and to evaluate for PNH), and bone marrow biopsy with subsequent cytogenetic, immunohistochemical, and molecular testing.³⁵ Typical findings in aplastic anemia include peripheral blood pancytopenia without dysplastic features and bone marrow biopsy demonstrating a hypocellular marrow.⁷ A relative lymphocytosis in the peripheral blood is common.⁷ In patients with a significant PNH clone, a macrocytosis along with elevated lactate dehydrogenase and elevated reticulocyte and granulocyte counts may be present.³⁶

The diagnosis (based on the Camitta criteria³⁷ and modified Camitta criteria³⁸ for severe aplastic anemia) requires 2 of the following findings on peripheral blood samples:

• Absolute neutrophil count (ANC) < 500 cells/µL
• Platelet count < 20,000 cells/µL
• Reticulocyte count < 1% corrected or < 20,000 cells/µL.³⁵

In addition to peripheral blood findings, bone marrow biopsy is essential for the diagnosis, and should demonstrate a markedly hypocellular marrow (cellularity < 25%), occasionally with an increase in T lymphocytes.^7,39 Because marrow cellularity varies with age and can be challenging to assess, additional biopsies may be needed to confirm the diagnosis.²⁹ A 1- to 2-cm core biopsy is necessary to confirm hypocellularity, as small areas of residual hematopoiesis may be present and obscure the diagnosis.³⁵

Excluding Hypocellular MDS and IMFS

Excluding hypocellular MDS is challenging, especially in the older adult presenting with aplastic anemia, as patients with aplastic anemia may have some degree of erythroid dysplasia on bone marrow morphology.³⁶ The presence of a PNH clone on flow cytometry can aid in diagnosing aplastic anemia and excluding MDS,³⁴ although PNH clones can be present in refractory anemia MDS. Patients with aplastic anemia have a lower ratio of CD34+ cells compared to those with hypoplastic MDS, with 1 study demonstrating a mean CD34+ percentage of < 0.5% in aplastic anemia versus 3.7% in hypoplastic MDS.⁴⁰ Cytogenetic and molecular testing can also aid in making this distinction by identifying mutations commonly implicated in MDS.⁷ The presence of monosomy 7 (-7) in aplastic anemia patients is associated with a poor overall prognosis.^34,41

Peripheral blood screening using chromosome breakage analysis (done using either mitomycin C or diepoxybutane as in vitro DNA-crosslinking agents)⁴² and telomere length testing (of peripheral blood leukocytes) is necessary to exclude the main IMFSs, Fanconi anemia and telomere biology disorders, respectively. Ruling out these conditions is imperative, as the approach to treatment varies significantly between IMFS and aplastic anemia. Patients with shortened telomeres should undergo genetic screening for mutations in the telomere maintenance genes to evaluate the underlying defect leading to shortened telomeres. Patients with increased peripheral blood breakage should have genetic testing to detect mutations associated with Fanconi anemia.

Classification

Once the diagnosis of aplastic anemia has been made, the patient should be classified according to the severity of their disease. Disease severity is determined based on peripheral blood ANC: non-severe aplastic anemia (NSAA), ANC > 500 polymorphonuclear neutrophils (PMNs)/µL; severe aplastic anemia (SAA), 200–500 PMNs/µL; and very severe aplastic anemia (VSAA), 0–200 PMNs/µL.^4,34 Disease classification is important, as VSAA is associated with a decreased OS compared to SAA.² Disease classification may affect treatment decisions, as patients with NSAA may be observed for a short period of time, while, conversely, patients with SAA have a worse prognosis with delays in therapy.^43-45

Treatment of Inherited Aplastic Anemia

First-line treatment options for patients with IMFS are androgen therapy and hematopoietic stem cell transplant (HSCT). When evaluating patients for HSCT, it is critical to identify the presence of an IMFS, as the risk and mortality associated with the conditioning regimen, stem cell source, graft-versus-host disease (GVHD), and secondary malignancies differ between patients with IMFS and those with acquired marrow failure syndromes or hematologic malignancies.

Potential sibling donors need to be screened for donor candidacy as well as for the inherited defect. Among patients with Fanconi anemia or a telomere biology disorder, the stem cell source must be considered, with multiple studies in IMFSs and SAA showing superior outcomes with a bone marrow product compared to peripheral blood stem cells.^46-48 In IMFS patients, the donor cell type may affect the choice of conditioning regimen.^5,6 Reduced-intensity conditioning in lieu of myeloablative conditioning without total body irradiation has proved feasible in patients with Fanconi anemia, and is associated with a reduced risk of secondary malignancies.^49,50 Incorporation of fludarabine in the conditioning regimen of patients without a matched sibling donor is associated with superior engraftment and survival^46,49,51 compared to cyclophosphamide conditioning, which was historically used in matched related donors.^50,52  Adding fludarabine appears to be especially beneficial in older patients, in whom its use is associated with lower rates of graft failure, likely due to increased immunosuppression at the time of engraftment.^51,53 Fludarabine has also been incorporated into conditioning regimens for patients with a telomere biology disorder, but outcomes data are limited.⁵

For patients presenting with AML or a high-risk MDS who are subsequently diagnosed with an IMFS, treatment can be more complex, as these patients are at high risk for toxicity from standard chemotherapy. Limited data suggest that induction therapy and transplantation are feasible in this group of patients, and this approach is associated with increased OS, despite lower OS rates than those of IMFS patients who present prior to the development of MDS or AML.^54,55 Further work is needed to determine the optimal induction regimen that balances the risks of treatment-related mortality and complications associated with conditioning regimens, risk of relapse, and risk of secondary malignancies, especially in the cohort of patients diagnosed at an older age.

Treatment of Acquired Aplastic Anemia

Supportive Care

While the workup and treatment plan are being established, attention should be directed at supportive care for prevention of complications. The most common complications leading to death in patients with significant pancytopenia and neutropenia are opportunistic infections and hemorrhagic complications.²

Transfusion support is critical to avoid symptomatic anemia and hemorrhagic complications related to thrombocytopenia, which typically occur with platelet counts lower than 10,000 cells/µL. However, transfusion carries the risk of alloimmunization (which may persist for years following transfusion) and transfusion-related graft versus host disease (trGVHD), and thus use of transfusion should be minimized when possible.^56,57 All blood products given to patients with aplastic anemia should be irradiated and leukoreduced to reduce the risk of both alloimmunization and trGVHD. Guidelines from the British Society for Haematology recommend routine screening for Rh and Kell antibodies to reduce the risk of alloimmunization.⁵⁸ Infectious complications remain a common cause of morbidity and mortality in patients with aplastic anemia who have prolonged neutropenia (defined as an ANC < 500 cells/µL).^59-62 Therefore, patients should receive broad-spectrum antibiotics with antipseudomonal coverage. In a study evaluating the role of granulocyte-colony stimulating factor (G-CSF) in patients with SAA receiving immunosuppressive therapy, 55% of all patient deaths were secondary to infection.⁶³ There was no OS benefit seen in patients who received G-CSF, though a significantly lower rate of infection was observed in the G-CSF arm compared to those not receiving G-CSF (56% versus 81%, P = 0.006). This difference was largely driven by a decrease in infectious episodes in patients with VSAA treated with G-CSF as compared to those who did not receive this therapy (22% versus 48%, P = 0.014).⁶³

Angio-invasive pulmonary aspergillosis and Zygomycetes (eg, Rhizopus, Mucor species) remain major causes of mortality related to opportunistic mycotic infections in patients with aplastic anemia.¹⁸ The infectious risk is directly related to the duration and severity of neutropenia, with one study demonstrating a significant increase in risk in AML patients with neutropenia lasting longer than 3 weeks.⁶⁴ Invasive fungal infections carry a high mortality in patients with severe neutropenia, though due to earlier recognition and empiric antifungal therapy with extended-spectrum azoles, overall mortality secondary to invasive fungal infections is declining.^62,65

While neutropenia related to cytotoxic chemotherapy is commonly associated with gram-negative bacteria due to disruption of mucosal barriers, patients with aplastic anemia have an increased incidence of gram-positive bacteremia with staphylococcal species compared to other neutropenic populations.^61,62 This appears to be changing with time. Valdez et al demonstrated a decrease in prevalence of coagulase-negative staphylococcal infections, increased prevalence of gram-positive bacilli bacteremia, and no change in prevalence of gram-negative bacteremia in patients with aplastic anemia treated between 1989 and 2008.⁶⁵ Gram-negative bacteremia caused by Stenotrophomonas maltophila, Escherichia coli, Klebsiella pneumoniae, Citrobacter, and Proteus has also been reported.⁶² Despite a lack of clinical trials investigating the role of antifungal and antibacterial prophylaxis for patients with aplastic anemia, most centers initiate antifungal prophylaxis in patients with SAA or VSAA with an anti-mold agent such as voriconazole or posaconazole (which has the additional benefit compared to voriconazole of covering Mucor species).^60,66 This is especially true for patients who have received ATG or undergone HSCT. For antimicrobial prophylaxis, a fluoroquinolone antibiotic with a spectrum of activity against Pseudomonas should be considered for patients with an ANC < 500 cells/µL.⁶⁰ Acyclovir or valacyclovir prophylaxis is recommended for varicella-zoster virus and herpes simplex virus. Cytomegalovirus reactivation is minimal in patients with aplastic anemia, unless multiple courses of ATG are used.

Iron overload is another complication the provider must be aware of in the setting of increased transfusions in aplastic anemia patients. Lee and colleagues showed that iron chelation therapy using deferasirox is effective at reducing serum ferritin levels in patients with aplastic anemia (median ferritin level of 3254 ng/mL prior to therapy, 1854 ng/mL following), and is associated with no serious adverse events (most common adverse events included nausea, diarrhea, vomiting, and rash).⁶⁷ Approximately 25% of patients in this trial had an increase in creatinine, with patients taking concomitant cyclosporine affected to a greater degree than those on chelation therapy alone. For patients following HSCT or with improved hematopoiesis following immunosuppressive therapy, phlebotomy can be used to treat iron overload in lieu of chelation therapy.⁵⁸

Approach to Therapy

The main treatment options for SAA and VSAA include allogeneic bone marrow transplant and immunosuppression. The deciding factors as to which treatment is best initially depends on the availability of HLA-matched related donors and age (Figure 1 and Figure 2). Survival is decreased in patients with SAA or VSAA who delay initiation of therapy, and therefore prompt referral for HLA typing and evaluation for bone marrow transplant is a very important first step in managing aplastic anemia.

Matched Sibling Donor Transplant. Current standards of care recommend HLA-matched sibling donor transplant for patients with SAA or VSAA who are younger than 50 years, with the caveat that integration of fludarabine and reduced cyclophosphamide dosing along with ATG shows the best overall outcomes. Locasciulli and colleagues examined outcomes in patients given either immunosuppressive therapy or sibling HSCT between 1991-1996 and 1997-2002, respectively, and found that sibling HSCT was associated with a superior 10-year OS compared to immunosuppressive therapy (73% versus 68%).⁴³ Interestingly in this study, there was no OS improvement seen with immunosuppressive therapy alone (69% versus 73%) between the 2 time periods, despite increased OS in both sibling HSCT (74% and 80%) and MUD HSCT (38% and 65%).⁴³ Though total body irradiation has been used in the past, it is typically not included in current conditioning regimens for matched related donor transplants.⁶⁸

Current conditioning regimens typically use a combination of cyclophosphamide and ATG,^69,70 with or without fludarabine. Fludarabine-based conditioning regimens have shown promise in patients undergoing sibling HSCT. Maury and colleagues evaluated the role of fludarabine in addition to low-dose cyclophosphamide and ATG compared to cyclophosphamide alone or in combination with ATG in patients over age 30 undergoing sibling HSCT.⁵³ There was a nonsignificant improvement in 5-year OS in the fludarabine arm compared to controls (77% ± 8% versus 60% ± 3%, P = 0.14) in the pooled analysis, but when adjusted for age the fludarabine arm had a significantly lower relative risk (RR) of death (0.44; P = 0.04) compared to the control arm. Shin et al reported outcomes with fludarabine/cyclophosphamide/ATG, with excellent overall outcomes and no difference in patients older or younger than 40 years.⁷¹

Kim et al evaluated their experience with patients older than 40 years receiving matched related donors, finding comparable outcomes in those ages 41 to 50 years compared to younger patients. Outcomes declined in those over the age of 50 years.⁷² Long-term data for matched related donor transplant for aplastic anemia show excellent long-term outcomes, with minimal chronic GVHD and good performance status.⁷³ Hence, these factors support the role of matched related donor transplant as the initial treatment in SAA and VSAA.

Regarding the role of transplant for patients who lack a matched related donor, a growing body of literature demonstrating identical outcomes between matched related and MUD transplants for pediatric patients^74,75 supports recent recommendations for upfront unrelated donor transplantation for aplastic anemia.^76,77

Immunosuppressive Therapy. For patients without an HLA-matched sibling donor or those who are older than 50 years of age, immunosuppressive therapy is the first-line therapy. ATG and cyclosporine A are the treatments of choice.⁷⁸ The potential effectiveness of immunosuppressive therapy in treating aplastic anemia was initially observed in patients in whom autologous transplant failed but who still experienced hematopoietic reconstitution despite the failed graft; this observation led to the hypothesis that the conditioning regimen may have an effect on hematopoiesis.^59,78,79

Immunosuppressive therapy with ATG has been used for the treatment of aplastic anemia since the 1980s.⁸⁰ Historically, rabbit ATG had been used, but a 2011 study of horse ATG demonstrated superior hematological response at 6 months compared to rabbit ATG (68% versus 37%).⁵⁹ Superior survival was also seen with horse ATG compared to rabbit ATG (3-year OS, 96% versus 76%). Due to these results, horse ATG is preferred over rabbit ATG. ATG should be used in combination with cyclosporine A to optimize outcomes.

Early studies also demonstrated the efficacy of cyclosporine A in the treatment of aplastic anemia, with response rates equivalent to that of ATG monotherapy.⁸¹ Recent publications still note the efficacy of cyclosporine A in the treatment of aplastic anemia. Its role as an affordable option for single-agent therapy in developing countries is intriguing.⁸¹ The combination of ATG and cyclosporine A was proven superior to either agent alone in a study by Frickhofen et al.⁷⁹ In this study, patients were randomly assigned to a control arm that received ATG plus methylprednisolone or to an arm that received ATG plus cyclosporine A and methylprednisolone. At 6 months, 70% of patients in the cyclosporine A arm had a complete remission (CR) or partial remission compared to 46% in the control arm.⁸² Further work confirmed the long-term efficacy of this regimen, reporting a 7-year OS of 55%.⁸³ Among a pediatric population, immunosuppressive therapy was associated with an 83% 10-year OS.⁸⁴

It is recommended that patients remain on cyclosporine therapy for a minimum of 6 months, after which a gradual taper may be considered, although there is variation among practitioners, with some continuing immunosuppressive therapy for a minimum of 12 months due to a proportion of patients being cyclosporine dependent.^34,84 A study found that within a population of patients who responded to immunosuppressive therapy, 18% became cyclosporine dependent.⁸⁴ The median duration of cyclosporine A treatment at full dose was 12 months, with tapering completed over a median of 19 months after patients had been in a stable CR for a minimum of 3 months. Relapse occurred more often when patients were tapered quickly (decrease ≥ 0.8 mg/kg/month) compared to slowly (0.4-0.7 mg/kg/month) or very slowly (< 0.3 mg/kg/month).

