Reviews

After discharge from the hospital, patients have a significantly elevated risk for adverse events, including emergency department use, hospital readmission, and death. More than 1 in 3 patients discharged from the hospital require acute care in the month after hospital discharge, and more than 1 in 6 require readmission, with readmission diagnoses frequently differing from those of the preceding hospitalization.^1-4 This heightened susceptibility to adverse events persists beyond 30 days but levels off by 7 weeks after discharge, suggesting that the period of increased risk is transient and dynamic.⁵

The term posthospital syndrome (PHS) describes this period of vulnerability to major adverse events following hospitalization.⁶ In addition to increased risk for readmission and mortality, patients in this period often show evidence of generalized dysfunction with new cognitive impairment, mobility disability, or functional decline.^7-12 To date, the etiology of this vulnerability is neither well understood nor effectively addressed by transitional care interventions.¹³

One hypothesis to explain PHS is that stressors associated with the experience of hospitalization contribute to transient multisystem dysfunction that induces susceptibility to a broad range of medical maladies. These stressors include frequent sleep disruption, noxious sounds, painful stimuli, mobility restrictions, and poor nutrition.¹² The stress hypothesis as a cause of PHS is therefore based, in large part, on evidence about allostasis and the deleterious effects of allostatic overload.

Allostasis defines a system functioning within normal stress-response parameters to promote adaptation and survival.¹⁴ In allostasis, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic and parasympathetic branches of the autonomic nervous system (ANS) exist in homeostatic balance and respond to environmental stimuli within a range of healthy physiologic parameters. The hallmark of a system in allostasis is the ability to rapidly activate, then successfully deactivate, a stress response once the stressor (ie, threat) has resolved.^14,15 To promote survival and potentiate “fight or flight” mechanisms, an appropriate stress response necessarily impacts multiple physiologic systems that result in hemodynamic augmentation and gluconeogenesis to support the anticipated action of large muscle groups, heightened vigilance and memory capabilities to improve rapid decision-making, and enhancement of innate and adaptive immune capabilities to prepare for wound repair and infection defense.^14-16 The stress response is subsequently terminated by negative feedback mechanisms of glucocorticoids as well as a shift of the ANS from sympathetic to parasympathetic tone.^17,18

Extended or repetitive stress exposure, however, leads to dysregulation of allostatic mechanisms responsible for stress adaptation and hinders an efficient and effective stress response. After extended stress exposure, baseline (ie, resting) HPA activity resets, causing a disruption of normal diurnal cortisol rhythm and an increase in total cortisol concentration. Moreover, in response to stress, HPA and ANS system excitation becomes impaired, and negative feedback properties are undermined.^14,15 This maladaptive state, known as allostatic overload, disrupts the finely tuned mechanisms that are the foundation of mind-body balance and yields pathophysiologic consequences to multiple organ systems. Downstream ramifications of allostatic overload include cognitive deterioration, cardiovascular and immune system dysfunction, and functional decline.^14,15,19

Although a stress response is an expected and necessary aspect of acute illness that promotes survival, the central thesis of this work is that additional environmental and social stressors inherent in hospitalization may unnecessarily compound stress and increase the risk of HPA axis dysfunction, allostatic overload, and subsequent multisystem dysfunction, predisposing individuals to adverse outcomes after hospital discharge. Based on data from both human subjects and animal models, we present a possible pathophysiologic mechanism for the postdischarge vulnerability of PHS, encourage critical contemplation of traditional hospitalization, and suggest interventions that might improve outcomes.

POSTHOSPITAL SYNDROME

Posthospital syndrome (PHS) describes a transient period of vulnerability after hospitalization during which patients are at elevated risk for adverse events from a broad range of conditions. In support of this characterization, epidemiologic data have demonstrated high rates of adverse outcomes following hospitalization. For example, data have shown that more than 1 in 6 older adults is readmitted to the hospital within 30 days of discharge.²⁰ Death is also common in this first month, during which rates of postdischarge mortality may exceed initial inpatient mortality.^21,22 Elevated vulnerability after hospitalization is not restricted to older adults, as readmission risk among younger patients 18 to 64 years of age may be even higher for selected conditions, such as heart failure.^3,23

Vulnerability after hospitalization is broad. In patients over age 65 initially admitted for heart failure or acute myocardial infarction, only 35% and 10% of readmissions are for recurrent heart failure or reinfarction, respectively.¹ Nearly half of readmissions are for noncardiovascular causes.¹ Similarly, following hospitalization for pneumonia, more than 60 percent of readmissions are for nonpulmonary etiologies. Moreover, the risk for all these causes of readmission is much higher than baseline risk, indicating an extended period of lack of resilience to many types of illness.²⁴ These patterns of broad susceptibility also extend to younger adults hospitalized with common medical conditions.³

Accumulating evidence suggests that hospitalized patients face functional decline, debility, and risk for adverse events despite resolution of the presenting illness, implying perhaps that the hospital environment itself is hazardous to patients’ health. In 1993, Creditor hypothesized that the “hazards of hospitalization,” including enforced bed-rest, sensory deprivation, social isolation, and malnutrition lead to a “cascade of dependency” in which a collection of small insults to multiple organ systems precipitates loss of function and debility despite cure or resolution of presenting illness.¹² Covinsky (2011) later defined hospitalization-associated disability as an iatrogenic hospital-related “disorder” characterized by new impairments in abilities to perform basic activities of daily living such as bathing, feeding, toileting, dressing, transferring, and walking at the time of hospital discharge.¹¹ Others have described a postintensive-care syndrome (PICS),²⁵ characterized by cognitive, psychiatric, and physical impairments acquired during hospitalization for critical illness that persist postdischarge and increase the long-term risk for adverse outcomes, including elevated mortality rates,^26,27 readmission rates,²⁸ and physical disabilities.²⁹ Similar to the “hazards of hospitalization,” PICS is thought to be related to common experiences of ICU stays, including mobility restriction, sensory deprivation, sleep disruption, sedation, malnutrition, and polypharmacy.^30-33

Taken together, these data suggest that adverse health consequences attributable to hospitalization extend across the spectrum of age, presenting disease severity, and hospital treatment location. As detailed below, the PHS hypothesis is rooted in a mechanistic understanding of the role of exogenous stressors in producing physiologic dysregulation and subsequent adverse health effects across multiple organ systems.

Nature of Stress in the Hospital

Compounding the stress of acute illness, hospitalized patients are routinely and repetitively exposed to a wide variety of environmental stressors that may have downstream adverse consequences (Table 1). In the absence of overt clinical manifestations of harm, the possible subclinical physiologic dysfunction generated by the following stress exposures may increase patients’ susceptibility to the manifestations of PHS.

Sleep Disruption

Sleep disruptions trigger potent stress responses,^34,35 yet they are common occurrences during hospitalization. In surveys, about half of patients report poor sleep quality during hospitalization that persists for many months after discharge.³⁶ In a simulated hospital setting, test subjects exposed to typical hospital sounds (paging system, machine alarms, etc.) experienced significant sleep-wake cycle abnormalities.³⁷ Although no work has yet focused specifically on the physiologic consequences of sleep disruption and stress in hospitalized patients, in healthy humans, mild sleep disruption has clear effects on allostasis by disrupting HPA activity, raising cortisol levels, diminishing parasympathetic tone, and impairing cognitive performance.^{18,34,35,38,39}

Malnourishment

Malnourishment in hospitalized patients is common, with one-fifth of hospitalized patients receiving nothing per mouth or clear liquid diets for more than 3 continuous days,⁴⁰ and one-fifth of hospitalized elderly patients receiving less than half of their calculated nutrition requirements.⁴¹ Although the relationship between food restriction, cortisol levels, and postdischarge outcomes has not been fully explored, in healthy humans, meal anticipation, meal withdrawal (withholding an expected meal), and self-reported dietary restraint are known to generate stress responses.^42,43 Furthermore, malnourishment during hospitalization is associated with increased 90-day and 1-year mortality after discharge,⁴⁴ adding malnourishment to the list of plausible components of hospital-related stress.

Mobility Restriction

Physical activity counterbalances stress responses and minimizes downstream consequences of allostatic load,¹⁵ yet mobility limitations via physical and chemical restraints are common in hospitalized patients, particularly among the elderly.^45-47 Many patients are tethered to devices that make ambulation hazardous, such as urinary catheters and infusion pumps. Even without physical or chemical restraints or a limited mobility order, patients may be hesitant to leave the room so as not to miss transport to a diagnostic study or an unscheduled physician’s visit. Indeed, mobility limitations of hospitalized patients increase the risk for adverse events after discharge, while interventions designed to encourage mobility are associated with improved postdischarge outcomes.^47,48

Other Stressors

Other hospital-related aversive stimuli are less commonly quantified, but clearly exist. According to surveys of hospitalized patients, sources of emotional stress include social isolation; loss of autonomy and privacy; fear of serious illness; lack of control over activities of daily living; lack of clear communication between treatment team and patients; and death of a patient roommate.^49,50 Furthermore, consider the physical discomfort and emotional distress of patients with urinary incontinence awaiting assistance for a diaper or bedding change or the pain of repetitive blood draws or other invasive testing. Although individualized, the subjective discomfort and emotional distress associated with these experiences undoubtedly contribute to the stress of hospitalization.

 

IMPACT OF ALLOSTATIC OVERLOAD ON PHYSIOLOGIC FUNCTION

Animal Models of Stress

Laboratory techniques reminiscent of the numerous environmental stressors associated with hospitalization have been used to reliably trigger allostatic overload in healthy young animals.⁵¹ These techniques include sequential exposure to aversive stimuli, including food and water deprivation, continuous overnight illumination, paired housing with known and unknown cagemates, mobility restriction, soiled cage conditions, and continuous noise. All of these techniques have been shown to cause HPA axis and ANS dysfunction, allostatic overload, and subsequent stress-mediated consequences to multiple organ systems.^19,52-54 Given the remarkable similarity of these protocols to common experiences during hospitalization, animal models of stress may be useful in understanding the spectrum of maladaptive consequences experienced by patients within the hospital (Figure 1).

These animal models of stress have resulted in a number of instructive findings. For example, in rodents, extended stress exposure induces structural and functional remodeling of neuronal networks that precipitate learning and memory, working memory, and attention impairments.^55-57 These exposures also result in cardiovascular abnormalities, including dyslipidemia, progressive atherosclerosis,^58,59 and enhanced inflammatory cytokine expression,⁶⁰ all of which increase both atherosclerotic burden and susceptibility to plaque rupture, leading to elevated risk for major cardiovascular adverse events. Moreover, these extended stress exposures in animals increase susceptibility to both bacterial and viral infections and increase their severity.^16,61 This outcome appears to be driven by a stress-induced elevation of glucocorticoid levels, decreased leukocyte proliferation, altered leukocyte trafficking, and a transition to a proinflammatory cytokine environment.^{16, 61} Allostatic overload has also been shown to contribute to metabolic dysregulation involving insulin resistance, persistence of hyperglycemia, dyslipidemia, catabolism of lean muscle, and visceral adipose tissue deposition.^62-64 In addition to cardiovascular, immune, and metabolic consequences of allostatic overload, the spectrum of physiologic dysfunction in animal models is broad and includes mood disorder symptoms,⁶⁵ intestinal barrier abnormalities,⁶⁶ airway reactivity exacerbation,⁶⁷ and enhanced tumor growth.⁶⁸

Although the majority of this research highlights the multisystem effects of variable stress exposure in healthy animals, preliminary evidence suggests that aged or diseased animals subjected to additional stressors display a heightened inflammatory cytokine response that contributes to exaggerated sickness behavior and greater and prolonged cognitive deficits.⁶⁹ Future studies exploring the consequences of extended stress exposure in animals with existing disease or debility may therefore more closely simulate the experience of hospitalized patients and perhaps further our understanding of PHS.

Hospitalized Patients

While no intervention studies have examined the effects of potential hospital stressors on the development of allostatic overload, there is evidence from small studies that dysregulated stress responses during hospitalization are associated with adverse events. For example, high serum cortisol, catecholamine, and proinflammatory cytokine levels during hospitalization have individually been associated with the development of cognitive dysfunction,^70-72 increased risk of cardiovascular events such as myocardial infarction and stroke in the year following discharge,^73-76 and the development of wound infections after discharge.⁷⁷ Moreover, elevated plasma glucose during admission for myocardial infarction in patients with or without diabetes has been associated with greater in-hospital and 1-year mortality,⁷⁸ with a similar relationship seen between elevated plasma glucose and survival after admission for stroke⁷⁹ and pneumonia.⁸⁰ Furthermore, in addition to atherothrombosis, stress may contribute to the risk for venous thromboembolism,⁸¹ resulting in readmissions for deep vein thrombosis or pulmonary embolism posthospitalization. Although potentially surrogate markers of illness acuity, a handful of studies have shown that these stress biomarkers are actually only weakly correlated with,⁸² or independent of,^72,76 disease severity. As discussed in detail below, future studies utilizing a summative measure of multisystem physiologic dysfunction as opposed to individual biomarkers may more accurately reflect the cumulative stress effects of hospitalization and subsequent risk for adverse events.

Additional Considerations

Elderly patients, in particular, may have heightened susceptibility to the consequences of allostatic overload due to common geriatric issues such as multimorbidity and frailty. Patients with chronic diseases display both baseline HPA axis abnormalities as well as dysregulated stress responses and may therefore be more vulnerable to hospitalization-related stress. For example, when subjected to psychosocial stress, patients with chronic conditions such as diabetes, heart failure, or atherosclerosis demonstrate elevated cortisol levels, increased circulating markers of inflammation, as well as prolonged hemodynamic recovery after stress resolution compared with normal controls.^83-85 Additionally, frailty may affect an individual’s susceptibility to exogenous stress. Indeed, frailty identified on hospital admission increases the risk for adverse outcomes during hospitalization and postdischarge.⁸⁶ Although the specific etiology of this relationship is unclear, persons with frailty are known to have elevated levels of cortisol and other inflammatory markers,^87,88 which may contribute to adverse outcomes in the face of additional stressors.