Townsley and colleagues recently investigated incorporating the use of the thrombopoietin receptor agonist eltrombopag with immunosuppressive therapy as first-line therapy in aplastic anemia.⁸⁵ When given at a dose of 150 mg daily in patients ages 12 years and older or 75 mg daily in patients younger than 12 years, in conjunction with cyclosporine A and ATG, patients demonstrated markedly improved hematological response compared to historical treatment with standard immunosuppressive therapy alone.⁴⁵ In the patient cohort administered eltrombopag starting on day 1 and continuing for 6 months, the complete response rate was 58%. Eltrombopag led to improvement in all cell lines among all treatment subgroups, and OS (censored for patients who proceeded to transplant) was 99% at 2 years.¹² Overall, toxicities associated with this therapy were low, with liver enzyme elevations most commonly observed.⁸⁵ Recently, a phase 2 trial of immunosuppressive therapy with or without eltrombopag was reported. Of the 38 patients enrolled, overall response, complete response, and time to response were not statistically different.⁸⁶ With this recent finding, the role of eltrombopag in addition to immunosuppressive therapy is not clearly defined, and further studies are warranted.

OS for patients who do not respond to immunosuppressive therapy is approximately 57% at 5 years, largely due to improved supportive measures among this patient population.^48,65 Therefore, it is important to recognize those patients who have a low chance of response so that second-line therapy can be pursued to improve outcomes.

Matched Unrelated Donor Transplant. For patients with refractory disease following immunosuppressive therapy who lack a matched sibling donor, MUD HSCT is considered standard therapy given the marked improvement in overall outcomes with modulating conditioning regimens and high-resolution HLA typing. A European Society for Blood and Marrow Transplantation (EBMT) analysis comparing matched sibling HSCT to MUD HSCT noted significantly higher rates of acute grade II-IV and grade III-IV GVHD (grade II-IV 13% versus 25%, grade III-IV 5% versus 10%) among patients undergoing MUD transplant.⁴⁷ Chronic GVHD rates were 14% in the sibling group, as compared to 26% in the MUD group. Factors associated with improved survival in this analysis include transplant under age 20 years (84% versus 72%), transplant within 6 months of diagnosis (85% versus 72%), the use of ATG in the conditioning regimen (81% versus 73%), and cytomegalovirus-negative donor and recipient as compared to other combinations (82% versus 76%).⁸⁷ Interestingly, this study demonstrated that OS was not significantly increased when using a sibling HSCT compared to a MUD HSCT, likely as a result of improved understanding of conditioning regimens, GVHD prophylaxis, and supportive care.

Additional studies of MUD HSCT have shown outcomes similar to those seen in sibling HSCT.^34,48 A French study found a significant increase in survival in patients undergoing MUD HSCT compared to historical cohorts (2000-2005: OS 52%; 2006-2012: OS 74%).⁷⁵ The majority of patients underwent conditioning with cyclophosphamide or a combination of busulfan and cyclophosphamide, with or without fludarabine; 81% of patients underwent in vivo T-cell depletion, and a bone marrow donor source was utilized. OS was significantly lower in patients over age 30 years undergoing MUD HSCT (57%) compared to those under age 30 years (70%). Improved OS was also seen when patients underwent transplant within 1 year of diagnosis and when a 10/10 matched donor (compared to a 9/10 mismatched donor) was utilized.⁴⁸

A 2015 study investigated the role of MUD HSCT as frontline therapy instead of immunosuppressive therapy in patients without a matched sibling donor.⁷⁵ The 2-year OS was 96% in the MUD HSCT cohort compared to 91%, 94%, and 74% in historical cohorts of sibling HSCT, frontline immunosuppressive therapy, and second-line MUD HSCT following failed immunosuppressive therapy, respectively. Additionally, event-free survival in the MUD HSCT cohort (defined by the authors as death, lack of response, relapse, occurrence of clonal evolution/clinical PNH, malignancies developing over follow‐up, and transplant for patients receiving immunosuppressive therapy frontline) was similar compared to sibling HSCT and superior to frontline immunosuppressive therapy and second-line MUD HSCT. Furthermore, Samarasinghe et al highlighted the importance of in vivo T-cell depletion with either ATG or alemtuzumab (anti-CD52 monoclonal antibody) in the prevention of acute and chronic GVHD in both sibling HSCT and MUD HSCT.⁸⁸

With continued improvement of less toxic and more immunomodulating conditioning regimens,utilization of bone marrow as a donor cell source, in vivo T-cell depletion, and use of GVHD and antimicrobial prophylaxis, more clinical evidence supports elevating MUD HSCT in the treatment plan for patients without a matched sibling donor.⁸⁹ However, there is still a large population of patients without matched sibling or unrelated donor options. Given the need to expand the transplant pool and thus avoid clonal hematopoiesis, clinically significant PNH, and relapsed aplastic anemia, more work continues to recognize the expanding role of alternative donor transplants (cord blood and haploidentical) as another viable treatment strategy for aplastic anemia after immunosuppressive therapy failure.⁹⁰

Summary

Aplastic anemia is a rare but potentially life-threatening disorder with pancytopenia and a marked reduction in the HSC compartment. It can be acquired or associated with an IMFS, and the treatment and prognosis vary dramatically between these 2 etiologies. Workup and diagnosis involves investigating IMFSs and ruling out malignant or infectious etiologies for pancytopenia. Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care.

Corresponding author: Gabrielle Meyers, MD, 3181 SW Sam Jackson Park Road, Mail Code UHN73C, Portland, OR 97239.

Financial disclosures: None.

From the Oregon Health and Science University, Portland, OR.

Abstract

• Objective: To describe the current approach to diagnosis and treatment of aplastic anemia.
• Methods: Review of the literature.
• Results: Aplastic anemia can be acquired or associated with an inherited marrow failure syndrome (IMFS), and the treatment and prognosis vary dramatically between these 2 etiologies. Patients may present along a spectrum, ranging from being asymptomatic with incidental findings on peripheral blood testing to life-threatening neutropenic infections or bleeding. Workup and diagnosis involves investigating IMFSs and ruling out malignant or infectious etiologies for pancytopenia.
• Conclusion: Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care for aplastic anemia.

Keywords: inherited marrow failure syndrome; Fanconi anemia; immunosuppression; transplant; stem cell.

Aplastic anemia is a clinical and pathological entity of bone marrow failure that causes progressive loss of hematopoietic progenitor stem cells (HPSC), resulting in pancytopenia.¹ Patients may present along a spectrum, ranging from being asymptomatic with incidental findings on peripheral blood testing to having life-threatening neutropenic infections or bleeding. Aplastic anemia results from either inherited or acquired causes, and the pathophysiology and treatment approach vary significantly between these 2 causes. Therefore, recognition of inherited marrow failure diseases, such as Fanconi anemia and telomere biology disorders, is critical to establishing the management plan. 

Epidemiology

Aplastic anemia is a rare disorder, with an incidence of approximately 1.5 to 7 cases per million individuals per year.^2,3 A recent Scandinavian study reported that the incidence of aplastic anemia among the Swedish population is 2.3 cases per million individuals per year, with a median age at diagnosis of 60 years and a slight female predominance (52% versus 48%, respectively).² This data is congruent with prior observations made in Barcelona, where the incidence was 2.34 cases per million individuals per year, albeit with a slightly higher incidence in males compared to females (2.54 versus 2.16, respectively).⁴ The incidence of aplastic anemia varies globally, with a disproportionate increase in incidence seen among Asian populations, with rates as high as 8.8 per million individuals per year.^3-5 This variation in incidence in Asia versus other countries has not been well explained. There appears to be a bimodal distribution, with incidence peaks seen in young adults and in older adults.^2,3,6

Pathophysiology

Acquired Aplastic Anemia

The leading hypothesis as to the cause of most cases of acquired aplastic anemia is that a dysregulated immune system destroys HPSCs. Inciting etiologies implicated in the development of acquired aplastic anemia include pregnancy, infection, medications, and exposure to certain chemicals, such as benzene.^1,7 The historical understanding of acquired aplastic anemia implicates cytotoxic T-lymphocyte–mediated destruction of CD34+ hematopoietic stem cells.^1,8,9 This hypothesis served as the basis for treatment of acquired aplastic anemia with immunosuppressive therapy, predominantly anti-thymocyte globulin (ATG) combined with cyclosporine A.^1,8 More recent work has focused on cytokine interactions, particularly the suppressive role of interferon (IFN)-γ on hematopoietic stem cells independent of T-lymphocyte–mediated destruction, which has been demonstrated in a murine model.⁸ The interaction of IFN-γ with the hematopoietic stem cell pool is dynamic. IFN-γ levels are elevated during an acute inflammatory response, such as a viral infection, providing further basis for the immune-mediated nature of the acquired disease.¹⁰ Specifically, in vitro studies suggest the effects of IFN-γ on HPSC may be secondary to interruption of thrombopoietin and its respective signaling pathways, which play a key role in hematopoietic stem cell renewal.¹¹ Eltrombopag, a thrombopoietin receptor antagonist, has shown promise in the treatment of refractory aplastic anemia, with studies indicating that its effectiveness is independent of IFN-γ levels.^11,12

Inherited Aplastic Anemia

The inherited marrow failure syndromes (IMFSs) are a group of disorders characterized by cellular maintenance and repair defects, leading to cytopenias, increased cancer risk, structural defects, and risk of end organ damage, such as liver cirrhosis and pulmonary fibrosis.^13-15 The most common diseases include Fanconi anemia, dyskeratosis congenita/telomere biology disorders, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome, but with the advent of whole exome sequencing, new syndromes continue to be discovered. While classically these disorders present in children, adult presentations are now commonplace. Broadly, the pathophysiology of inherited aplastic anemia relates to the defective HPSCs and an accelerated decline of the hematopoietic stem cell compartment.

The most common IMFSs, Fanconi anemia and telomere biology disorders, are associated with numerous mutations in DNA damage repair pathways and telomere maintenance pathways. TERT, DKC, and TERC mutations are most commonly associated with dyskeratosis congenita, but may also be found infrequently in patients with aplastic anemia presenting at an older age in the absence of the classic phenotypical features.^1,16,17 The recognition of an underlying genetic disorder or telomere biology disorder leading to constitutional aplastic anemia is significant, as these conditions are associated not only with marrow failure, but also with endocrinopathies, organ fibrosis, and and hematopoietic and solid organ malignancies.^13-15 In particular, TERT and TERC gene mutations have been associated with dyskeratosis congenita as well as pulmonary fibrosis and cirrhosis.^18,19 The implications of early diagnosis of an IMFS lie in the approach to treatment and prognosis.

Clonal Disorders and Secondary Malignancies

Myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) are 2 clonal disorders that may arise from a background of aplastic anemia.^9,20,21 Hypoplastic MDS can be difficult to differentiate from aplastic anemia at diagnosis based on morphology alone, although recent work has demonstrated that molecular testing for somatic mutations in ASXL1, DNMT3A, and BCOR can aid in differentiating a subset of aplastic anemia patients who are more likely to progress to MDS.²¹ Clonal populations of cells harboring 6p uniparental disomy are seen in more than 10% of patients with aplastic anemia on cytogenetic analysis, which can help differentiate the diseases.⁹ Yoshizato and colleagues found lower rates of ASXL1 and DNMT3A mutations in patients with aplastic anemia as compared with patients with MDS or AML. In this study, patients with aplastic anemia had higher rates of mutations in PIGA (reflecting the increased paroxysmal nocturnal hemoglobinuria [PNH] clonality seen in aplastic anemia) and BCOR.⁹ Mutations were also found in genes commonly mutated in MDS and AML, including TET2, RUNX1, TP53, and JAK2, albeit at lower frequencies.⁹ These mutations as a whole have not predicted response to therapy or prognosis. However, when performing survival analysis in patients with specific mutations, those commonly encountered in MDS/AML (ASXL1, DNMT3A, TP53, RUNX1, CSMD1) are associated with faster progression to overt MDS/AML and decreased overall survival (OS),^20,21 suggesting these mutations may represent early clonality that can lead to clonal evolution and the development of secondary malignancies. Conversely, mutations in BCOR and BCORL appear to identify patients who may have a favorable outcome in response to immunosuppressive therapy and, similar to patients with PIGA mutations, improved OS.⁹

Paroxysmal Nocturnal Hemoglobinuria

In addition to having an increased risk of myelodysplasia and malignancy due to the development of a dominant pre-malignant clone, patients with aplastic anemia often harbor progenitor cell clones associated with PNH.^1,17 PNH clones have been identified in more than 50% of patients with aplastic anemia.^22,23 PNH represents a clonal disorder of hematopoiesis in which cells harbor X-linked somatic mutations in the PIGA gene; this gene encodes a protein responsible for the synthesis of glycosylphosphatidylinositol anchors on the cell surface.^22,24 The lack of these cell surface proteins, specifically CD55 (also known as decay accelerating factor) and CD59 (also known as membrane inhibitor of reactive lysis), predisposes red cells to increased complement-mediated lysis.²⁵ The exact mechanism for the development of these clones in patients with aplastic anemia is not fully understood. Current theories hypothesize that the clones are protected from the immune-mediated destruction of normal hematopoietic stem cells due to the absence of the cell surface proteins.^1,20 The role of these clones over time in patients with aplastic anemia is less clear, though recent work demonstrated that despite differences in clonality over the disease course, aplastic anemia patients with small PNH clones are less likely to develop overt hemolysis and larger PNH clones compared to patients harboring larger (≥ 50%) PNH clones at diagnosis.^23,26,27 Additionally, PNH clones in patients with aplastic anemia infrequently become clinically significant.²⁷ It should be noted that these conditions exist along a continuum; that is, patients with aplastic anemia may develop PNH clones, while conversely patients with PNH may develop aplastic anemia.²⁰ Patients with PNH clones should be followed via peripheral blood flow cytometry and complete blood count to track clonal stability and identify clinically significant PNH among aplastic anemia patients.²⁸

Clinical Presentation

Patients with aplastic anemia typically are diagnosed either due to asymptomatic cytopenias found on peripheral blood sampling, symptomatic anemia, bleeding secondary to thrombocytopenia, or wound healing and infectious complications related to neutropenia.²⁹ A thorough history to understand the timing of symptoms, recent infectious symptoms/exposure, habits, and chemical or toxin exposures (including medications, travel, and supplements) helps guide diagnostic testing. Family history is also critical, with attention given to premature graying; pulmonary, renal, and liver disease; and blood disorders.

Patients with an IMFS (eg, Fanconi anemia or dyskeratosis congenita) may have associated phenotypical findings such as urogenital abnormalities or short stature; in addition, those with dyskeratosis congenita may present with the classic triad of oral leukoplakia, lacy skin pigmentation, and dystrophic nails.⁷ However, classic phenotypical findings may be lacking in up to 30% to 40% of patients with an IMFS.⁷ As described previously, while congenital malformations are common in Fanconi anemia and dyskeratosis congenita, a third of patients may have no or only subtle phenotypical abnormalities, including alterations in skin or hair pigmentation, skeletal and growth abnormalities, and endocrine disorders.³⁰ The International Fanconi Anemia Registry identified central nervous system, genitourinary, skin and musculoskeletal, ophthalmic, and gastrointestinal system malformations among children with Fanconi anemia.^31,32 Patients with dyskeratosis congenita may present with pulmonary fibrosis, hepatic cirrhosis, or premature graying, as highlighted in a recent study by DiNardo and colleagues.³³ Therefore, physicians must have a heightened index of suspicion in patients with subtle phenotypical findings and associated cytopenias.

The diagnosis of aplastic anemia should be suspected in any patient presenting with pancytopenia. Aplastic anemia is a diagnosis of exclusion.³⁴ Other conditions associated with peripheral blood pancytopenia should be considered, including infections (HIV, hepatitis, parvovirus B19, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus), nutritional deficiencies (vitamin B12, folate, copper, zinc), autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, hemophagocytic lymphohistiocytosis), hypersplenism, marrow-occupying diseases (eg, leukemia, lymphoma, MDS), solid malignancies, and fibrosis (Table).⁷

Diagnostic Evaluation

The workup for aplastic anemia should include a thorough history and physical exam to search simultaneously for alternative diagnoses and clues pointing to potential etiologic agents.⁷ Diagnostic tests to be performed include a complete blood count with differential, reticulocyte count, immature platelet fraction, flow cytometry (to rule out lymphoproliferative disorders and atypical myeloid cells and to evaluate for PNH), and bone marrow biopsy with subsequent cytogenetic, immunohistochemical, and molecular testing.³⁵ Typical findings in aplastic anemia include peripheral blood pancytopenia without dysplastic features and bone marrow biopsy demonstrating a hypocellular marrow.⁷ A relative lymphocytosis in the peripheral blood is common.⁷ In patients with a significant PNH clone, a macrocytosis along with elevated lactate dehydrogenase and elevated reticulocyte and granulocyte counts may be present.³⁶

The diagnosis (based on the Camitta criteria³⁷ and modified Camitta criteria³⁸ for severe aplastic anemia) requires 2 of the following findings on peripheral blood samples:

• Absolute neutrophil count (ANC) < 500 cells/µL
• Platelet count < 20,000 cells/µL
• Reticulocyte count < 1% corrected or < 20,000 cells/µL.³⁵

In addition to peripheral blood findings, bone marrow biopsy is essential for the diagnosis, and should demonstrate a markedly hypocellular marrow (cellularity < 25%), occasionally with an increase in T lymphocytes.^7,39 Because marrow cellularity varies with age and can be challenging to assess, additional biopsies may be needed to confirm the diagnosis.²⁹ A 1- to 2-cm core biopsy is necessary to confirm hypocellularity, as small areas of residual hematopoiesis may be present and obscure the diagnosis.³⁵

Excluding Hypocellular MDS and IMFS

Excluding hypocellular MDS is challenging, especially in the older adult presenting with aplastic anemia, as patients with aplastic anemia may have some degree of erythroid dysplasia on bone marrow morphology.³⁶ The presence of a PNH clone on flow cytometry can aid in diagnosing aplastic anemia and excluding MDS,³⁴ although PNH clones can be present in refractory anemia MDS. Patients with aplastic anemia have a lower ratio of CD34+ cells compared to those with hypoplastic MDS, with 1 study demonstrating a mean CD34+ percentage of < 0.5% in aplastic anemia versus 3.7% in hypoplastic MDS.⁴⁰ Cytogenetic and molecular testing can also aid in making this distinction by identifying mutations commonly implicated in MDS.⁷ The presence of monosomy 7 (-7) in aplastic anemia patients is associated with a poor overall prognosis.^34,41

Peripheral blood screening using chromosome breakage analysis (done using either mitomycin C or diepoxybutane as in vitro DNA-crosslinking agents)⁴² and telomere length testing (of peripheral blood leukocytes) is necessary to exclude the main IMFSs, Fanconi anemia and telomere biology disorders, respectively. Ruling out these conditions is imperative, as the approach to treatment varies significantly between IMFS and aplastic anemia. Patients with shortened telomeres should undergo genetic screening for mutations in the telomere maintenance genes to evaluate the underlying defect leading to shortened telomeres. Patients with increased peripheral blood breakage should have genetic testing to detect mutations associated with Fanconi anemia.

Classification

Once the diagnosis of aplastic anemia has been made, the patient should be classified according to the severity of their disease. Disease severity is determined based on peripheral blood ANC: non-severe aplastic anemia (NSAA), ANC > 500 polymorphonuclear neutrophils (PMNs)/µL; severe aplastic anemia (SAA), 200–500 PMNs/µL; and very severe aplastic anemia (VSAA), 0–200 PMNs/µL.^4,34 Disease classification is important, as VSAA is associated with a decreased OS compared to SAA.² Disease classification may affect treatment decisions, as patients with NSAA may be observed for a short period of time, while, conversely, patients with SAA have a worse prognosis with delays in therapy.^43-45

Treatment of Inherited Aplastic Anemia

First-line treatment options for patients with IMFS are androgen therapy and hematopoietic stem cell transplant (HSCT). When evaluating patients for HSCT, it is critical to identify the presence of an IMFS, as the risk and mortality associated with the conditioning regimen, stem cell source, graft-versus-host disease (GVHD), and secondary malignancies differ between patients with IMFS and those with acquired marrow failure syndromes or hematologic malignancies.

Potential sibling donors need to be screened for donor candidacy as well as for the inherited defect. Among patients with Fanconi anemia or a telomere biology disorder, the stem cell source must be considered, with multiple studies in IMFSs and SAA showing superior outcomes with a bone marrow product compared to peripheral blood stem cells.^46-48 In IMFS patients, the donor cell type may affect the choice of conditioning regimen.^5,6 Reduced-intensity conditioning in lieu of myeloablative conditioning without total body irradiation has proved feasible in patients with Fanconi anemia, and is associated with a reduced risk of secondary malignancies.^49,50 Incorporation of fludarabine in the conditioning regimen of patients without a matched sibling donor is associated with superior engraftment and survival^46,49,51 compared to cyclophosphamide conditioning, which was historically used in matched related donors.^50,52  Adding fludarabine appears to be especially beneficial in older patients, in whom its use is associated with lower rates of graft failure, likely due to increased immunosuppression at the time of engraftment.^51,53 Fludarabine has also been incorporated into conditioning regimens for patients with a telomere biology disorder, but outcomes data are limited.⁵

For patients presenting with AML or a high-risk MDS who are subsequently diagnosed with an IMFS, treatment can be more complex, as these patients are at high risk for toxicity from standard chemotherapy. Limited data suggest that induction therapy and transplantation are feasible in this group of patients, and this approach is associated with increased OS, despite lower OS rates than those of IMFS patients who present prior to the development of MDS or AML.^54,55 Further work is needed to determine the optimal induction regimen that balances the risks of treatment-related mortality and complications associated with conditioning regimens, risk of relapse, and risk of secondary malignancies, especially in the cohort of patients diagnosed at an older age.

Treatment of Acquired Aplastic Anemia

Supportive Care

While the workup and treatment plan are being established, attention should be directed at supportive care for prevention of complications. The most common complications leading to death in patients with significant pancytopenia and neutropenia are opportunistic infections and hemorrhagic complications.²

Transfusion support is critical to avoid symptomatic anemia and hemorrhagic complications related to thrombocytopenia, which typically occur with platelet counts lower than 10,000 cells/µL. However, transfusion carries the risk of alloimmunization (which may persist for years following transfusion) and transfusion-related graft versus host disease (trGVHD), and thus use of transfusion should be minimized when possible.^56,57 All blood products given to patients with aplastic anemia should be irradiated and leukoreduced to reduce the risk of both alloimmunization and trGVHD. Guidelines from the British Society for Haematology recommend routine screening for Rh and Kell antibodies to reduce the risk of alloimmunization.⁵⁸ Infectious complications remain a common cause of morbidity and mortality in patients with aplastic anemia who have prolonged neutropenia (defined as an ANC < 500 cells/µL).^59-62 Therefore, patients should receive broad-spectrum antibiotics with antipseudomonal coverage. In a study evaluating the role of granulocyte-colony stimulating factor (G-CSF) in patients with SAA receiving immunosuppressive therapy, 55% of all patient deaths were secondary to infection.⁶³ There was no OS benefit seen in patients who received G-CSF, though a significantly lower rate of infection was observed in the G-CSF arm compared to those not receiving G-CSF (56% versus 81%, P = 0.006). This difference was largely driven by a decrease in infectious episodes in patients with VSAA treated with G-CSF as compared to those who did not receive this therapy (22% versus 48%, P = 0.014).⁶³

Angio-invasive pulmonary aspergillosis and Zygomycetes (eg, Rhizopus, Mucor species) remain major causes of mortality related to opportunistic mycotic infections in patients with aplastic anemia.¹⁸ The infectious risk is directly related to the duration and severity of neutropenia, with one study demonstrating a significant increase in risk in AML patients with neutropenia lasting longer than 3 weeks.⁶⁴ Invasive fungal infections carry a high mortality in patients with severe neutropenia, though due to earlier recognition and empiric antifungal therapy with extended-spectrum azoles, overall mortality secondary to invasive fungal infections is declining.^62,65

While neutropenia related to cytotoxic chemotherapy is commonly associated with gram-negative bacteria due to disruption of mucosal barriers, patients with aplastic anemia have an increased incidence of gram-positive bacteremia with staphylococcal species compared to other neutropenic populations.^61,62 This appears to be changing with time. Valdez et al demonstrated a decrease in prevalence of coagulase-negative staphylococcal infections, increased prevalence of gram-positive bacilli bacteremia, and no change in prevalence of gram-negative bacteremia in patients with aplastic anemia treated between 1989 and 2008.⁶⁵ Gram-negative bacteremia caused by Stenotrophomonas maltophila, Escherichia coli, Klebsiella pneumoniae, Citrobacter, and Proteus has also been reported.⁶² Despite a lack of clinical trials investigating the role of antifungal and antibacterial prophylaxis for patients with aplastic anemia, most centers initiate antifungal prophylaxis in patients with SAA or VSAA with an anti-mold agent such as voriconazole or posaconazole (which has the additional benefit compared to voriconazole of covering Mucor species).^60,66 This is especially true for patients who have received ATG or undergone HSCT. For antimicrobial prophylaxis, a fluoroquinolone antibiotic with a spectrum of activity against Pseudomonas should be considered for patients with an ANC < 500 cells/µL.⁶⁰ Acyclovir or valacyclovir prophylaxis is recommended for varicella-zoster virus and herpes simplex virus. Cytomegalovirus reactivation is minimal in patients with aplastic anemia, unless multiple courses of ATG are used.

Iron overload is another complication the provider must be aware of in the setting of increased transfusions in aplastic anemia patients. Lee and colleagues showed that iron chelation therapy using deferasirox is effective at reducing serum ferritin levels in patients with aplastic anemia (median ferritin level of 3254 ng/mL prior to therapy, 1854 ng/mL following), and is associated with no serious adverse events (most common adverse events included nausea, diarrhea, vomiting, and rash).⁶⁷ Approximately 25% of patients in this trial had an increase in creatinine, with patients taking concomitant cyclosporine affected to a greater degree than those on chelation therapy alone. For patients following HSCT or with improved hematopoiesis following immunosuppressive therapy, phlebotomy can be used to treat iron overload in lieu of chelation therapy.⁵⁸

Approach to Therapy

The main treatment options for SAA and VSAA include allogeneic bone marrow transplant and immunosuppression. The deciding factors as to which treatment is best initially depends on the availability of HLA-matched related donors and age (Figure 1 and Figure 2). Survival is decreased in patients with SAA or VSAA who delay initiation of therapy, and therefore prompt referral for HLA typing and evaluation for bone marrow transplant is a very important first step in managing aplastic anemia.

Matched Sibling Donor Transplant. Current standards of care recommend HLA-matched sibling donor transplant for patients with SAA or VSAA who are younger than 50 years, with the caveat that integration of fludarabine and reduced cyclophosphamide dosing along with ATG shows the best overall outcomes. Locasciulli and colleagues examined outcomes in patients given either immunosuppressive therapy or sibling HSCT between 1991-1996 and 1997-2002, respectively, and found that sibling HSCT was associated with a superior 10-year OS compared to immunosuppressive therapy (73% versus 68%).⁴³ Interestingly in this study, there was no OS improvement seen with immunosuppressive therapy alone (69% versus 73%) between the 2 time periods, despite increased OS in both sibling HSCT (74% and 80%) and MUD HSCT (38% and 65%).⁴³ Though total body irradiation has been used in the past, it is typically not included in current conditioning regimens for matched related donor transplants.⁶⁸

Current conditioning regimens typically use a combination of cyclophosphamide and ATG,^69,70 with or without fludarabine. Fludarabine-based conditioning regimens have shown promise in patients undergoing sibling HSCT. Maury and colleagues evaluated the role of fludarabine in addition to low-dose cyclophosphamide and ATG compared to cyclophosphamide alone or in combination with ATG in patients over age 30 undergoing sibling HSCT.⁵³ There was a nonsignificant improvement in 5-year OS in the fludarabine arm compared to controls (77% ± 8% versus 60% ± 3%, P = 0.14) in the pooled analysis, but when adjusted for age the fludarabine arm had a significantly lower relative risk (RR) of death (0.44; P = 0.04) compared to the control arm. Shin et al reported outcomes with fludarabine/cyclophosphamide/ATG, with excellent overall outcomes and no difference in patients older or younger than 40 years.⁷¹

Kim et al evaluated their experience with patients older than 40 years receiving matched related donors, finding comparable outcomes in those ages 41 to 50 years compared to younger patients. Outcomes declined in those over the age of 50 years.⁷² Long-term data for matched related donor transplant for aplastic anemia show excellent long-term outcomes, with minimal chronic GVHD and good performance status.⁷³ Hence, these factors support the role of matched related donor transplant as the initial treatment in SAA and VSAA.

Regarding the role of transplant for patients who lack a matched related donor, a growing body of literature demonstrating identical outcomes between matched related and MUD transplants for pediatric patients^74,75 supports recent recommendations for upfront unrelated donor transplantation for aplastic anemia.^76,77

Immunosuppressive Therapy. For patients without an HLA-matched sibling donor or those who are older than 50 years of age, immunosuppressive therapy is the first-line therapy. ATG and cyclosporine A are the treatments of choice.⁷⁸ The potential effectiveness of immunosuppressive therapy in treating aplastic anemia was initially observed in patients in whom autologous transplant failed but who still experienced hematopoietic reconstitution despite the failed graft; this observation led to the hypothesis that the conditioning regimen may have an effect on hematopoiesis.^59,78,79

Immunosuppressive therapy with ATG has been used for the treatment of aplastic anemia since the 1980s.⁸⁰ Historically, rabbit ATG had been used, but a 2011 study of horse ATG demonstrated superior hematological response at 6 months compared to rabbit ATG (68% versus 37%).⁵⁹ Superior survival was also seen with horse ATG compared to rabbit ATG (3-year OS, 96% versus 76%). Due to these results, horse ATG is preferred over rabbit ATG. ATG should be used in combination with cyclosporine A to optimize outcomes.