 

IMPLICATIONS AND NEXT STEPS

A large body of evidence stretching from bench to bedside suggests that environmental stressors associated with hospitalization are toxic. Understanding PHS within the context of hospital-induced allostatic overload presents a unifying theory for the interrelated multisystem dysfunction and increased susceptibility to adverse events that patients experience after discharge (Figure 2). Furthermore, it defines a potential pathophysiological mechanism for the cognitive impairment, elevated cardiovascular risk, immune system dysfunction, metabolic derangements, and functional decline associated with PHS. Additionally, this theory highlights environmental interventions to limit PHS development and suggests mechanisms to promote stress resilience. Although it is difficult to disentangle the consequences of the endogenous stress triggered by an acute illness from the exogenous stressors related to hospitalization, it is likely that the 2 simultaneous exposures compound risk for stress system dysregulation and allostatic overload. Moreover, hospitalized patients with preexisting HPA axis dysfunction at baseline from chronic disease or advancing age may be even more susceptible to these adverse outcomes. If this hypothesis is true, a reduction in PHS would require mitigation of the modifiable environmental stressors encountered by patients during hospitalization. Directed efforts to diminish ambient noise, limit nighttime disruptions, thoughtfully plan procedures, consider ongoing nutritional status, and promote opportunities for patients to exert some control over their environment may diminish the burden of extrinsic stressors encountered by all patients in the hospital and improve outcomes after discharge.

Hospitals are increasingly recognizing the importance of improving patients’ experience of hospitalization by reducing exposure to potential toxicities. For example, many hospitals are now attempting to reduce sleep disturbances and sleep latency through reduced nighttime noise and light levels, fewer nighttime interruptions for vital signs checks and medication administration, and commonsensical interventions like massages, herbal teas, and warm milk prior to bedtime.⁸⁹ Likewise, intensive care units are targeting environmental and physical stressors with a multifaceted approach to decrease sedative use, promote healthy sleep cycles, and encourage exercise and ambulation even in those patients who are mechanically ventilated.³⁰ Another promising development has been the increase of Hospital at Home programs. In these programs, patients who meet the criteria for inpatient admission are instead comprehensively managed at home for their acute illness through a multidisciplinary effort between physicians, nurses, social workers, physical therapists, and others. Patients hospitalized at home report higher levels of satisfaction and have modest functional gains, improved health-related quality of life, and decreased risk of mortality at 6 months compared with hospitalized patients.^90,91 With some admitting diagnoses (eg, heart failure), hospitalization at home may be associated with decreased readmission risk.⁹² Although not yet investigated on a physiologic level, perhaps the benefits of hospital at home are partially due to the dramatic difference in exposure to environmental stressors.

A tool that quantifies hospital-associated stress may help health providers appreciate the experience of patients and better target interventions to aspects of their structure and process that contribute to allostatic overload. Importantly, allostatic overload cannot be identified by one biomarker of stress but instead requires evidence of dysregulation across inflammatory, neuroendocrine, hormonal, and cardiometabolic systems. Future studies to address the burden of stress faced by hospitalized patients should consider a summative measure of multisystem dysregulation as opposed to isolated assessments of individual biomarkers. Allostatic load has previously been operationalized as the summation of a variety of hemodynamic, hormonal, and metabolic factors, including blood pressure, lipid profile, glycosylated hemoglobin, cortisol, catecholamine levels, and inflammatory markers.⁹³ To develop a hospital-associated allostatic load index, models should ideally be adjusted for acute illness severity, patient-reported stress, and capacity for stress resilience. This tool could then be used to quantify hospitalization-related allostatic load and identify those at greatest risk for adverse events after discharge, as well as measure the effectiveness of strategic environmental interventions (Table 2). A natural first experiment may be a comparison of the allostatic load of hospitalized patients versus those hospitalized at home.

The risk of adverse outcomes after discharge is likely a function of the vulnerability of the patient and the degree to which the patient’s healthcare team and social support network mitigates this vulnerability. That is, there is a risk that a person struggles in the postdischarge period and, in many circumstances, a strong healthcare team and social network can identify health problems early and prevent them from progressing to the point that they require hospitalization.^13,94-96 There are also hospital occurrences, outside of allostatic load, that can lead to complications that lengthen the stay, weaken the patient, and directly contribute to subsequent vulnerability.^94,97 Our contention is that the allostatic load of hospitalization, which may also vary by patient depending on the circumstances of hospitalization, is just one contributor, albeit potentially an important one, to vulnerability to medical problems after discharge.

In conclusion, a plausible etiology of PHS is the maladaptive mind-body consequences of common stressors during hospitalization that compound the stress of acute illness and produce allostatic overload. This stress-induced dysfunction potentially contributes to a spectrum of generalized disease susceptibility and risk of adverse outcomes after discharge. Focused efforts to diminish patient exposure to hospital-related stressors during and after hospitalization might diminish the presence or severity of PHS. Viewing PHS from this perspective enables the development of hypothesis-driven risk-prediction models, encourages critical contemplation of traditional hospitalization, and suggests that targeted environmental interventions may significantly reduce adverse outcomes.

 

After discharge from the hospital, patients have a significantly elevated risk for adverse events, including emergency department use, hospital readmission, and death. More than 1 in 3 patients discharged from the hospital require acute care in the month after hospital discharge, and more than 1 in 6 require readmission, with readmission diagnoses frequently differing from those of the preceding hospitalization.^1-4 This heightened susceptibility to adverse events persists beyond 30 days but levels off by 7 weeks after discharge, suggesting that the period of increased risk is transient and dynamic.⁵

The term posthospital syndrome (PHS) describes this period of vulnerability to major adverse events following hospitalization.⁶ In addition to increased risk for readmission and mortality, patients in this period often show evidence of generalized dysfunction with new cognitive impairment, mobility disability, or functional decline.^7-12 To date, the etiology of this vulnerability is neither well understood nor effectively addressed by transitional care interventions.¹³

One hypothesis to explain PHS is that stressors associated with the experience of hospitalization contribute to transient multisystem dysfunction that induces susceptibility to a broad range of medical maladies. These stressors include frequent sleep disruption, noxious sounds, painful stimuli, mobility restrictions, and poor nutrition.¹² The stress hypothesis as a cause of PHS is therefore based, in large part, on evidence about allostasis and the deleterious effects of allostatic overload.