Early studies also demonstrated the efficacy of cyclosporine A in the treatment of aplastic anemia, with response rates equivalent to that of ATG monotherapy.⁸¹ Recent publications still note the efficacy of cyclosporine A in the treatment of aplastic anemia. Its role as an affordable option for single-agent therapy in developing countries is intriguing.⁸¹ The combination of ATG and cyclosporine A was proven superior to either agent alone in a study by Frickhofen et al.⁷⁹ In this study, patients were randomly assigned to a control arm that received ATG plus methylprednisolone or to an arm that received ATG plus cyclosporine A and methylprednisolone. At 6 months, 70% of patients in the cyclosporine A arm had a complete remission (CR) or partial remission compared to 46% in the control arm.⁸² Further work confirmed the long-term efficacy of this regimen, reporting a 7-year OS of 55%.⁸³ Among a pediatric population, immunosuppressive therapy was associated with an 83% 10-year OS.⁸⁴

It is recommended that patients remain on cyclosporine therapy for a minimum of 6 months, after which a gradual taper may be considered, although there is variation among practitioners, with some continuing immunosuppressive therapy for a minimum of 12 months due to a proportion of patients being cyclosporine dependent.^34,84 A study found that within a population of patients who responded to immunosuppressive therapy, 18% became cyclosporine dependent.⁸⁴ The median duration of cyclosporine A treatment at full dose was 12 months, with tapering completed over a median of 19 months after patients had been in a stable CR for a minimum of 3 months. Relapse occurred more often when patients were tapered quickly (decrease ≥ 0.8 mg/kg/month) compared to slowly (0.4-0.7 mg/kg/month) or very slowly (< 0.3 mg/kg/month).

Townsley and colleagues recently investigated incorporating the use of the thrombopoietin receptor agonist eltrombopag with immunosuppressive therapy as first-line therapy in aplastic anemia.⁸⁵ When given at a dose of 150 mg daily in patients ages 12 years and older or 75 mg daily in patients younger than 12 years, in conjunction with cyclosporine A and ATG, patients demonstrated markedly improved hematological response compared to historical treatment with standard immunosuppressive therapy alone.⁴⁵ In the patient cohort administered eltrombopag starting on day 1 and continuing for 6 months, the complete response rate was 58%. Eltrombopag led to improvement in all cell lines among all treatment subgroups, and OS (censored for patients who proceeded to transplant) was 99% at 2 years.¹² Overall, toxicities associated with this therapy were low, with liver enzyme elevations most commonly observed.⁸⁵ Recently, a phase 2 trial of immunosuppressive therapy with or without eltrombopag was reported. Of the 38 patients enrolled, overall response, complete response, and time to response were not statistically different.⁸⁶ With this recent finding, the role of eltrombopag in addition to immunosuppressive therapy is not clearly defined, and further studies are warranted.

OS for patients who do not respond to immunosuppressive therapy is approximately 57% at 5 years, largely due to improved supportive measures among this patient population.^48,65 Therefore, it is important to recognize those patients who have a low chance of response so that second-line therapy can be pursued to improve outcomes.

Matched Unrelated Donor Transplant. For patients with refractory disease following immunosuppressive therapy who lack a matched sibling donor, MUD HSCT is considered standard therapy given the marked improvement in overall outcomes with modulating conditioning regimens and high-resolution HLA typing. A European Society for Blood and Marrow Transplantation (EBMT) analysis comparing matched sibling HSCT to MUD HSCT noted significantly higher rates of acute grade II-IV and grade III-IV GVHD (grade II-IV 13% versus 25%, grade III-IV 5% versus 10%) among patients undergoing MUD transplant.⁴⁷ Chronic GVHD rates were 14% in the sibling group, as compared to 26% in the MUD group. Factors associated with improved survival in this analysis include transplant under age 20 years (84% versus 72%), transplant within 6 months of diagnosis (85% versus 72%), the use of ATG in the conditioning regimen (81% versus 73%), and cytomegalovirus-negative donor and recipient as compared to other combinations (82% versus 76%).⁸⁷ Interestingly, this study demonstrated that OS was not significantly increased when using a sibling HSCT compared to a MUD HSCT, likely as a result of improved understanding of conditioning regimens, GVHD prophylaxis, and supportive care.

Additional studies of MUD HSCT have shown outcomes similar to those seen in sibling HSCT.^34,48 A French study found a significant increase in survival in patients undergoing MUD HSCT compared to historical cohorts (2000-2005: OS 52%; 2006-2012: OS 74%).⁷⁵ The majority of patients underwent conditioning with cyclophosphamide or a combination of busulfan and cyclophosphamide, with or without fludarabine; 81% of patients underwent in vivo T-cell depletion, and a bone marrow donor source was utilized. OS was significantly lower in patients over age 30 years undergoing MUD HSCT (57%) compared to those under age 30 years (70%). Improved OS was also seen when patients underwent transplant within 1 year of diagnosis and when a 10/10 matched donor (compared to a 9/10 mismatched donor) was utilized.⁴⁸

A 2015 study investigated the role of MUD HSCT as frontline therapy instead of immunosuppressive therapy in patients without a matched sibling donor.⁷⁵ The 2-year OS was 96% in the MUD HSCT cohort compared to 91%, 94%, and 74% in historical cohorts of sibling HSCT, frontline immunosuppressive therapy, and second-line MUD HSCT following failed immunosuppressive therapy, respectively. Additionally, event-free survival in the MUD HSCT cohort (defined by the authors as death, lack of response, relapse, occurrence of clonal evolution/clinical PNH, malignancies developing over follow‐up, and transplant for patients receiving immunosuppressive therapy frontline) was similar compared to sibling HSCT and superior to frontline immunosuppressive therapy and second-line MUD HSCT. Furthermore, Samarasinghe et al highlighted the importance of in vivo T-cell depletion with either ATG or alemtuzumab (anti-CD52 monoclonal antibody) in the prevention of acute and chronic GVHD in both sibling HSCT and MUD HSCT.⁸⁸

With continued improvement of less toxic and more immunomodulating conditioning regimens,utilization of bone marrow as a donor cell source, in vivo T-cell depletion, and use of GVHD and antimicrobial prophylaxis, more clinical evidence supports elevating MUD HSCT in the treatment plan for patients without a matched sibling donor.⁸⁹ However, there is still a large population of patients without matched sibling or unrelated donor options. Given the need to expand the transplant pool and thus avoid clonal hematopoiesis, clinically significant PNH, and relapsed aplastic anemia, more work continues to recognize the expanding role of alternative donor transplants (cord blood and haploidentical) as another viable treatment strategy for aplastic anemia after immunosuppressive therapy failure.⁹⁰

Summary

Aplastic anemia is a rare but potentially life-threatening disorder with pancytopenia and a marked reduction in the HSC compartment. It can be acquired or associated with an IMFS, and the treatment and prognosis vary dramatically between these 2 etiologies. Workup and diagnosis involves investigating IMFSs and ruling out malignant or infectious etiologies for pancytopenia. Treatment outcomes are excellent with modern supportive care and the current approach to allogeneic transplantation, and therefore referral to a bone marrow transplant program to evaluate for early transplantation is the new standard of care.

Corresponding author: Gabrielle Meyers, MD, 3181 SW Sam Jackson Park Road, Mail Code UHN73C, Portland, OR 97239.

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX (Drs. Narayanan, Lopez, Chaoul, Liu, Milbury, and Cohen, and Ms. Mallaiah); the University of Texas Health Science Center at Tyler (Dr. Meegada); and Texas Tech University Health Sciences Center, Lubbock, TX (Ms. Francisco).

Abstract

• Objective: To review the effects of yoga as an adjunct supportive care modality alongside conventional cancer treatment on quality of life (QOL), physical and mental health outcomes, and physiological and biological measures of cancer survivors.
• Methods: Nonsystematic review of the literature.
• Results: Yoga therapy, one of the most frequently used mind-body modalities, has been studied extensively in cancer survivors (from the time of diagnosis through long-term recovery). Yoga affects human physiology on multiple levels, including psychological outcomes, immune and endocrine function, and cardiovascular parameters, as well as multiple areas of QOL. It has been found to reduce psychological stress and fatigue and improve QOL in cancer patients and survivors. Yoga has also been used to manage symptoms such as arthralgia, fatigue, and insomnia. In addition, yoga offers benefits not only for cancer survivors but also for their caregivers.
• Conclusion: As part of an integrative, evidence-informed approach to cancer care, yoga may provide benefits that support the health of cancer survivors and caregivers.

Keywords: fatigue; cancer; proinflammatory cytokines; integrative; mind-body practices; meditation; DNA damage; stress; psychoneuro-immunoendocrine axis; lymphedema; insomnia.

A diagnosis of cancer and adverse effects related to its treatment may have negative effects on quality of life (QOL), contributing to emotional and physical distress in patients and caregivers. Many patients express an interest in pursuing nonpharmacological options, alone or as an adjunct to conventional therapy, to help manage symptoms. The use of complementary medicine approaches to health, including nonpharmacological approaches to symptom management, is highest among individuals with cancer.¹ According to a published expert consensus, integrative oncology is defined as a “patient-centered, evidence-informed field of cancer care that utilizes mind and body practices, natural products, and/or lifestyle modifications from different traditions alongside conventional cancer treatments. Integrative oncology aims to optimize health, QOL, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and become active participants before, during, and beyond cancer treatment.”² A key component of this definition, often misunderstood in the field of oncology, is that these modalities and treatments are used alongside conventional cancer treatments and not as an alternative. In an attempt to meet patients’ needs and appropriately use these approaches, integrative oncology programs are now part of most cancer centers in the United States.^3-6

Because of their overall safety, mind-body therapies are commonly used by patients and recommended by clinicians. Mind-body therapies include yoga, tai chi, qigong, meditation, and relaxation. Expressive arts such as journaling and music, art, and dance therapies also fall in the mind-body category.⁷ Yoga is a movement-based mind-body practice that focuses on synchronizing body, breath, and mind. Yoga has been increasingly used by patients for health benefits,⁸ and numerous studies have evaluated yoga as a complementary intervention for individuals with cancer.^9-14 Here, we review the physiological basis of yoga in oncology and the effects of yoga on biological processes, QOL, and symptoms during and after cancer treatment.

Physiological Basis

Many patients may use mind-body programs such as yoga to help manage the psychological and physiological consequences of unmanaged chronic stress and improve their overall QOL. The central nervous system, endocrine system, and immune system influence and interact with each other in a complex manner in response to chronic stress.^15,16 In a stressful situation, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are activated. HPA axis stimulation leads to adrenocorticotrophic hormone production by the pituitary gland, which releases glucocorticoid hormones. SNS axis stimulation leads to epinephrine and norepinephrine production by the adrenal gland.^17,18 Recently, studies have explored modulation of signal transduction between the nervous and immune systems and how that may impact tumor growth and metastasis.¹⁹ Multiple studies, controlled for prognosis, disease stage, and other factors, have shown that patients experiencing more distress or higher levels of depressive symptoms do not live as long as their counterparts with low distress or depression levels.²⁰ Both the meditative and physical components of yoga can lead to enhanced relaxation, reduced SNS activation, and greater parasympathetic tone, countering the negative physiological effects of chronic stress. The effects of yoga on the HPA axis and SNS, proinflammatory cytokines, immune function, and DNA damage are discussed below.

Biological Processes

Nervous System

The effects of yoga and other forms of meditation on brain functions have been established through several studies. Yoga seems to influence basal ganglia function by improving circuits that are involved in complex cognitive functions, motor coordination, and somatosensory and emotional processes.^21,22 Additionally, changes in neurotransmitter levels have been observed after yoga practice. For instance, in a 12-week yoga intervention in healthy subjects, increased levels of thalamic gamma-aminobutyric acid (GABA) in the yoga group were reported to have a positive correlation with improved mood and decreased anxiety compared with a group who did metabolically matched walking exercise.²³ Levels of GABA, an inhibitory neurotransmitter, are decreased in conditions such as anxiety, depression, and epilepsy.²⁴ Yoga therapy has been shown to improve symptoms of mood disorders and epilepsy, which leads to the hypothesis that the mechanism driving the benefits of yoga may work through stimulation of vagal efferents and an increase in GABA-mediated cortical-inhibitory tone.^24,25

Stress activates the HPA/SNS axis, which releases hormones such as cortisol and norepinephrine. These hormones may play a role in angiogenesis, inflammation, immune suppression, and other physiological functions, and may even reduce the effect of chemotherapeutic agents.^26,27 Regular yoga practice has been shown to reduce SNS and HPA axis activity, most likely by increasing parasympathetic dominance through vagal stimulation, as demonstrated through increases in heart rate variability.²⁸ One indicator of HPA axis dysregulation, diurnal salivary cortisol rhythm, was shown to predict survival in patients with advanced breast and renal cancer.^29-33 Yoga has been shown to lead to less cortisol dysregulation due to radiotherapy and to reductions in mean cortisol levels and early morning cortisol levels in breast cancer patients undergoing radiotherapy.³⁴ This lends support to the hypothesis that yoga helps restore HPA axis balance.

Proinflammatory Cytokines

Cancer patients tend to have increased levels of inflammatory markers such as interleukin (IL)-4, IL-10, tumor necrosis factor (TNF), interferon-γ, and C-reactive protein. This increase in inflammation is associated with worse outcomes in cancer.³⁵ This association becomes highly relevant because the effect of inflammation on host cells in the tumor microenvironment is connected to disease progression.²⁶ Inflammatory cytokines are also implicated in cancer-related symptoms such as fatigue, cognitive dysfunction, peripheral neuropathy, and sleep disturbances.³⁶

Yoga is known to reduce stress and may directly or indirectly decrease inflammatory cytokines. A randomized clinical trial of a 12-week hatha yoga intervention among breast cancer survivors demonstrated decreases in IL-6, IL-1β, TNF, corticotropin-releasing factor, and cognitive complaints in the yoga group compared with those in the standard care group after 3 months.^37,38 Furthermore, Carlson et al showed that, after mindfulness-based stress reduction involving a combination of gentle yoga, meditation techniques, and relaxation exercises, breast and prostate cancer patients had reduced levels of proinflammatory cytokines and cortisol.³⁹ These reductions translated into patients reporting decreased stress levels and enhanced QOL.

Immune Function

The effects of yoga practice on the immune system have been studied in both healthy individuals and individuals with cancer. The effects on T and B lymphocytes, natural killer (NK) cells, and other immune effector cells demonstrate that meditation and yoga have beneficial effects on immune activity.⁴⁰ Hormones such as catecholamines and glucocorticoids are thought to influence the availability and function of NK cells, and, as noted above, yoga has been shown to modulate stress hormones and lead to reduced immune suppression in patients with early-stage breast cancer undergoing chemotherapy.⁴¹ Additional evidence supports the ability of yoga to reduce immune suppression in the postsurgical setting, with no observed decrease in NK cell percentage after surgery for those in a yoga group compared with a control group.⁴² This finding is relevant to patients undergoing surgical management of their cancer and highlights the impact of yoga on the immune system.

DNA Damage

Radiation damages DNA in the peripheral blood lymphocytes of patients undergoing treatment.^43,44 This damage is significant in breast cancer patients undergoing radiotherapy.⁴⁵ Stress additionally causes DNA damage⁴⁶ and is correlated to impaired DNA repair capacity.^47,48 In a study conducted by Banerjee et al, breast cancer patients were randomly assigned to a yoga group or a supportive therapy group for 6 weeks during radiotherapy.⁴⁹ Prior to the intervention, patients in the study had significant genomic instability. After treatment, patients in the yoga group experienced not only a significant reduction in anxiety and depression levels, but also a reduction in DNA damage due to radiotherapy.

There is evidence showing that yoga therapy improves multiple aspects of QOL, including physical functioning, emotional health outcomes, and the symptoms cancer patients may experience, such as sleep disturbances, fatigue, and pain. Danhauer et al systematically reviewed both nonrandomized trials and randomized controlled trials involving yoga during cancer treatment.⁵⁰ They found that yoga improved depression and anxiety as well as sleep and fatigue. Benefits of yoga in cancer based on randomized controlled trials are summarized in the Table. The role of yoga in improving QOL and managing symptoms patients experience during and after treatment is discussed in the following sections.

Quality of Life

Danhauer et al’s systematic review of trials involving yoga during cancer treatment found that yoga improved multiple aspects of QOL.⁵⁰ For example, yoga has been shown to improve QOL in breast cancer patients undergoing radiotherapy. In a study by Chandwani et al, yoga (60-minute sessions twice a week for 6 weeks) was associated with better general health perception and physical functioning scores as well as greater benefit finding, or finding meaning in their experience, after radiotherapy compared with a wait-list group.⁵¹ The yoga group had an increase in intrusive thoughts, believed to be due to a more thorough processing of the cancer experience, which helps to improve patients’ outlook on life.⁵² The benefits of yoga extend beyond psychological measures during radiation treatment. Yoga was found to increase physical functioning compared with stretching in breast cancer patients undergoing radiotherapy.⁵³

Cognitive Function

Cancer-related cognitive impairment commonly occurs during cancer treatments (eg, chemotherapy, radiotherapy, surgery, hormone therapy) and persists for months or years in survivors.⁵⁴ Impairment of memory, executive function, attention, and concentration are commonly reported. In a trial of a combined hatha and restorative yoga program called Yoga for Cancer Survivors (YOCAS), which was designed by researchers at the University of Rochester, patients in the yoga arm had less memory difficulty than did patients in the standard care arm.⁵⁵ However, the primary aim of the trial was to treat insomnia, so this secondary outcome needs to be interpreted with caution. Deficits in attention, memory, and executive function are often seen in cancer-related cognitive impairment, and the meditative aspect of yoga may have behavioral and neurophysical benefits that could improve cognitive functions.⁵⁶ More evidence is needed to understand the role of yoga in improving cognitive functioning.

Emotional Health

Psychosocial stress is high among breast cancer patients and survivors.^57,58 This causes circadian rhythm and cortisol regulation abnormalities, which are reported in women with breast cancer.^59-64 Yoga is known to help stress and psychosocial and physical functioning in patients with cancer.⁶⁵ Yoga was also shown to be equivalent to cognitive behavioral therapy in stress management in a population of patients without cancer.⁶⁶ Daily yoga sessions lasting 60 minutes were shown to reduce reactive anxiety and trait anxiety in early-stage breast cancer patients undergoing conventional radiotherapy and chemotherapy compared with patients receiving supportive therapy, highlighting the role of yoga in managing anxiety related to treatment.⁶⁷ In a study done by Culos-Reed et al, 20 cancer survivors who did 75 minutes of yoga per week for 7 weeks were compared with 18 cancer survivors who served as a control group.⁶⁸ The intervention group reported significant improvement in emotional well-being, depression, concentration, and mood disturbances. In a longitudinal study by Mackenzie et al, 66 cancer survivors completed a 7-week yoga program and were assessed at baseline, immediately after the final yoga session, and at 3 and 6 months after the final session.⁶⁹ Participants had significantly improved energy levels and affect. They also had moderate improvement in mindfulness and a moderate decrease in stress. Breast cancer patients who underwent restorative yoga sessions found improvements in mental health, depression, positive affect, and spirituality (peace/meaning).⁷⁰ This was more pronounced in women with higher negative affect and lower emotional well-being at baseline. In a study of patients with ovarian cancer receiving chemotherapy, patients were instructed to perform up to 15-minute sessions including awareness, body movement, and breathing.⁷¹ Even with just 1 session of yoga intervention, patients experienced decreased anxiety.

Fatigue

Studies on yoga show improvement in fatigue both during and after treatment. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit cognitive fatigue.⁷² Older cancer survivors also seem to benefit from yoga interventions.⁷³ In a trial of a DVD-based yoga program, the benefits of yoga were similar to those of strengthening exercises, and both interventions helped decrease fatigue and improve QOL during the first year after diagnosis in early-stage breast cancer patients with cancer-related fatigue.⁷⁴ Bower et al also showed that, for breast cancer survivors experiencing persistent chronic fatigue, a targeted yoga intervention led to significant improvements in fatigue and vigor over a 3-month follow-up compared with controls.⁷⁵ Fatigue is commonly seen in breast cancer patients who are receiving adjuvant chemotherapy. In a study by Taso et al, women with breast cancer receiving chemotherapy were assigned to 60-minute yoga sessions incorporating Anusara yoga, gentle stretching, and relaxation twice a week for 8 weeks.⁷⁶ By week 4, patients with low pretest fatigue in the yoga group experienced a reduction in fatigue. By week 8, all patients in the yoga group experienced a reduction in fatigue. Four weeks after the yoga intervention, patients in the group maintained the reduction in fatigue. This study shows the feasibility of an 8-week yoga program for women undergoing breast cancer therapy by improving fatigue. Yoga recently was added to National Comprehensive Cancer Network (NCCN) guidelines for management of cancer-related fatigue (level 1 evidence).⁷⁷ However, the evidence was based on studies in women with breast cancer and survivors; therefore, more studies are needed in men and women with other cancers.

Distress surrounding surgery in patients with breast cancer can impact postoperative outcomes. Yoga interventions, including breathing exercises, regulated breathing, and yogic relaxation techniques, improved several postsurgical measures such as length of hospital stay, drain retention, and suture removal.⁷⁸ In this study, patients who practiced yoga also experienced a decrease in plasma TNF and better wound healing. Symptoms of anxiety and distress that occur preoperatively can lead to impaired immune function in addition to decreased QOL. In a study of yoga in early-stage breast cancer patients undergoing surgery, the benefit of yoga was seen not only with stress reduction but also with immune enhancement.⁴²

Yoga has been shown to help alleviate acute pain and distress in women undergoing major surgery for gynecological cancer. A regimen of 3 15-minute sessions of yoga, including awareness meditation, coordination of breath with movement, and relaxation breathing, was shown to reduce acute pain and distress in such patients in an inpatient setting.⁷⁹

Menopausal Symptoms

Breast cancer survivors have more severe menopausal symptoms compared with women without cancer.^80,81 Hot flashes cause sleep disturbances and worsen fatigue and QOL.⁸² Tamoxifen and aromatase inhibitors significantly worsen menopausal symptoms such as hot flashes.⁸¹ Carson et al conducted a study of yoga that included postures, breathing techniques, didactic presentations, and group discussions.⁸³ The yoga awareness regimen consisted of 8 weekly 120-minute group classes. Patients in the yoga arm had statistically significant improvements in the frequency, severity, and number of hot flashes. There were also improvements in arthralgia (joint pain), fatigue, sleep disturbance, vigor, and acceptance.

Arthralgia

Joint pain can be a major side effect that interferes with daily functions and activities in postmenopausal breast cancer survivors who receive aromatase inhibitor therapy.⁸⁴ Arthralgia is reported in up to 50% of patients treated with aromatase inhibitors.^84,85 It can affect functional status and lead to discontinuation of aromatase inhibitor therapy, jeopardizing clinical outcomes.⁸⁶ Yoga as a complementary therapy has been shown to improve conditions such as low back pain⁸⁷ and knee osteoarthritis⁸⁸ in patients who do not have cancer. In a single-arm pilot trial by Galantino et al, breast cancer patients with aromatase inhibitor–related joint pain were provided with twice-weekly yoga sessions for 8 weeks. There were statistically significant improvements in balance, flexibility, pain severity, and health-related QOL.⁸⁹ As noted above, improvement in arthralgia was also found in the study conducted by Carson et al.⁸³

Insomnia

Insomnia is common among cancer patients and survivors^90,91 and leads to increased fatigue and depression, decreased adherence to cancer treatments, and poor physical function and QOL.^90-92 Management of insomnia consists of pharmacologic therapies such as benzodiazepines^93,94 and nonpharmacologic options such as cognitive behavioral therapy.⁹⁵

The first study of yoga found to improve sleep quality was conducted at MD Anderson Cancer Center in lymphoma patients.⁹⁶ The effects of Tibetan yoga practices incorporating controlled breathing and visualization, mindfulness techniques, and low-impact postures were studied. Patients in the Tibetan yoga group had better subjective sleep quality, faster sleep latency, longer sleep duration, and less use of sleep medications. Mustian et al conducted a large yoga study in cancer survivors in which patients reporting chronic sleep disturbances were randomly assigned to the YOCAS program, which consisted of pranayama (breath control), 16 gentle hatha and restorative yoga postures, and meditation, or to usual care.⁹² The study reported improvements in global sleep quality, subjective sleep quality, actigraphy measures (wake after sleep onset, sleep efficiency), daytime dysfunction, and use of sleep medication after the yoga intervention compared with participants who received standard care.

Yoga to Address Other Symptoms

There is preliminary evidence supporting yoga as an integrative therapy for other symptoms unique to cancer survivors. For example, in head and neck cancer survivors, soft tissue damage involving the jaw, neck, shoulders, and chest results in swallowing issues, trismus, and aspiration, which are more pronounced in patients treated with conventional radiotherapy than in those treated with intensity-modulated radiotherapy.⁹⁷ Some late effects of radiotherapy for head and neck cancer—such as pain, anxiety, and impaired shoulder function—were shown to be improved through the practice of hatha yoga in 1 study.⁹⁸ Similarly, in a randomized controlled pilot study of patients with stage I to III breast cancer 6 months after treatment, participants in an 8-week yoga program experienced a reduction in arm induration and improvement in a QOL subscale of lymphedema symptoms. However, more evidence is needed to support the use of yoga as a therapeutic measure for breast cancer lymphedema.^99,100

Yoga for Caregivers

Along with cancer patients, caregivers face psychological and physical burdens as well as deterioration in their QOL. Caregivers tend to report clinical levels of anxiety, depression, sleep disturbance, and fatigue and have similar or in fact higher levels than those of the patients for whom they are caring.^101,102 Yoga has been found to help caregivers of patients with cancer. Recently, MD Anderson researchers conducted a trial in patients with high-grade glioma and their caregivers as dyads.^103,104 Each dyad attended 2 or 3 60-minute weekly Vivekananda yoga sessions involving breathing exercises, physical exercises, relaxation, and meditation. The researchers found that the yoga program was safe, feasible, acceptable, and subjectively useful for patients with high-grade glioma and their caregivers. Preliminary evidence of QOL improvement for both patients and caregivers was noted. An improvement in QOL was also demonstrated in another preliminary study of yoga in patients undergoing thoracic radiotherapy and their caregivers.¹⁰⁵

Another study by the group at MD Anderson evaluated a couple-based Tibetan yoga program that emphasized breathing exercises, gentle movements, guided visualizations, and emotional connectedness during radiotherapy for lung cancer.¹⁰⁶ This study included 10 patient‐caregiver dyads and found the program to be feasible, safe, and acceptable. The researchers also found preliminary evidence of improved QOL by the end of radiotherapy relative to baseline—specifically in the areas of spiritual well‐being for patients, fatigue for caregivers, and sleep disturbances and mental health issues such as anxiety and depressive symptoms for both patients and caregivers. This is noteworthy, as QOL typically deteriorates during the course of radiotherapy, and the yoga program was able to buffer these changes.

Conclusion

Yoga therapy has been used successfully as an adjunct modality to improve QOL and cancer-related symptoms. As a part of an integrative medicine approach, yoga is commonly recommended for patients undergoing cancer treatment. Danhauer et al reviewed randomized controlled trials during and after treatment and concluded that the evidence is clearly positive for QOL, fatigue, and perceived stress.¹⁰⁷ Results are less consistent but supportive for psychosocial outcomes such as benefit finding and spirituality. Evidence is mixed for sleep, anxiety, and depression. Post-treatment studies demonstrate improvements in fatigue, sleep, and multiple QOL domains. Yoga has been included in NCCN guidelines for fatigue management. Yoga, if approved by a physician, is also included among the behavioral therapies for anticipatory emesis and prevention and treatment of nausea in the recent update of the NCCN guidelines.¹⁰⁸ The Society for Integrative Oncology guidelines include yoga for anxiety/stress reduction as a part of integrative treatment in breast cancer patients during and after therapy, which was endorsed by the American Society of Clinical Oncology.¹⁰⁹

Because of the strong evidence for its benefits and a low side-effect profile, yoga is offered in group-class settings for patients during and after treatment and/or for caregivers in our institution. We often prescribe yoga as a therapeutic modality for selected groups of patients in our clinical practice. However, some patients may have restrictions after surgery that must be considered. In general, yoga has an excellent safety profile, the evidence base is strong, and we recommend that yoga therapy should be part of the standard of care as an integrative approach for patients with cancer undergoing active treatment as well as for cancer survivors and caregivers.

Acknowledgement: The authors thank Bryan Tutt for providing editorial assistance.

Corresponding author: Santhosshi Narayanan, MD, Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030; [email protected].

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX (Drs. Narayanan, Lopez, Chaoul, Liu, Milbury, and Cohen, and Ms. Mallaiah); the University of Texas Health Science Center at Tyler (Dr. Meegada); and Texas Tech University Health Sciences Center, Lubbock, TX (Ms. Francisco).

Abstract

• Objective: To review the effects of yoga as an adjunct supportive care modality alongside conventional cancer treatment on quality of life (QOL), physical and mental health outcomes, and physiological and biological measures of cancer survivors.
• Methods: Nonsystematic review of the literature.
• Results: Yoga therapy, one of the most frequently used mind-body modalities, has been studied extensively in cancer survivors (from the time of diagnosis through long-term recovery). Yoga affects human physiology on multiple levels, including psychological outcomes, immune and endocrine function, and cardiovascular parameters, as well as multiple areas of QOL. It has been found to reduce psychological stress and fatigue and improve QOL in cancer patients and survivors. Yoga has also been used to manage symptoms such as arthralgia, fatigue, and insomnia. In addition, yoga offers benefits not only for cancer survivors but also for their caregivers.
• Conclusion: As part of an integrative, evidence-informed approach to cancer care, yoga may provide benefits that support the health of cancer survivors and caregivers.

Keywords: fatigue; cancer; proinflammatory cytokines; integrative; mind-body practices; meditation; DNA damage; stress; psychoneuro-immunoendocrine axis; lymphedema; insomnia.

A diagnosis of cancer and adverse effects related to its treatment may have negative effects on quality of life (QOL), contributing to emotional and physical distress in patients and caregivers. Many patients express an interest in pursuing nonpharmacological options, alone or as an adjunct to conventional therapy, to help manage symptoms. The use of complementary medicine approaches to health, including nonpharmacological approaches to symptom management, is highest among individuals with cancer.¹ According to a published expert consensus, integrative oncology is defined as a “patient-centered, evidence-informed field of cancer care that utilizes mind and body practices, natural products, and/or lifestyle modifications from different traditions alongside conventional cancer treatments. Integrative oncology aims to optimize health, QOL, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and become active participants before, during, and beyond cancer treatment.”² A key component of this definition, often misunderstood in the field of oncology, is that these modalities and treatments are used alongside conventional cancer treatments and not as an alternative. In an attempt to meet patients’ needs and appropriately use these approaches, integrative oncology programs are now part of most cancer centers in the United States.^3-6

Because of their overall safety, mind-body therapies are commonly used by patients and recommended by clinicians. Mind-body therapies include yoga, tai chi, qigong, meditation, and relaxation. Expressive arts such as journaling and music, art, and dance therapies also fall in the mind-body category.⁷ Yoga is a movement-based mind-body practice that focuses on synchronizing body, breath, and mind. Yoga has been increasingly used by patients for health benefits,⁸ and numerous studies have evaluated yoga as a complementary intervention for individuals with cancer.^9-14 Here, we review the physiological basis of yoga in oncology and the effects of yoga on biological processes, QOL, and symptoms during and after cancer treatment.