Allostasis defines a system functioning within normal stress-response parameters to promote adaptation and survival.¹⁴ In allostasis, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic and parasympathetic branches of the autonomic nervous system (ANS) exist in homeostatic balance and respond to environmental stimuli within a range of healthy physiologic parameters. The hallmark of a system in allostasis is the ability to rapidly activate, then successfully deactivate, a stress response once the stressor (ie, threat) has resolved.^14,15 To promote survival and potentiate “fight or flight” mechanisms, an appropriate stress response necessarily impacts multiple physiologic systems that result in hemodynamic augmentation and gluconeogenesis to support the anticipated action of large muscle groups, heightened vigilance and memory capabilities to improve rapid decision-making, and enhancement of innate and adaptive immune capabilities to prepare for wound repair and infection defense.^14-16 The stress response is subsequently terminated by negative feedback mechanisms of glucocorticoids as well as a shift of the ANS from sympathetic to parasympathetic tone.^17,18

Extended or repetitive stress exposure, however, leads to dysregulation of allostatic mechanisms responsible for stress adaptation and hinders an efficient and effective stress response. After extended stress exposure, baseline (ie, resting) HPA activity resets, causing a disruption of normal diurnal cortisol rhythm and an increase in total cortisol concentration. Moreover, in response to stress, HPA and ANS system excitation becomes impaired, and negative feedback properties are undermined.^14,15 This maladaptive state, known as allostatic overload, disrupts the finely tuned mechanisms that are the foundation of mind-body balance and yields pathophysiologic consequences to multiple organ systems. Downstream ramifications of allostatic overload include cognitive deterioration, cardiovascular and immune system dysfunction, and functional decline.^14,15,19

Although a stress response is an expected and necessary aspect of acute illness that promotes survival, the central thesis of this work is that additional environmental and social stressors inherent in hospitalization may unnecessarily compound stress and increase the risk of HPA axis dysfunction, allostatic overload, and subsequent multisystem dysfunction, predisposing individuals to adverse outcomes after hospital discharge. Based on data from both human subjects and animal models, we present a possible pathophysiologic mechanism for the postdischarge vulnerability of PHS, encourage critical contemplation of traditional hospitalization, and suggest interventions that might improve outcomes.

POSTHOSPITAL SYNDROME

Posthospital syndrome (PHS) describes a transient period of vulnerability after hospitalization during which patients are at elevated risk for adverse events from a broad range of conditions. In support of this characterization, epidemiologic data have demonstrated high rates of adverse outcomes following hospitalization. For example, data have shown that more than 1 in 6 older adults is readmitted to the hospital within 30 days of discharge.²⁰ Death is also common in this first month, during which rates of postdischarge mortality may exceed initial inpatient mortality.^21,22 Elevated vulnerability after hospitalization is not restricted to older adults, as readmission risk among younger patients 18 to 64 years of age may be even higher for selected conditions, such as heart failure.^3,23

Vulnerability after hospitalization is broad. In patients over age 65 initially admitted for heart failure or acute myocardial infarction, only 35% and 10% of readmissions are for recurrent heart failure or reinfarction, respectively.¹ Nearly half of readmissions are for noncardiovascular causes.¹ Similarly, following hospitalization for pneumonia, more than 60 percent of readmissions are for nonpulmonary etiologies. Moreover, the risk for all these causes of readmission is much higher than baseline risk, indicating an extended period of lack of resilience to many types of illness.²⁴ These patterns of broad susceptibility also extend to younger adults hospitalized with common medical conditions.³

Accumulating evidence suggests that hospitalized patients face functional decline, debility, and risk for adverse events despite resolution of the presenting illness, implying perhaps that the hospital environment itself is hazardous to patients’ health. In 1993, Creditor hypothesized that the “hazards of hospitalization,” including enforced bed-rest, sensory deprivation, social isolation, and malnutrition lead to a “cascade of dependency” in which a collection of small insults to multiple organ systems precipitates loss of function and debility despite cure or resolution of presenting illness.¹² Covinsky (2011) later defined hospitalization-associated disability as an iatrogenic hospital-related “disorder” characterized by new impairments in abilities to perform basic activities of daily living such as bathing, feeding, toileting, dressing, transferring, and walking at the time of hospital discharge.¹¹ Others have described a postintensive-care syndrome (PICS),²⁵ characterized by cognitive, psychiatric, and physical impairments acquired during hospitalization for critical illness that persist postdischarge and increase the long-term risk for adverse outcomes, including elevated mortality rates,^26,27 readmission rates,²⁸ and physical disabilities.²⁹ Similar to the “hazards of hospitalization,” PICS is thought to be related to common experiences of ICU stays, including mobility restriction, sensory deprivation, sleep disruption, sedation, malnutrition, and polypharmacy.^30-33

Taken together, these data suggest that adverse health consequences attributable to hospitalization extend across the spectrum of age, presenting disease severity, and hospital treatment location. As detailed below, the PHS hypothesis is rooted in a mechanistic understanding of the role of exogenous stressors in producing physiologic dysregulation and subsequent adverse health effects across multiple organ systems.

Nature of Stress in the Hospital

Compounding the stress of acute illness, hospitalized patients are routinely and repetitively exposed to a wide variety of environmental stressors that may have downstream adverse consequences (Table 1). In the absence of overt clinical manifestations of harm, the possible subclinical physiologic dysfunction generated by the following stress exposures may increase patients’ susceptibility to the manifestations of PHS.

Sleep Disruption

Sleep disruptions trigger potent stress responses,^34,35 yet they are common occurrences during hospitalization. In surveys, about half of patients report poor sleep quality during hospitalization that persists for many months after discharge.³⁶ In a simulated hospital setting, test subjects exposed to typical hospital sounds (paging system, machine alarms, etc.) experienced significant sleep-wake cycle abnormalities.³⁷ Although no work has yet focused specifically on the physiologic consequences of sleep disruption and stress in hospitalized patients, in healthy humans, mild sleep disruption has clear effects on allostasis by disrupting HPA activity, raising cortisol levels, diminishing parasympathetic tone, and impairing cognitive performance.^{18,34,35,38,39}

Malnourishment

Malnourishment in hospitalized patients is common, with one-fifth of hospitalized patients receiving nothing per mouth or clear liquid diets for more than 3 continuous days,⁴⁰ and one-fifth of hospitalized elderly patients receiving less than half of their calculated nutrition requirements.⁴¹ Although the relationship between food restriction, cortisol levels, and postdischarge outcomes has not been fully explored, in healthy humans, meal anticipation, meal withdrawal (withholding an expected meal), and self-reported dietary restraint are known to generate stress responses.^42,43 Furthermore, malnourishment during hospitalization is associated with increased 90-day and 1-year mortality after discharge,⁴⁴ adding malnourishment to the list of plausible components of hospital-related stress.

Mobility Restriction

Physical activity counterbalances stress responses and minimizes downstream consequences of allostatic load,¹⁵ yet mobility limitations via physical and chemical restraints are common in hospitalized patients, particularly among the elderly.^45-47 Many patients are tethered to devices that make ambulation hazardous, such as urinary catheters and infusion pumps. Even without physical or chemical restraints or a limited mobility order, patients may be hesitant to leave the room so as not to miss transport to a diagnostic study or an unscheduled physician’s visit. Indeed, mobility limitations of hospitalized patients increase the risk for adverse events after discharge, while interventions designed to encourage mobility are associated with improved postdischarge outcomes.^47,48

Other Stressors

Other hospital-related aversive stimuli are less commonly quantified, but clearly exist. According to surveys of hospitalized patients, sources of emotional stress include social isolation; loss of autonomy and privacy; fear of serious illness; lack of control over activities of daily living; lack of clear communication between treatment team and patients; and death of a patient roommate.^49,50 Furthermore, consider the physical discomfort and emotional distress of patients with urinary incontinence awaiting assistance for a diaper or bedding change or the pain of repetitive blood draws or other invasive testing. Although individualized, the subjective discomfort and emotional distress associated with these experiences undoubtedly contribute to the stress of hospitalization.