Physiological Basis

Many patients may use mind-body programs such as yoga to help manage the psychological and physiological consequences of unmanaged chronic stress and improve their overall QOL. The central nervous system, endocrine system, and immune system influence and interact with each other in a complex manner in response to chronic stress.^15,16 In a stressful situation, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are activated. HPA axis stimulation leads to adrenocorticotrophic hormone production by the pituitary gland, which releases glucocorticoid hormones. SNS axis stimulation leads to epinephrine and norepinephrine production by the adrenal gland.^17,18 Recently, studies have explored modulation of signal transduction between the nervous and immune systems and how that may impact tumor growth and metastasis.¹⁹ Multiple studies, controlled for prognosis, disease stage, and other factors, have shown that patients experiencing more distress or higher levels of depressive symptoms do not live as long as their counterparts with low distress or depression levels.²⁰ Both the meditative and physical components of yoga can lead to enhanced relaxation, reduced SNS activation, and greater parasympathetic tone, countering the negative physiological effects of chronic stress. The effects of yoga on the HPA axis and SNS, proinflammatory cytokines, immune function, and DNA damage are discussed below.

Biological Processes

Nervous System

The effects of yoga and other forms of meditation on brain functions have been established through several studies. Yoga seems to influence basal ganglia function by improving circuits that are involved in complex cognitive functions, motor coordination, and somatosensory and emotional processes.^21,22 Additionally, changes in neurotransmitter levels have been observed after yoga practice. For instance, in a 12-week yoga intervention in healthy subjects, increased levels of thalamic gamma-aminobutyric acid (GABA) in the yoga group were reported to have a positive correlation with improved mood and decreased anxiety compared with a group who did metabolically matched walking exercise.²³ Levels of GABA, an inhibitory neurotransmitter, are decreased in conditions such as anxiety, depression, and epilepsy.²⁴ Yoga therapy has been shown to improve symptoms of mood disorders and epilepsy, which leads to the hypothesis that the mechanism driving the benefits of yoga may work through stimulation of vagal efferents and an increase in GABA-mediated cortical-inhibitory tone.^24,25

Stress activates the HPA/SNS axis, which releases hormones such as cortisol and norepinephrine. These hormones may play a role in angiogenesis, inflammation, immune suppression, and other physiological functions, and may even reduce the effect of chemotherapeutic agents.^26,27 Regular yoga practice has been shown to reduce SNS and HPA axis activity, most likely by increasing parasympathetic dominance through vagal stimulation, as demonstrated through increases in heart rate variability.²⁸ One indicator of HPA axis dysregulation, diurnal salivary cortisol rhythm, was shown to predict survival in patients with advanced breast and renal cancer.^29-33 Yoga has been shown to lead to less cortisol dysregulation due to radiotherapy and to reductions in mean cortisol levels and early morning cortisol levels in breast cancer patients undergoing radiotherapy.³⁴ This lends support to the hypothesis that yoga helps restore HPA axis balance.

Proinflammatory Cytokines

Cancer patients tend to have increased levels of inflammatory markers such as interleukin (IL)-4, IL-10, tumor necrosis factor (TNF), interferon-γ, and C-reactive protein. This increase in inflammation is associated with worse outcomes in cancer.³⁵ This association becomes highly relevant because the effect of inflammation on host cells in the tumor microenvironment is connected to disease progression.²⁶ Inflammatory cytokines are also implicated in cancer-related symptoms such as fatigue, cognitive dysfunction, peripheral neuropathy, and sleep disturbances.³⁶

Yoga is known to reduce stress and may directly or indirectly decrease inflammatory cytokines. A randomized clinical trial of a 12-week hatha yoga intervention among breast cancer survivors demonstrated decreases in IL-6, IL-1β, TNF, corticotropin-releasing factor, and cognitive complaints in the yoga group compared with those in the standard care group after 3 months.^37,38 Furthermore, Carlson et al showed that, after mindfulness-based stress reduction involving a combination of gentle yoga, meditation techniques, and relaxation exercises, breast and prostate cancer patients had reduced levels of proinflammatory cytokines and cortisol.³⁹ These reductions translated into patients reporting decreased stress levels and enhanced QOL.

Immune Function

The effects of yoga practice on the immune system have been studied in both healthy individuals and individuals with cancer. The effects on T and B lymphocytes, natural killer (NK) cells, and other immune effector cells demonstrate that meditation and yoga have beneficial effects on immune activity.⁴⁰ Hormones such as catecholamines and glucocorticoids are thought to influence the availability and function of NK cells, and, as noted above, yoga has been shown to modulate stress hormones and lead to reduced immune suppression in patients with early-stage breast cancer undergoing chemotherapy.⁴¹ Additional evidence supports the ability of yoga to reduce immune suppression in the postsurgical setting, with no observed decrease in NK cell percentage after surgery for those in a yoga group compared with a control group.⁴² This finding is relevant to patients undergoing surgical management of their cancer and highlights the impact of yoga on the immune system.

DNA Damage

Radiation damages DNA in the peripheral blood lymphocytes of patients undergoing treatment.^43,44 This damage is significant in breast cancer patients undergoing radiotherapy.⁴⁵ Stress additionally causes DNA damage⁴⁶ and is correlated to impaired DNA repair capacity.^47,48 In a study conducted by Banerjee et al, breast cancer patients were randomly assigned to a yoga group or a supportive therapy group for 6 weeks during radiotherapy.⁴⁹ Prior to the intervention, patients in the study had significant genomic instability. After treatment, patients in the yoga group experienced not only a significant reduction in anxiety and depression levels, but also a reduction in DNA damage due to radiotherapy.

There is evidence showing that yoga therapy improves multiple aspects of QOL, including physical functioning, emotional health outcomes, and the symptoms cancer patients may experience, such as sleep disturbances, fatigue, and pain. Danhauer et al systematically reviewed both nonrandomized trials and randomized controlled trials involving yoga during cancer treatment.⁵⁰ They found that yoga improved depression and anxiety as well as sleep and fatigue. Benefits of yoga in cancer based on randomized controlled trials are summarized in the Table. The role of yoga in improving QOL and managing symptoms patients experience during and after treatment is discussed in the following sections.

Quality of Life

Danhauer et al’s systematic review of trials involving yoga during cancer treatment found that yoga improved multiple aspects of QOL.⁵⁰ For example, yoga has been shown to improve QOL in breast cancer patients undergoing radiotherapy. In a study by Chandwani et al, yoga (60-minute sessions twice a week for 6 weeks) was associated with better general health perception and physical functioning scores as well as greater benefit finding, or finding meaning in their experience, after radiotherapy compared with a wait-list group.⁵¹ The yoga group had an increase in intrusive thoughts, believed to be due to a more thorough processing of the cancer experience, which helps to improve patients’ outlook on life.⁵² The benefits of yoga extend beyond psychological measures during radiation treatment. Yoga was found to increase physical functioning compared with stretching in breast cancer patients undergoing radiotherapy.⁵³

Cognitive Function

Cancer-related cognitive impairment commonly occurs during cancer treatments (eg, chemotherapy, radiotherapy, surgery, hormone therapy) and persists for months or years in survivors.⁵⁴ Impairment of memory, executive function, attention, and concentration are commonly reported. In a trial of a combined hatha and restorative yoga program called Yoga for Cancer Survivors (YOCAS), which was designed by researchers at the University of Rochester, patients in the yoga arm had less memory difficulty than did patients in the standard care arm.⁵⁵ However, the primary aim of the trial was to treat insomnia, so this secondary outcome needs to be interpreted with caution. Deficits in attention, memory, and executive function are often seen in cancer-related cognitive impairment, and the meditative aspect of yoga may have behavioral and neurophysical benefits that could improve cognitive functions.⁵⁶ More evidence is needed to understand the role of yoga in improving cognitive functioning.

Emotional Health

Psychosocial stress is high among breast cancer patients and survivors.^57,58 This causes circadian rhythm and cortisol regulation abnormalities, which are reported in women with breast cancer.^59-64 Yoga is known to help stress and psychosocial and physical functioning in patients with cancer.⁶⁵ Yoga was also shown to be equivalent to cognitive behavioral therapy in stress management in a population of patients without cancer.⁶⁶ Daily yoga sessions lasting 60 minutes were shown to reduce reactive anxiety and trait anxiety in early-stage breast cancer patients undergoing conventional radiotherapy and chemotherapy compared with patients receiving supportive therapy, highlighting the role of yoga in managing anxiety related to treatment.⁶⁷ In a study done by Culos-Reed et al, 20 cancer survivors who did 75 minutes of yoga per week for 7 weeks were compared with 18 cancer survivors who served as a control group.⁶⁸ The intervention group reported significant improvement in emotional well-being, depression, concentration, and mood disturbances. In a longitudinal study by Mackenzie et al, 66 cancer survivors completed a 7-week yoga program and were assessed at baseline, immediately after the final yoga session, and at 3 and 6 months after the final session.⁶⁹ Participants had significantly improved energy levels and affect. They also had moderate improvement in mindfulness and a moderate decrease in stress. Breast cancer patients who underwent restorative yoga sessions found improvements in mental health, depression, positive affect, and spirituality (peace/meaning).⁷⁰ This was more pronounced in women with higher negative affect and lower emotional well-being at baseline. In a study of patients with ovarian cancer receiving chemotherapy, patients were instructed to perform up to 15-minute sessions including awareness, body movement, and breathing.⁷¹ Even with just 1 session of yoga intervention, patients experienced decreased anxiety.

Fatigue

Studies on yoga show improvement in fatigue both during and after treatment. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit cognitive fatigue.⁷² Older cancer survivors also seem to benefit from yoga interventions.⁷³ In a trial of a DVD-based yoga program, the benefits of yoga were similar to those of strengthening exercises, and both interventions helped decrease fatigue and improve QOL during the first year after diagnosis in early-stage breast cancer patients with cancer-related fatigue.⁷⁴ Bower et al also showed that, for breast cancer survivors experiencing persistent chronic fatigue, a targeted yoga intervention led to significant improvements in fatigue and vigor over a 3-month follow-up compared with controls.⁷⁵ Fatigue is commonly seen in breast cancer patients who are receiving adjuvant chemotherapy. In a study by Taso et al, women with breast cancer receiving chemotherapy were assigned to 60-minute yoga sessions incorporating Anusara yoga, gentle stretching, and relaxation twice a week for 8 weeks.⁷⁶ By week 4, patients with low pretest fatigue in the yoga group experienced a reduction in fatigue. By week 8, all patients in the yoga group experienced a reduction in fatigue. Four weeks after the yoga intervention, patients in the group maintained the reduction in fatigue. This study shows the feasibility of an 8-week yoga program for women undergoing breast cancer therapy by improving fatigue. Yoga recently was added to National Comprehensive Cancer Network (NCCN) guidelines for management of cancer-related fatigue (level 1 evidence).⁷⁷ However, the evidence was based on studies in women with breast cancer and survivors; therefore, more studies are needed in men and women with other cancers.

Distress surrounding surgery in patients with breast cancer can impact postoperative outcomes. Yoga interventions, including breathing exercises, regulated breathing, and yogic relaxation techniques, improved several postsurgical measures such as length of hospital stay, drain retention, and suture removal.⁷⁸ In this study, patients who practiced yoga also experienced a decrease in plasma TNF and better wound healing. Symptoms of anxiety and distress that occur preoperatively can lead to impaired immune function in addition to decreased QOL. In a study of yoga in early-stage breast cancer patients undergoing surgery, the benefit of yoga was seen not only with stress reduction but also with immune enhancement.⁴²

Yoga has been shown to help alleviate acute pain and distress in women undergoing major surgery for gynecological cancer. A regimen of 3 15-minute sessions of yoga, including awareness meditation, coordination of breath with movement, and relaxation breathing, was shown to reduce acute pain and distress in such patients in an inpatient setting.⁷⁹

Menopausal Symptoms

Breast cancer survivors have more severe menopausal symptoms compared with women without cancer.^80,81 Hot flashes cause sleep disturbances and worsen fatigue and QOL.⁸² Tamoxifen and aromatase inhibitors significantly worsen menopausal symptoms such as hot flashes.⁸¹ Carson et al conducted a study of yoga that included postures, breathing techniques, didactic presentations, and group discussions.⁸³ The yoga awareness regimen consisted of 8 weekly 120-minute group classes. Patients in the yoga arm had statistically significant improvements in the frequency, severity, and number of hot flashes. There were also improvements in arthralgia (joint pain), fatigue, sleep disturbance, vigor, and acceptance.

Arthralgia

Joint pain can be a major side effect that interferes with daily functions and activities in postmenopausal breast cancer survivors who receive aromatase inhibitor therapy.⁸⁴ Arthralgia is reported in up to 50% of patients treated with aromatase inhibitors.^84,85 It can affect functional status and lead to discontinuation of aromatase inhibitor therapy, jeopardizing clinical outcomes.⁸⁶ Yoga as a complementary therapy has been shown to improve conditions such as low back pain⁸⁷ and knee osteoarthritis⁸⁸ in patients who do not have cancer. In a single-arm pilot trial by Galantino et al, breast cancer patients with aromatase inhibitor–related joint pain were provided with twice-weekly yoga sessions for 8 weeks. There were statistically significant improvements in balance, flexibility, pain severity, and health-related QOL.⁸⁹ As noted above, improvement in arthralgia was also found in the study conducted by Carson et al.⁸³

Insomnia

Insomnia is common among cancer patients and survivors^90,91 and leads to increased fatigue and depression, decreased adherence to cancer treatments, and poor physical function and QOL.^90-92 Management of insomnia consists of pharmacologic therapies such as benzodiazepines^93,94 and nonpharmacologic options such as cognitive behavioral therapy.⁹⁵

The first study of yoga found to improve sleep quality was conducted at MD Anderson Cancer Center in lymphoma patients.⁹⁶ The effects of Tibetan yoga practices incorporating controlled breathing and visualization, mindfulness techniques, and low-impact postures were studied. Patients in the Tibetan yoga group had better subjective sleep quality, faster sleep latency, longer sleep duration, and less use of sleep medications. Mustian et al conducted a large yoga study in cancer survivors in which patients reporting chronic sleep disturbances were randomly assigned to the YOCAS program, which consisted of pranayama (breath control), 16 gentle hatha and restorative yoga postures, and meditation, or to usual care.⁹² The study reported improvements in global sleep quality, subjective sleep quality, actigraphy measures (wake after sleep onset, sleep efficiency), daytime dysfunction, and use of sleep medication after the yoga intervention compared with participants who received standard care.