 

IMPACT OF ALLOSTATIC OVERLOAD ON PHYSIOLOGIC FUNCTION

Animal Models of Stress

Laboratory techniques reminiscent of the numerous environmental stressors associated with hospitalization have been used to reliably trigger allostatic overload in healthy young animals.⁵¹ These techniques include sequential exposure to aversive stimuli, including food and water deprivation, continuous overnight illumination, paired housing with known and unknown cagemates, mobility restriction, soiled cage conditions, and continuous noise. All of these techniques have been shown to cause HPA axis and ANS dysfunction, allostatic overload, and subsequent stress-mediated consequences to multiple organ systems.^19,52-54 Given the remarkable similarity of these protocols to common experiences during hospitalization, animal models of stress may be useful in understanding the spectrum of maladaptive consequences experienced by patients within the hospital (Figure 1).

These animal models of stress have resulted in a number of instructive findings. For example, in rodents, extended stress exposure induces structural and functional remodeling of neuronal networks that precipitate learning and memory, working memory, and attention impairments.^55-57 These exposures also result in cardiovascular abnormalities, including dyslipidemia, progressive atherosclerosis,^58,59 and enhanced inflammatory cytokine expression,⁶⁰ all of which increase both atherosclerotic burden and susceptibility to plaque rupture, leading to elevated risk for major cardiovascular adverse events. Moreover, these extended stress exposures in animals increase susceptibility to both bacterial and viral infections and increase their severity.^16,61 This outcome appears to be driven by a stress-induced elevation of glucocorticoid levels, decreased leukocyte proliferation, altered leukocyte trafficking, and a transition to a proinflammatory cytokine environment.^{16, 61} Allostatic overload has also been shown to contribute to metabolic dysregulation involving insulin resistance, persistence of hyperglycemia, dyslipidemia, catabolism of lean muscle, and visceral adipose tissue deposition.^62-64 In addition to cardiovascular, immune, and metabolic consequences of allostatic overload, the spectrum of physiologic dysfunction in animal models is broad and includes mood disorder symptoms,⁶⁵ intestinal barrier abnormalities,⁶⁶ airway reactivity exacerbation,⁶⁷ and enhanced tumor growth.⁶⁸

Although the majority of this research highlights the multisystem effects of variable stress exposure in healthy animals, preliminary evidence suggests that aged or diseased animals subjected to additional stressors display a heightened inflammatory cytokine response that contributes to exaggerated sickness behavior and greater and prolonged cognitive deficits.⁶⁹ Future studies exploring the consequences of extended stress exposure in animals with existing disease or debility may therefore more closely simulate the experience of hospitalized patients and perhaps further our understanding of PHS.

Hospitalized Patients

While no intervention studies have examined the effects of potential hospital stressors on the development of allostatic overload, there is evidence from small studies that dysregulated stress responses during hospitalization are associated with adverse events. For example, high serum cortisol, catecholamine, and proinflammatory cytokine levels during hospitalization have individually been associated with the development of cognitive dysfunction,^70-72 increased risk of cardiovascular events such as myocardial infarction and stroke in the year following discharge,^73-76 and the development of wound infections after discharge.⁷⁷ Moreover, elevated plasma glucose during admission for myocardial infarction in patients with or without diabetes has been associated with greater in-hospital and 1-year mortality,⁷⁸ with a similar relationship seen between elevated plasma glucose and survival after admission for stroke⁷⁹ and pneumonia.⁸⁰ Furthermore, in addition to atherothrombosis, stress may contribute to the risk for venous thromboembolism,⁸¹ resulting in readmissions for deep vein thrombosis or pulmonary embolism posthospitalization. Although potentially surrogate markers of illness acuity, a handful of studies have shown that these stress biomarkers are actually only weakly correlated with,⁸² or independent of,^72,76 disease severity. As discussed in detail below, future studies utilizing a summative measure of multisystem physiologic dysfunction as opposed to individual biomarkers may more accurately reflect the cumulative stress effects of hospitalization and subsequent risk for adverse events.

Additional Considerations

Elderly patients, in particular, may have heightened susceptibility to the consequences of allostatic overload due to common geriatric issues such as multimorbidity and frailty. Patients with chronic diseases display both baseline HPA axis abnormalities as well as dysregulated stress responses and may therefore be more vulnerable to hospitalization-related stress. For example, when subjected to psychosocial stress, patients with chronic conditions such as diabetes, heart failure, or atherosclerosis demonstrate elevated cortisol levels, increased circulating markers of inflammation, as well as prolonged hemodynamic recovery after stress resolution compared with normal controls.^83-85 Additionally, frailty may affect an individual’s susceptibility to exogenous stress. Indeed, frailty identified on hospital admission increases the risk for adverse outcomes during hospitalization and postdischarge.⁸⁶ Although the specific etiology of this relationship is unclear, persons with frailty are known to have elevated levels of cortisol and other inflammatory markers,^87,88 which may contribute to adverse outcomes in the face of additional stressors.

 

IMPLICATIONS AND NEXT STEPS

A large body of evidence stretching from bench to bedside suggests that environmental stressors associated with hospitalization are toxic. Understanding PHS within the context of hospital-induced allostatic overload presents a unifying theory for the interrelated multisystem dysfunction and increased susceptibility to adverse events that patients experience after discharge (Figure 2). Furthermore, it defines a potential pathophysiological mechanism for the cognitive impairment, elevated cardiovascular risk, immune system dysfunction, metabolic derangements, and functional decline associated with PHS. Additionally, this theory highlights environmental interventions to limit PHS development and suggests mechanisms to promote stress resilience. Although it is difficult to disentangle the consequences of the endogenous stress triggered by an acute illness from the exogenous stressors related to hospitalization, it is likely that the 2 simultaneous exposures compound risk for stress system dysregulation and allostatic overload. Moreover, hospitalized patients with preexisting HPA axis dysfunction at baseline from chronic disease or advancing age may be even more susceptible to these adverse outcomes. If this hypothesis is true, a reduction in PHS would require mitigation of the modifiable environmental stressors encountered by patients during hospitalization. Directed efforts to diminish ambient noise, limit nighttime disruptions, thoughtfully plan procedures, consider ongoing nutritional status, and promote opportunities for patients to exert some control over their environment may diminish the burden of extrinsic stressors encountered by all patients in the hospital and improve outcomes after discharge.

Hospitals are increasingly recognizing the importance of improving patients’ experience of hospitalization by reducing exposure to potential toxicities. For example, many hospitals are now attempting to reduce sleep disturbances and sleep latency through reduced nighttime noise and light levels, fewer nighttime interruptions for vital signs checks and medication administration, and commonsensical interventions like massages, herbal teas, and warm milk prior to bedtime.⁸⁹ Likewise, intensive care units are targeting environmental and physical stressors with a multifaceted approach to decrease sedative use, promote healthy sleep cycles, and encourage exercise and ambulation even in those patients who are mechanically ventilated.³⁰ Another promising development has been the increase of Hospital at Home programs. In these programs, patients who meet the criteria for inpatient admission are instead comprehensively managed at home for their acute illness through a multidisciplinary effort between physicians, nurses, social workers, physical therapists, and others. Patients hospitalized at home report higher levels of satisfaction and have modest functional gains, improved health-related quality of life, and decreased risk of mortality at 6 months compared with hospitalized patients.^90,91 With some admitting diagnoses (eg, heart failure), hospitalization at home may be associated with decreased readmission risk.⁹² Although not yet investigated on a physiologic level, perhaps the benefits of hospital at home are partially due to the dramatic difference in exposure to environmental stressors.