Yoga to Address Other Symptoms

There is preliminary evidence supporting yoga as an integrative therapy for other symptoms unique to cancer survivors. For example, in head and neck cancer survivors, soft tissue damage involving the jaw, neck, shoulders, and chest results in swallowing issues, trismus, and aspiration, which are more pronounced in patients treated with conventional radiotherapy than in those treated with intensity-modulated radiotherapy.⁹⁷ Some late effects of radiotherapy for head and neck cancer—such as pain, anxiety, and impaired shoulder function—were shown to be improved through the practice of hatha yoga in 1 study.⁹⁸ Similarly, in a randomized controlled pilot study of patients with stage I to III breast cancer 6 months after treatment, participants in an 8-week yoga program experienced a reduction in arm induration and improvement in a QOL subscale of lymphedema symptoms. However, more evidence is needed to support the use of yoga as a therapeutic measure for breast cancer lymphedema.^99,100

Yoga for Caregivers

Along with cancer patients, caregivers face psychological and physical burdens as well as deterioration in their QOL. Caregivers tend to report clinical levels of anxiety, depression, sleep disturbance, and fatigue and have similar or in fact higher levels than those of the patients for whom they are caring.^101,102 Yoga has been found to help caregivers of patients with cancer. Recently, MD Anderson researchers conducted a trial in patients with high-grade glioma and their caregivers as dyads.^103,104 Each dyad attended 2 or 3 60-minute weekly Vivekananda yoga sessions involving breathing exercises, physical exercises, relaxation, and meditation. The researchers found that the yoga program was safe, feasible, acceptable, and subjectively useful for patients with high-grade glioma and their caregivers. Preliminary evidence of QOL improvement for both patients and caregivers was noted. An improvement in QOL was also demonstrated in another preliminary study of yoga in patients undergoing thoracic radiotherapy and their caregivers.¹⁰⁵

Another study by the group at MD Anderson evaluated a couple-based Tibetan yoga program that emphasized breathing exercises, gentle movements, guided visualizations, and emotional connectedness during radiotherapy for lung cancer.¹⁰⁶ This study included 10 patient‐caregiver dyads and found the program to be feasible, safe, and acceptable. The researchers also found preliminary evidence of improved QOL by the end of radiotherapy relative to baseline—specifically in the areas of spiritual well‐being for patients, fatigue for caregivers, and sleep disturbances and mental health issues such as anxiety and depressive symptoms for both patients and caregivers. This is noteworthy, as QOL typically deteriorates during the course of radiotherapy, and the yoga program was able to buffer these changes.

Conclusion

Yoga therapy has been used successfully as an adjunct modality to improve QOL and cancer-related symptoms. As a part of an integrative medicine approach, yoga is commonly recommended for patients undergoing cancer treatment. Danhauer et al reviewed randomized controlled trials during and after treatment and concluded that the evidence is clearly positive for QOL, fatigue, and perceived stress.¹⁰⁷ Results are less consistent but supportive for psychosocial outcomes such as benefit finding and spirituality. Evidence is mixed for sleep, anxiety, and depression. Post-treatment studies demonstrate improvements in fatigue, sleep, and multiple QOL domains. Yoga has been included in NCCN guidelines for fatigue management. Yoga, if approved by a physician, is also included among the behavioral therapies for anticipatory emesis and prevention and treatment of nausea in the recent update of the NCCN guidelines.¹⁰⁸ The Society for Integrative Oncology guidelines include yoga for anxiety/stress reduction as a part of integrative treatment in breast cancer patients during and after therapy, which was endorsed by the American Society of Clinical Oncology.¹⁰⁹

Because of the strong evidence for its benefits and a low side-effect profile, yoga is offered in group-class settings for patients during and after treatment and/or for caregivers in our institution. We often prescribe yoga as a therapeutic modality for selected groups of patients in our clinical practice. However, some patients may have restrictions after surgery that must be considered. In general, yoga has an excellent safety profile, the evidence base is strong, and we recommend that yoga therapy should be part of the standard of care as an integrative approach for patients with cancer undergoing active treatment as well as for cancer survivors and caregivers.

Acknowledgement: The authors thank Bryan Tutt for providing editorial assistance.

Corresponding author: Santhosshi Narayanan, MD, Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030; [email protected].

Financial disclosures: None.

From the University of Texas MD Anderson Cancer Center, Houston, TX (Drs. Narayanan, Lopez, Chaoul, Liu, Milbury, and Cohen, and Ms. Mallaiah); the University of Texas Health Science Center at Tyler (Dr. Meegada); and Texas Tech University Health Sciences Center, Lubbock, TX (Ms. Francisco).

Abstract

• Objective: To review the effects of yoga as an adjunct supportive care modality alongside conventional cancer treatment on quality of life (QOL), physical and mental health outcomes, and physiological and biological measures of cancer survivors.
• Methods: Nonsystematic review of the literature.
• Results: Yoga therapy, one of the most frequently used mind-body modalities, has been studied extensively in cancer survivors (from the time of diagnosis through long-term recovery). Yoga affects human physiology on multiple levels, including psychological outcomes, immune and endocrine function, and cardiovascular parameters, as well as multiple areas of QOL. It has been found to reduce psychological stress and fatigue and improve QOL in cancer patients and survivors. Yoga has also been used to manage symptoms such as arthralgia, fatigue, and insomnia. In addition, yoga offers benefits not only for cancer survivors but also for their caregivers.
• Conclusion: As part of an integrative, evidence-informed approach to cancer care, yoga may provide benefits that support the health of cancer survivors and caregivers.

Keywords: fatigue; cancer; proinflammatory cytokines; integrative; mind-body practices; meditation; DNA damage; stress; psychoneuro-immunoendocrine axis; lymphedema; insomnia.

A diagnosis of cancer and adverse effects related to its treatment may have negative effects on quality of life (QOL), contributing to emotional and physical distress in patients and caregivers. Many patients express an interest in pursuing nonpharmacological options, alone or as an adjunct to conventional therapy, to help manage symptoms. The use of complementary medicine approaches to health, including nonpharmacological approaches to symptom management, is highest among individuals with cancer.¹ According to a published expert consensus, integrative oncology is defined as a “patient-centered, evidence-informed field of cancer care that utilizes mind and body practices, natural products, and/or lifestyle modifications from different traditions alongside conventional cancer treatments. Integrative oncology aims to optimize health, QOL, and clinical outcomes across the cancer care continuum and to empower people to prevent cancer and become active participants before, during, and beyond cancer treatment.”² A key component of this definition, often misunderstood in the field of oncology, is that these modalities and treatments are used alongside conventional cancer treatments and not as an alternative. In an attempt to meet patients’ needs and appropriately use these approaches, integrative oncology programs are now part of most cancer centers in the United States.^3-6

Because of their overall safety, mind-body therapies are commonly used by patients and recommended by clinicians. Mind-body therapies include yoga, tai chi, qigong, meditation, and relaxation. Expressive arts such as journaling and music, art, and dance therapies also fall in the mind-body category.⁷ Yoga is a movement-based mind-body practice that focuses on synchronizing body, breath, and mind. Yoga has been increasingly used by patients for health benefits,⁸ and numerous studies have evaluated yoga as a complementary intervention for individuals with cancer.^9-14 Here, we review the physiological basis of yoga in oncology and the effects of yoga on biological processes, QOL, and symptoms during and after cancer treatment.

Physiological Basis

Many patients may use mind-body programs such as yoga to help manage the psychological and physiological consequences of unmanaged chronic stress and improve their overall QOL. The central nervous system, endocrine system, and immune system influence and interact with each other in a complex manner in response to chronic stress.^15,16 In a stressful situation, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are activated. HPA axis stimulation leads to adrenocorticotrophic hormone production by the pituitary gland, which releases glucocorticoid hormones. SNS axis stimulation leads to epinephrine and norepinephrine production by the adrenal gland.^17,18 Recently, studies have explored modulation of signal transduction between the nervous and immune systems and how that may impact tumor growth and metastasis.¹⁹ Multiple studies, controlled for prognosis, disease stage, and other factors, have shown that patients experiencing more distress or higher levels of depressive symptoms do not live as long as their counterparts with low distress or depression levels.²⁰ Both the meditative and physical components of yoga can lead to enhanced relaxation, reduced SNS activation, and greater parasympathetic tone, countering the negative physiological effects of chronic stress. The effects of yoga on the HPA axis and SNS, proinflammatory cytokines, immune function, and DNA damage are discussed below.

Biological Processes

Nervous System

The effects of yoga and other forms of meditation on brain functions have been established through several studies. Yoga seems to influence basal ganglia function by improving circuits that are involved in complex cognitive functions, motor coordination, and somatosensory and emotional processes.^21,22 Additionally, changes in neurotransmitter levels have been observed after yoga practice. For instance, in a 12-week yoga intervention in healthy subjects, increased levels of thalamic gamma-aminobutyric acid (GABA) in the yoga group were reported to have a positive correlation with improved mood and decreased anxiety compared with a group who did metabolically matched walking exercise.²³ Levels of GABA, an inhibitory neurotransmitter, are decreased in conditions such as anxiety, depression, and epilepsy.²⁴ Yoga therapy has been shown to improve symptoms of mood disorders and epilepsy, which leads to the hypothesis that the mechanism driving the benefits of yoga may work through stimulation of vagal efferents and an increase in GABA-mediated cortical-inhibitory tone.^24,25

Stress activates the HPA/SNS axis, which releases hormones such as cortisol and norepinephrine. These hormones may play a role in angiogenesis, inflammation, immune suppression, and other physiological functions, and may even reduce the effect of chemotherapeutic agents.^26,27 Regular yoga practice has been shown to reduce SNS and HPA axis activity, most likely by increasing parasympathetic dominance through vagal stimulation, as demonstrated through increases in heart rate variability.²⁸ One indicator of HPA axis dysregulation, diurnal salivary cortisol rhythm, was shown to predict survival in patients with advanced breast and renal cancer.^29-33 Yoga has been shown to lead to less cortisol dysregulation due to radiotherapy and to reductions in mean cortisol levels and early morning cortisol levels in breast cancer patients undergoing radiotherapy.³⁴ This lends support to the hypothesis that yoga helps restore HPA axis balance.

Proinflammatory Cytokines

Cancer patients tend to have increased levels of inflammatory markers such as interleukin (IL)-4, IL-10, tumor necrosis factor (TNF), interferon-γ, and C-reactive protein. This increase in inflammation is associated with worse outcomes in cancer.³⁵ This association becomes highly relevant because the effect of inflammation on host cells in the tumor microenvironment is connected to disease progression.²⁶ Inflammatory cytokines are also implicated in cancer-related symptoms such as fatigue, cognitive dysfunction, peripheral neuropathy, and sleep disturbances.³⁶

Yoga is known to reduce stress and may directly or indirectly decrease inflammatory cytokines. A randomized clinical trial of a 12-week hatha yoga intervention among breast cancer survivors demonstrated decreases in IL-6, IL-1β, TNF, corticotropin-releasing factor, and cognitive complaints in the yoga group compared with those in the standard care group after 3 months.^37,38 Furthermore, Carlson et al showed that, after mindfulness-based stress reduction involving a combination of gentle yoga, meditation techniques, and relaxation exercises, breast and prostate cancer patients had reduced levels of proinflammatory cytokines and cortisol.³⁹ These reductions translated into patients reporting decreased stress levels and enhanced QOL.

Immune Function

The effects of yoga practice on the immune system have been studied in both healthy individuals and individuals with cancer. The effects on T and B lymphocytes, natural killer (NK) cells, and other immune effector cells demonstrate that meditation and yoga have beneficial effects on immune activity.⁴⁰ Hormones such as catecholamines and glucocorticoids are thought to influence the availability and function of NK cells, and, as noted above, yoga has been shown to modulate stress hormones and lead to reduced immune suppression in patients with early-stage breast cancer undergoing chemotherapy.⁴¹ Additional evidence supports the ability of yoga to reduce immune suppression in the postsurgical setting, with no observed decrease in NK cell percentage after surgery for those in a yoga group compared with a control group.⁴² This finding is relevant to patients undergoing surgical management of their cancer and highlights the impact of yoga on the immune system.

DNA Damage

Radiation damages DNA in the peripheral blood lymphocytes of patients undergoing treatment.^43,44 This damage is significant in breast cancer patients undergoing radiotherapy.⁴⁵ Stress additionally causes DNA damage⁴⁶ and is correlated to impaired DNA repair capacity.^47,48 In a study conducted by Banerjee et al, breast cancer patients were randomly assigned to a yoga group or a supportive therapy group for 6 weeks during radiotherapy.⁴⁹ Prior to the intervention, patients in the study had significant genomic instability. After treatment, patients in the yoga group experienced not only a significant reduction in anxiety and depression levels, but also a reduction in DNA damage due to radiotherapy.

There is evidence showing that yoga therapy improves multiple aspects of QOL, including physical functioning, emotional health outcomes, and the symptoms cancer patients may experience, such as sleep disturbances, fatigue, and pain. Danhauer et al systematically reviewed both nonrandomized trials and randomized controlled trials involving yoga during cancer treatment.⁵⁰ They found that yoga improved depression and anxiety as well as sleep and fatigue. Benefits of yoga in cancer based on randomized controlled trials are summarized in the Table. The role of yoga in improving QOL and managing symptoms patients experience during and after treatment is discussed in the following sections.

Quality of Life

Danhauer et al’s systematic review of trials involving yoga during cancer treatment found that yoga improved multiple aspects of QOL.⁵⁰ For example, yoga has been shown to improve QOL in breast cancer patients undergoing radiotherapy. In a study by Chandwani et al, yoga (60-minute sessions twice a week for 6 weeks) was associated with better general health perception and physical functioning scores as well as greater benefit finding, or finding meaning in their experience, after radiotherapy compared with a wait-list group.⁵¹ The yoga group had an increase in intrusive thoughts, believed to be due to a more thorough processing of the cancer experience, which helps to improve patients’ outlook on life.⁵² The benefits of yoga extend beyond psychological measures during radiation treatment. Yoga was found to increase physical functioning compared with stretching in breast cancer patients undergoing radiotherapy.⁵³

Cognitive Function

Cancer-related cognitive impairment commonly occurs during cancer treatments (eg, chemotherapy, radiotherapy, surgery, hormone therapy) and persists for months or years in survivors.⁵⁴ Impairment of memory, executive function, attention, and concentration are commonly reported. In a trial of a combined hatha and restorative yoga program called Yoga for Cancer Survivors (YOCAS), which was designed by researchers at the University of Rochester, patients in the yoga arm had less memory difficulty than did patients in the standard care arm.⁵⁵ However, the primary aim of the trial was to treat insomnia, so this secondary outcome needs to be interpreted with caution. Deficits in attention, memory, and executive function are often seen in cancer-related cognitive impairment, and the meditative aspect of yoga may have behavioral and neurophysical benefits that could improve cognitive functions.⁵⁶ More evidence is needed to understand the role of yoga in improving cognitive functioning.

Emotional Health

Psychosocial stress is high among breast cancer patients and survivors.^57,58 This causes circadian rhythm and cortisol regulation abnormalities, which are reported in women with breast cancer.^59-64 Yoga is known to help stress and psychosocial and physical functioning in patients with cancer.⁶⁵ Yoga was also shown to be equivalent to cognitive behavioral therapy in stress management in a population of patients without cancer.⁶⁶ Daily yoga sessions lasting 60 minutes were shown to reduce reactive anxiety and trait anxiety in early-stage breast cancer patients undergoing conventional radiotherapy and chemotherapy compared with patients receiving supportive therapy, highlighting the role of yoga in managing anxiety related to treatment.⁶⁷ In a study done by Culos-Reed et al, 20 cancer survivors who did 75 minutes of yoga per week for 7 weeks were compared with 18 cancer survivors who served as a control group.⁶⁸ The intervention group reported significant improvement in emotional well-being, depression, concentration, and mood disturbances. In a longitudinal study by Mackenzie et al, 66 cancer survivors completed a 7-week yoga program and were assessed at baseline, immediately after the final yoga session, and at 3 and 6 months after the final session.⁶⁹ Participants had significantly improved energy levels and affect. They also had moderate improvement in mindfulness and a moderate decrease in stress. Breast cancer patients who underwent restorative yoga sessions found improvements in mental health, depression, positive affect, and spirituality (peace/meaning).⁷⁰ This was more pronounced in women with higher negative affect and lower emotional well-being at baseline. In a study of patients with ovarian cancer receiving chemotherapy, patients were instructed to perform up to 15-minute sessions including awareness, body movement, and breathing.⁷¹ Even with just 1 session of yoga intervention, patients experienced decreased anxiety.