A tool that quantifies hospital-associated stress may help health providers appreciate the experience of patients and better target interventions to aspects of their structure and process that contribute to allostatic overload. Importantly, allostatic overload cannot be identified by one biomarker of stress but instead requires evidence of dysregulation across inflammatory, neuroendocrine, hormonal, and cardiometabolic systems. Future studies to address the burden of stress faced by hospitalized patients should consider a summative measure of multisystem dysregulation as opposed to isolated assessments of individual biomarkers. Allostatic load has previously been operationalized as the summation of a variety of hemodynamic, hormonal, and metabolic factors, including blood pressure, lipid profile, glycosylated hemoglobin, cortisol, catecholamine levels, and inflammatory markers.⁹³ To develop a hospital-associated allostatic load index, models should ideally be adjusted for acute illness severity, patient-reported stress, and capacity for stress resilience. This tool could then be used to quantify hospitalization-related allostatic load and identify those at greatest risk for adverse events after discharge, as well as measure the effectiveness of strategic environmental interventions (Table 2). A natural first experiment may be a comparison of the allostatic load of hospitalized patients versus those hospitalized at home.

The risk of adverse outcomes after discharge is likely a function of the vulnerability of the patient and the degree to which the patient’s healthcare team and social support network mitigates this vulnerability. That is, there is a risk that a person struggles in the postdischarge period and, in many circumstances, a strong healthcare team and social network can identify health problems early and prevent them from progressing to the point that they require hospitalization.^13,94-96 There are also hospital occurrences, outside of allostatic load, that can lead to complications that lengthen the stay, weaken the patient, and directly contribute to subsequent vulnerability.^94,97 Our contention is that the allostatic load of hospitalization, which may also vary by patient depending on the circumstances of hospitalization, is just one contributor, albeit potentially an important one, to vulnerability to medical problems after discharge.

In conclusion, a plausible etiology of PHS is the maladaptive mind-body consequences of common stressors during hospitalization that compound the stress of acute illness and produce allostatic overload. This stress-induced dysfunction potentially contributes to a spectrum of generalized disease susceptibility and risk of adverse outcomes after discharge. Focused efforts to diminish patient exposure to hospital-related stressors during and after hospitalization might diminish the presence or severity of PHS. Viewing PHS from this perspective enables the development of hypothesis-driven risk-prediction models, encourages critical contemplation of traditional hospitalization, and suggests that targeted environmental interventions may significantly reduce adverse outcomes.

 

After discharge from the hospital, patients have a significantly elevated risk for adverse events, including emergency department use, hospital readmission, and death. More than 1 in 3 patients discharged from the hospital require acute care in the month after hospital discharge, and more than 1 in 6 require readmission, with readmission diagnoses frequently differing from those of the preceding hospitalization.^1-4 This heightened susceptibility to adverse events persists beyond 30 days but levels off by 7 weeks after discharge, suggesting that the period of increased risk is transient and dynamic.⁵

The term posthospital syndrome (PHS) describes this period of vulnerability to major adverse events following hospitalization.⁶ In addition to increased risk for readmission and mortality, patients in this period often show evidence of generalized dysfunction with new cognitive impairment, mobility disability, or functional decline.^7-12 To date, the etiology of this vulnerability is neither well understood nor effectively addressed by transitional care interventions.¹³

One hypothesis to explain PHS is that stressors associated with the experience of hospitalization contribute to transient multisystem dysfunction that induces susceptibility to a broad range of medical maladies. These stressors include frequent sleep disruption, noxious sounds, painful stimuli, mobility restrictions, and poor nutrition.¹² The stress hypothesis as a cause of PHS is therefore based, in large part, on evidence about allostasis and the deleterious effects of allostatic overload.

Allostasis defines a system functioning within normal stress-response parameters to promote adaptation and survival.¹⁴ In allostasis, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic and parasympathetic branches of the autonomic nervous system (ANS) exist in homeostatic balance and respond to environmental stimuli within a range of healthy physiologic parameters. The hallmark of a system in allostasis is the ability to rapidly activate, then successfully deactivate, a stress response once the stressor (ie, threat) has resolved.^14,15 To promote survival and potentiate “fight or flight” mechanisms, an appropriate stress response necessarily impacts multiple physiologic systems that result in hemodynamic augmentation and gluconeogenesis to support the anticipated action of large muscle groups, heightened vigilance and memory capabilities to improve rapid decision-making, and enhancement of innate and adaptive immune capabilities to prepare for wound repair and infection defense.^14-16 The stress response is subsequently terminated by negative feedback mechanisms of glucocorticoids as well as a shift of the ANS from sympathetic to parasympathetic tone.^17,18

Extended or repetitive stress exposure, however, leads to dysregulation of allostatic mechanisms responsible for stress adaptation and hinders an efficient and effective stress response. After extended stress exposure, baseline (ie, resting) HPA activity resets, causing a disruption of normal diurnal cortisol rhythm and an increase in total cortisol concentration. Moreover, in response to stress, HPA and ANS system excitation becomes impaired, and negative feedback properties are undermined.^14,15 This maladaptive state, known as allostatic overload, disrupts the finely tuned mechanisms that are the foundation of mind-body balance and yields pathophysiologic consequences to multiple organ systems. Downstream ramifications of allostatic overload include cognitive deterioration, cardiovascular and immune system dysfunction, and functional decline.^14,15,19

Although a stress response is an expected and necessary aspect of acute illness that promotes survival, the central thesis of this work is that additional environmental and social stressors inherent in hospitalization may unnecessarily compound stress and increase the risk of HPA axis dysfunction, allostatic overload, and subsequent multisystem dysfunction, predisposing individuals to adverse outcomes after hospital discharge. Based on data from both human subjects and animal models, we present a possible pathophysiologic mechanism for the postdischarge vulnerability of PHS, encourage critical contemplation of traditional hospitalization, and suggest interventions that might improve outcomes.