Fatigue

Studies on yoga show improvement in fatigue both during and after treatment. In breast cancer patients undergoing chemotherapy, yoga was shown to benefit cognitive fatigue.⁷² Older cancer survivors also seem to benefit from yoga interventions.⁷³ In a trial of a DVD-based yoga program, the benefits of yoga were similar to those of strengthening exercises, and both interventions helped decrease fatigue and improve QOL during the first year after diagnosis in early-stage breast cancer patients with cancer-related fatigue.⁷⁴ Bower et al also showed that, for breast cancer survivors experiencing persistent chronic fatigue, a targeted yoga intervention led to significant improvements in fatigue and vigor over a 3-month follow-up compared with controls.⁷⁵ Fatigue is commonly seen in breast cancer patients who are receiving adjuvant chemotherapy. In a study by Taso et al, women with breast cancer receiving chemotherapy were assigned to 60-minute yoga sessions incorporating Anusara yoga, gentle stretching, and relaxation twice a week for 8 weeks.⁷⁶ By week 4, patients with low pretest fatigue in the yoga group experienced a reduction in fatigue. By week 8, all patients in the yoga group experienced a reduction in fatigue. Four weeks after the yoga intervention, patients in the group maintained the reduction in fatigue. This study shows the feasibility of an 8-week yoga program for women undergoing breast cancer therapy by improving fatigue. Yoga recently was added to National Comprehensive Cancer Network (NCCN) guidelines for management of cancer-related fatigue (level 1 evidence).⁷⁷ However, the evidence was based on studies in women with breast cancer and survivors; therefore, more studies are needed in men and women with other cancers.

Distress surrounding surgery in patients with breast cancer can impact postoperative outcomes. Yoga interventions, including breathing exercises, regulated breathing, and yogic relaxation techniques, improved several postsurgical measures such as length of hospital stay, drain retention, and suture removal.⁷⁸ In this study, patients who practiced yoga also experienced a decrease in plasma TNF and better wound healing. Symptoms of anxiety and distress that occur preoperatively can lead to impaired immune function in addition to decreased QOL. In a study of yoga in early-stage breast cancer patients undergoing surgery, the benefit of yoga was seen not only with stress reduction but also with immune enhancement.⁴²

Yoga has been shown to help alleviate acute pain and distress in women undergoing major surgery for gynecological cancer. A regimen of 3 15-minute sessions of yoga, including awareness meditation, coordination of breath with movement, and relaxation breathing, was shown to reduce acute pain and distress in such patients in an inpatient setting.⁷⁹

Menopausal Symptoms

Breast cancer survivors have more severe menopausal symptoms compared with women without cancer.^80,81 Hot flashes cause sleep disturbances and worsen fatigue and QOL.⁸² Tamoxifen and aromatase inhibitors significantly worsen menopausal symptoms such as hot flashes.⁸¹ Carson et al conducted a study of yoga that included postures, breathing techniques, didactic presentations, and group discussions.⁸³ The yoga awareness regimen consisted of 8 weekly 120-minute group classes. Patients in the yoga arm had statistically significant improvements in the frequency, severity, and number of hot flashes. There were also improvements in arthralgia (joint pain), fatigue, sleep disturbance, vigor, and acceptance.

Arthralgia

Joint pain can be a major side effect that interferes with daily functions and activities in postmenopausal breast cancer survivors who receive aromatase inhibitor therapy.⁸⁴ Arthralgia is reported in up to 50% of patients treated with aromatase inhibitors.^84,85 It can affect functional status and lead to discontinuation of aromatase inhibitor therapy, jeopardizing clinical outcomes.⁸⁶ Yoga as a complementary therapy has been shown to improve conditions such as low back pain⁸⁷ and knee osteoarthritis⁸⁸ in patients who do not have cancer. In a single-arm pilot trial by Galantino et al, breast cancer patients with aromatase inhibitor–related joint pain were provided with twice-weekly yoga sessions for 8 weeks. There were statistically significant improvements in balance, flexibility, pain severity, and health-related QOL.⁸⁹ As noted above, improvement in arthralgia was also found in the study conducted by Carson et al.⁸³

Insomnia

Insomnia is common among cancer patients and survivors^90,91 and leads to increased fatigue and depression, decreased adherence to cancer treatments, and poor physical function and QOL.^90-92 Management of insomnia consists of pharmacologic therapies such as benzodiazepines^93,94 and nonpharmacologic options such as cognitive behavioral therapy.⁹⁵

The first study of yoga found to improve sleep quality was conducted at MD Anderson Cancer Center in lymphoma patients.⁹⁶ The effects of Tibetan yoga practices incorporating controlled breathing and visualization, mindfulness techniques, and low-impact postures were studied. Patients in the Tibetan yoga group had better subjective sleep quality, faster sleep latency, longer sleep duration, and less use of sleep medications. Mustian et al conducted a large yoga study in cancer survivors in which patients reporting chronic sleep disturbances were randomly assigned to the YOCAS program, which consisted of pranayama (breath control), 16 gentle hatha and restorative yoga postures, and meditation, or to usual care.⁹² The study reported improvements in global sleep quality, subjective sleep quality, actigraphy measures (wake after sleep onset, sleep efficiency), daytime dysfunction, and use of sleep medication after the yoga intervention compared with participants who received standard care.

Yoga to Address Other Symptoms

There is preliminary evidence supporting yoga as an integrative therapy for other symptoms unique to cancer survivors. For example, in head and neck cancer survivors, soft tissue damage involving the jaw, neck, shoulders, and chest results in swallowing issues, trismus, and aspiration, which are more pronounced in patients treated with conventional radiotherapy than in those treated with intensity-modulated radiotherapy.⁹⁷ Some late effects of radiotherapy for head and neck cancer—such as pain, anxiety, and impaired shoulder function—were shown to be improved through the practice of hatha yoga in 1 study.⁹⁸ Similarly, in a randomized controlled pilot study of patients with stage I to III breast cancer 6 months after treatment, participants in an 8-week yoga program experienced a reduction in arm induration and improvement in a QOL subscale of lymphedema symptoms. However, more evidence is needed to support the use of yoga as a therapeutic measure for breast cancer lymphedema.^99,100

Yoga for Caregivers

Along with cancer patients, caregivers face psychological and physical burdens as well as deterioration in their QOL. Caregivers tend to report clinical levels of anxiety, depression, sleep disturbance, and fatigue and have similar or in fact higher levels than those of the patients for whom they are caring.^101,102 Yoga has been found to help caregivers of patients with cancer. Recently, MD Anderson researchers conducted a trial in patients with high-grade glioma and their caregivers as dyads.^103,104 Each dyad attended 2 or 3 60-minute weekly Vivekananda yoga sessions involving breathing exercises, physical exercises, relaxation, and meditation. The researchers found that the yoga program was safe, feasible, acceptable, and subjectively useful for patients with high-grade glioma and their caregivers. Preliminary evidence of QOL improvement for both patients and caregivers was noted. An improvement in QOL was also demonstrated in another preliminary study of yoga in patients undergoing thoracic radiotherapy and their caregivers.¹⁰⁵

Another study by the group at MD Anderson evaluated a couple-based Tibetan yoga program that emphasized breathing exercises, gentle movements, guided visualizations, and emotional connectedness during radiotherapy for lung cancer.¹⁰⁶ This study included 10 patient‐caregiver dyads and found the program to be feasible, safe, and acceptable. The researchers also found preliminary evidence of improved QOL by the end of radiotherapy relative to baseline—specifically in the areas of spiritual well‐being for patients, fatigue for caregivers, and sleep disturbances and mental health issues such as anxiety and depressive symptoms for both patients and caregivers. This is noteworthy, as QOL typically deteriorates during the course of radiotherapy, and the yoga program was able to buffer these changes.

Conclusion

Yoga therapy has been used successfully as an adjunct modality to improve QOL and cancer-related symptoms. As a part of an integrative medicine approach, yoga is commonly recommended for patients undergoing cancer treatment. Danhauer et al reviewed randomized controlled trials during and after treatment and concluded that the evidence is clearly positive for QOL, fatigue, and perceived stress.¹⁰⁷ Results are less consistent but supportive for psychosocial outcomes such as benefit finding and spirituality. Evidence is mixed for sleep, anxiety, and depression. Post-treatment studies demonstrate improvements in fatigue, sleep, and multiple QOL domains. Yoga has been included in NCCN guidelines for fatigue management. Yoga, if approved by a physician, is also included among the behavioral therapies for anticipatory emesis and prevention and treatment of nausea in the recent update of the NCCN guidelines.¹⁰⁸ The Society for Integrative Oncology guidelines include yoga for anxiety/stress reduction as a part of integrative treatment in breast cancer patients during and after therapy, which was endorsed by the American Society of Clinical Oncology.¹⁰⁹

Because of the strong evidence for its benefits and a low side-effect profile, yoga is offered in group-class settings for patients during and after treatment and/or for caregivers in our institution. We often prescribe yoga as a therapeutic modality for selected groups of patients in our clinical practice. However, some patients may have restrictions after surgery that must be considered. In general, yoga has an excellent safety profile, the evidence base is strong, and we recommend that yoga therapy should be part of the standard of care as an integrative approach for patients with cancer undergoing active treatment as well as for cancer survivors and caregivers.

Acknowledgement: The authors thank Bryan Tutt for providing editorial assistance.

Corresponding author: Santhosshi Narayanan, MD, Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Houston, TX 77030; [email protected].

Financial disclosures: None.

Physician burnout has been labeled a public health crisis by the Harvard School of Public Health and other institutions.¹ A 2018 Physician’s Foundation survey found that 78% of physicians had symptoms of burnout,² which result from chronic workplace stress and include feeling depleted of energy or exhausted, mentally distanced from or cynical about one’s job, and problems getting one’s job done successfully.³ Among ObGyns, almost half (46%) report burnout.⁴ One-third of ObGyns responded on a recent Medscape Burnout Report that the computerization of practice is contributing to their burnout, and 54% said too many bureaucratic tasks, including charting, were adding to their burnout.⁵

Inefficient electronic medical records (EMRs) have been implicated as one reason for burnout, with improvements in efficiency cited as one of several potential resolutions to the problem. About 96% of hospitals have adopted EMRs today, compared with only 9% in 2008,⁶ and many physicians report recognizing value in the technology. For instance, 60% of participants in Stanford Medicine’s 2018 National Physician Poll said EMRs had led to improved patient care. At the same time, however, about as many (59%) said EMRs needed a “complete overhaul” and that the systems had detracted from their professional satisfaction (54%) as well as from their clinical effectiveness (49%).⁷

With this roundtable, we explore the concerns with hours spent on the EMR with several experts, and whether it is a problem that has been contributing to burnout among staff at their institutions. In addition, are there solutions that their institutions have implemented that they can share to help to cope with the problem?
 

OBG Management: ObGyns report that the computerization of practice and too many bureaucratic tasks, including charting, are contributing to burnout. Do you see this problem at your institution?

John J. Dougherty, MD, MBA: Yes, absolutely. There is not a day that goes by that I don’t hear about or experience “Epic Fails.” (We use Epic’s EMR product at our institution.) Too many clicks are needed to navigate even the simplest tasks—finding notes or results, documenting visits, and billing for services are all unnecessarily complex. In addition, we are being held accountable for achieving a long and growing list of “metrics” measures, education projects (HealthStream), and productivity goals. When do we have time to treat patients? And it is not just practicing physicians and clinicians. Our resident physicians spend an inordinate amount of time in front of the computer documenting, placing orders, and transferring patients using a system with a very inefficient user interface, to say the least.

Megan L. Evans, MD, MPH: I absolutely agree. Over the years, my institution has created a conglomerate of EMRs, requiring physicians across the hospital to be fluent in a multitude of systems. For example, you finish your clinic notes in one system, sign off on discharge summaries in another, and complete your operative notes in an entirely different system. As busy attendings, it is hard to keep ahead of all of these tasks, especially when the systems do not talk to one another. Fortunately, my hospital is changing our EMR to a single system within the next year. Until then, however, we will work in this piecemeal system.

Mark Woodland, MS, MD: EMR and computerization of medicine is the number 1 issue relating to dissatisfaction by ObGyn providers in our institution. Providers are earnest in their attempt to be compliant with EMR requirements, but the reality is that they are dealing with an automated system that does not have realistic expectations for management of results, follow-up tasks, and patient communications for a human provider. The actual charting, ordering of tests and consults, and communication between providers has been enhanced. However, the “in-basket” of tasks to be accomplished are extraordinary and much of it relies on the provider, which requires an inordinate amount of time. Additionally, while other members of the medical staff are stationary at a desk, physicians and other providers are not. They are mobile between inpatient units, labor and delivery, operating rooms, and emergency rooms. Time management does not always allow for providers to access computers from all of these areas to facilitate their managing the expectations of the EMR. This requires providers to access the EMR at off hours, extending their workload. Finally, the EMR is neither personal nor friendly. It is not designed with the clinician in mind, and it is not fun or engaging for a provider.

Continue to: OBG Management: What solutions have been instituted...

OBG Management: What solutions have been instituted in order to help physicians with data entry into the EMR?

Dr. Dougherty: When our institution compared EMR offerings, EMR companies put their best collective marketing feet forward. The general notion, at least with the Epic EMR, was that “you can customize Epic to your liking.” It did not take long for a bunch of motivated Epic users to create “smart” stuff (lists, phrases, and texts) in an effort to customize workflows and create fancy-looking electronic notes. Shortly thereafter, it was obvious that, as an institution, our reporting efforts kept coming up short—our reports lacked accuracy and meaning. Everyone was documenting in different ways and in different areas. Considering that reports are currently generated using (mostly) discrete data entries (data placed in specific fields within the EMR), it became obvious that our data entry paradigm needed to change. Therefore, standardization became the leading buzzword. Our institution recently initiated a project aimed at standardizing our workflows and documentation habits. In addition, we have incorporated a third-party information exchange product into our health system data aggregation and analysis workflow. Much more needs to be done, but it is a start.

Dr. Evans: At my institution, as a group, we have created templates for routine procedures and visits that also auto populate billing codes. I know that some departments have used scribes. From the hospital side, there has been improved access to the EMR from home. Some of my colleagues like this feature; however, others, like myself, believe this contributes to some of our burnout. I like to leave work at work. Having the ability to continue working at home is not a solution in my mind.

Dr. Woodland: At our institution, we have engaged our chaperones and medical assistants to help facilitate completion of the medical records during the office visit. Providers work with their assistants to accommodate documentation of history and physical findings while also listening to the provider as they are speaking in order to document patient care plans and orders. This saves the clinicians time in reviewing and editing the record as well as making sure the appropriate care plan is instituted. Our EMR provider recently has begun experimenting with personalization of color themes as well as pictures as part of the interface. Having said this, I still ask, “Why have medical professionals allowed non–clinical agencies and information technology groups to run this show?” It is also inconceivable to me that this unfunded mandate—that has increased cost, decreased clinical efficiency, and decreased clinician satisfaction—has not been addressed by national and international medical communities.