POSTHOSPITAL SYNDROME

Posthospital syndrome (PHS) describes a transient period of vulnerability after hospitalization during which patients are at elevated risk for adverse events from a broad range of conditions. In support of this characterization, epidemiologic data have demonstrated high rates of adverse outcomes following hospitalization. For example, data have shown that more than 1 in 6 older adults is readmitted to the hospital within 30 days of discharge.²⁰ Death is also common in this first month, during which rates of postdischarge mortality may exceed initial inpatient mortality.^21,22 Elevated vulnerability after hospitalization is not restricted to older adults, as readmission risk among younger patients 18 to 64 years of age may be even higher for selected conditions, such as heart failure.^3,23

Vulnerability after hospitalization is broad. In patients over age 65 initially admitted for heart failure or acute myocardial infarction, only 35% and 10% of readmissions are for recurrent heart failure or reinfarction, respectively.¹ Nearly half of readmissions are for noncardiovascular causes.¹ Similarly, following hospitalization for pneumonia, more than 60 percent of readmissions are for nonpulmonary etiologies. Moreover, the risk for all these causes of readmission is much higher than baseline risk, indicating an extended period of lack of resilience to many types of illness.²⁴ These patterns of broad susceptibility also extend to younger adults hospitalized with common medical conditions.³

Accumulating evidence suggests that hospitalized patients face functional decline, debility, and risk for adverse events despite resolution of the presenting illness, implying perhaps that the hospital environment itself is hazardous to patients’ health. In 1993, Creditor hypothesized that the “hazards of hospitalization,” including enforced bed-rest, sensory deprivation, social isolation, and malnutrition lead to a “cascade of dependency” in which a collection of small insults to multiple organ systems precipitates loss of function and debility despite cure or resolution of presenting illness.¹² Covinsky (2011) later defined hospitalization-associated disability as an iatrogenic hospital-related “disorder” characterized by new impairments in abilities to perform basic activities of daily living such as bathing, feeding, toileting, dressing, transferring, and walking at the time of hospital discharge.¹¹ Others have described a postintensive-care syndrome (PICS),²⁵ characterized by cognitive, psychiatric, and physical impairments acquired during hospitalization for critical illness that persist postdischarge and increase the long-term risk for adverse outcomes, including elevated mortality rates,^26,27 readmission rates,²⁸ and physical disabilities.²⁹ Similar to the “hazards of hospitalization,” PICS is thought to be related to common experiences of ICU stays, including mobility restriction, sensory deprivation, sleep disruption, sedation, malnutrition, and polypharmacy.^30-33

Taken together, these data suggest that adverse health consequences attributable to hospitalization extend across the spectrum of age, presenting disease severity, and hospital treatment location. As detailed below, the PHS hypothesis is rooted in a mechanistic understanding of the role of exogenous stressors in producing physiologic dysregulation and subsequent adverse health effects across multiple organ systems.

Nature of Stress in the Hospital

Compounding the stress of acute illness, hospitalized patients are routinely and repetitively exposed to a wide variety of environmental stressors that may have downstream adverse consequences (Table 1). In the absence of overt clinical manifestations of harm, the possible subclinical physiologic dysfunction generated by the following stress exposures may increase patients’ susceptibility to the manifestations of PHS.

Sleep Disruption

Sleep disruptions trigger potent stress responses,^34,35 yet they are common occurrences during hospitalization. In surveys, about half of patients report poor sleep quality during hospitalization that persists for many months after discharge.³⁶ In a simulated hospital setting, test subjects exposed to typical hospital sounds (paging system, machine alarms, etc.) experienced significant sleep-wake cycle abnormalities.³⁷ Although no work has yet focused specifically on the physiologic consequences of sleep disruption and stress in hospitalized patients, in healthy humans, mild sleep disruption has clear effects on allostasis by disrupting HPA activity, raising cortisol levels, diminishing parasympathetic tone, and impairing cognitive performance.^{18,34,35,38,39}

Malnourishment

Malnourishment in hospitalized patients is common, with one-fifth of hospitalized patients receiving nothing per mouth or clear liquid diets for more than 3 continuous days,⁴⁰ and one-fifth of hospitalized elderly patients receiving less than half of their calculated nutrition requirements.⁴¹ Although the relationship between food restriction, cortisol levels, and postdischarge outcomes has not been fully explored, in healthy humans, meal anticipation, meal withdrawal (withholding an expected meal), and self-reported dietary restraint are known to generate stress responses.^42,43 Furthermore, malnourishment during hospitalization is associated with increased 90-day and 1-year mortality after discharge,⁴⁴ adding malnourishment to the list of plausible components of hospital-related stress.

Mobility Restriction

Physical activity counterbalances stress responses and minimizes downstream consequences of allostatic load,¹⁵ yet mobility limitations via physical and chemical restraints are common in hospitalized patients, particularly among the elderly.^45-47 Many patients are tethered to devices that make ambulation hazardous, such as urinary catheters and infusion pumps. Even without physical or chemical restraints or a limited mobility order, patients may be hesitant to leave the room so as not to miss transport to a diagnostic study or an unscheduled physician’s visit. Indeed, mobility limitations of hospitalized patients increase the risk for adverse events after discharge, while interventions designed to encourage mobility are associated with improved postdischarge outcomes.^47,48

Other Stressors

Other hospital-related aversive stimuli are less commonly quantified, but clearly exist. According to surveys of hospitalized patients, sources of emotional stress include social isolation; loss of autonomy and privacy; fear of serious illness; lack of control over activities of daily living; lack of clear communication between treatment team and patients; and death of a patient roommate.^49,50 Furthermore, consider the physical discomfort and emotional distress of patients with urinary incontinence awaiting assistance for a diaper or bedding change or the pain of repetitive blood draws or other invasive testing. Although individualized, the subjective discomfort and emotional distress associated with these experiences undoubtedly contribute to the stress of hospitalization.

 

IMPACT OF ALLOSTATIC OVERLOAD ON PHYSIOLOGIC FUNCTION

Animal Models of Stress

Laboratory techniques reminiscent of the numerous environmental stressors associated with hospitalization have been used to reliably trigger allostatic overload in healthy young animals.⁵¹ These techniques include sequential exposure to aversive stimuli, including food and water deprivation, continuous overnight illumination, paired housing with known and unknown cagemates, mobility restriction, soiled cage conditions, and continuous noise. All of these techniques have been shown to cause HPA axis and ANS dysfunction, allostatic overload, and subsequent stress-mediated consequences to multiple organ systems.^19,52-54 Given the remarkable similarity of these protocols to common experiences during hospitalization, animal models of stress may be useful in understanding the spectrum of maladaptive consequences experienced by patients within the hospital (Figure 1).

These animal models of stress have resulted in a number of instructive findings. For example, in rodents, extended stress exposure induces structural and functional remodeling of neuronal networks that precipitate learning and memory, working memory, and attention impairments.^55-57 These exposures also result in cardiovascular abnormalities, including dyslipidemia, progressive atherosclerosis,^58,59 and enhanced inflammatory cytokine expression,⁶⁰ all of which increase both atherosclerotic burden and susceptibility to plaque rupture, leading to elevated risk for major cardiovascular adverse events. Moreover, these extended stress exposures in animals increase susceptibility to both bacterial and viral infections and increase their severity.^16,61 This outcome appears to be driven by a stress-induced elevation of glucocorticoid levels, decreased leukocyte proliferation, altered leukocyte trafficking, and a transition to a proinflammatory cytokine environment.^{16, 61} Allostatic overload has also been shown to contribute to metabolic dysregulation involving insulin resistance, persistence of hyperglycemia, dyslipidemia, catabolism of lean muscle, and visceral adipose tissue deposition.^62-64 In addition to cardiovascular, immune, and metabolic consequences of allostatic overload, the spectrum of physiologic dysfunction in animal models is broad and includes mood disorder symptoms,⁶⁵ intestinal barrier abnormalities,⁶⁶ airway reactivity exacerbation,⁶⁷ and enhanced tumor growth.⁶⁸

Although the majority of this research highlights the multisystem effects of variable stress exposure in healthy animals, preliminary evidence suggests that aged or diseased animals subjected to additional stressors display a heightened inflammatory cytokine response that contributes to exaggerated sickness behavior and greater and prolonged cognitive deficits.⁶⁹ Future studies exploring the consequences of extended stress exposure in animals with existing disease or debility may therefore more closely simulate the experience of hospitalized patients and perhaps further our understanding of PHS.

Hospitalized Patients

While no intervention studies have examined the effects of potential hospital stressors on the development of allostatic overload, there is evidence from small studies that dysregulated stress responses during hospitalization are associated with adverse events. For example, high serum cortisol, catecholamine, and proinflammatory cytokine levels during hospitalization have individually been associated with the development of cognitive dysfunction,^70-72 increased risk of cardiovascular events such as myocardial infarction and stroke in the year following discharge,^73-76 and the development of wound infections after discharge.⁷⁷ Moreover, elevated plasma glucose during admission for myocardial infarction in patients with or without diabetes has been associated with greater in-hospital and 1-year mortality,⁷⁸ with a similar relationship seen between elevated plasma glucose and survival after admission for stroke⁷⁹ and pneumonia.⁸⁰ Furthermore, in addition to atherothrombosis, stress may contribute to the risk for venous thromboembolism,⁸¹ resulting in readmissions for deep vein thrombosis or pulmonary embolism posthospitalization. Although potentially surrogate markers of illness acuity, a handful of studies have shown that these stress biomarkers are actually only weakly correlated with,⁸² or independent of,^72,76 disease severity. As discussed in detail below, future studies utilizing a summative measure of multisystem physiologic dysfunction as opposed to individual biomarkers may more accurately reflect the cumulative stress effects of hospitalization and subsequent risk for adverse events.

Additional Considerations

Elderly patients, in particular, may have heightened susceptibility to the consequences of allostatic overload due to common geriatric issues such as multimorbidity and frailty. Patients with chronic diseases display both baseline HPA axis abnormalities as well as dysregulated stress responses and may therefore be more vulnerable to hospitalization-related stress. For example, when subjected to psychosocial stress, patients with chronic conditions such as diabetes, heart failure, or atherosclerosis demonstrate elevated cortisol levels, increased circulating markers of inflammation, as well as prolonged hemodynamic recovery after stress resolution compared with normal controls.^83-85 Additionally, frailty may affect an individual’s susceptibility to exogenous stress. Indeed, frailty identified on hospital admission increases the risk for adverse outcomes during hospitalization and postdischarge.⁸⁶ Although the specific etiology of this relationship is unclear, persons with frailty are known to have elevated levels of cortisol and other inflammatory markers,^87,88 which may contribute to adverse outcomes in the face of additional stressors.

 

IMPLICATIONS AND NEXT STEPS

A large body of evidence stretching from bench to bedside suggests that environmental stressors associated with hospitalization are toxic. Understanding PHS within the context of hospital-induced allostatic overload presents a unifying theory for the interrelated multisystem dysfunction and increased susceptibility to adverse events that patients experience after discharge (Figure 2). Furthermore, it defines a potential pathophysiological mechanism for the cognitive impairment, elevated cardiovascular risk, immune system dysfunction, metabolic derangements, and functional decline associated with PHS. Additionally, this theory highlights environmental interventions to limit PHS development and suggests mechanisms to promote stress resilience. Although it is difficult to disentangle the consequences of the endogenous stress triggered by an acute illness from the exogenous stressors related to hospitalization, it is likely that the 2 simultaneous exposures compound risk for stress system dysregulation and allostatic overload. Moreover, hospitalized patients with preexisting HPA axis dysfunction at baseline from chronic disease or advancing age may be even more susceptible to these adverse outcomes. If this hypothesis is true, a reduction in PHS would require mitigation of the modifiable environmental stressors encountered by patients during hospitalization. Directed efforts to diminish ambient noise, limit nighttime disruptions, thoughtfully plan procedures, consider ongoing nutritional status, and promote opportunities for patients to exert some control over their environment may diminish the burden of extrinsic stressors encountered by all patients in the hospital and improve outcomes after discharge.

Hospitals are increasingly recognizing the importance of improving patients’ experience of hospitalization by reducing exposure to potential toxicities. For example, many hospitals are now attempting to reduce sleep disturbances and sleep latency through reduced nighttime noise and light levels, fewer nighttime interruptions for vital signs checks and medication administration, and commonsensical interventions like massages, herbal teas, and warm milk prior to bedtime.⁸⁹ Likewise, intensive care units are targeting environmental and physical stressors with a multifaceted approach to decrease sedative use, promote healthy sleep cycles, and encourage exercise and ambulation even in those patients who are mechanically ventilated.³⁰ Another promising development has been the increase of Hospital at Home programs. In these programs, patients who meet the criteria for inpatient admission are instead comprehensively managed at home for their acute illness through a multidisciplinary effort between physicians, nurses, social workers, physical therapists, and others. Patients hospitalized at home report higher levels of satisfaction and have modest functional gains, improved health-related quality of life, and decreased risk of mortality at 6 months compared with hospitalized patients.^90,91 With some admitting diagnoses (eg, heart failure), hospitalization at home may be associated with decreased readmission risk.⁹² Although not yet investigated on a physiologic level, perhaps the benefits of hospital at home are partially due to the dramatic difference in exposure to environmental stressors.

A tool that quantifies hospital-associated stress may help health providers appreciate the experience of patients and better target interventions to aspects of their structure and process that contribute to allostatic overload. Importantly, allostatic overload cannot be identified by one biomarker of stress but instead requires evidence of dysregulation across inflammatory, neuroendocrine, hormonal, and cardiometabolic systems. Future studies to address the burden of stress faced by hospitalized patients should consider a summative measure of multisystem dysregulation as opposed to isolated assessments of individual biomarkers. Allostatic load has previously been operationalized as the summation of a variety of hemodynamic, hormonal, and metabolic factors, including blood pressure, lipid profile, glycosylated hemoglobin, cortisol, catecholamine levels, and inflammatory markers.⁹³ To develop a hospital-associated allostatic load index, models should ideally be adjusted for acute illness severity, patient-reported stress, and capacity for stress resilience. This tool could then be used to quantify hospitalization-related allostatic load and identify those at greatest risk for adverse events after discharge, as well as measure the effectiveness of strategic environmental interventions (Table 2). A natural first experiment may be a comparison of the allostatic load of hospitalized patients versus those hospitalized at home.

The risk of adverse outcomes after discharge is likely a function of the vulnerability of the patient and the degree to which the patient’s healthcare team and social support network mitigates this vulnerability. That is, there is a risk that a person struggles in the postdischarge period and, in many circumstances, a strong healthcare team and social network can identify health problems early and prevent them from progressing to the point that they require hospitalization.^13,94-96 There are also hospital occurrences, outside of allostatic load, that can lead to complications that lengthen the stay, weaken the patient, and directly contribute to subsequent vulnerability.^94,97 Our contention is that the allostatic load of hospitalization, which may also vary by patient depending on the circumstances of hospitalization, is just one contributor, albeit potentially an important one, to vulnerability to medical problems after discharge.

In conclusion, a plausible etiology of PHS is the maladaptive mind-body consequences of common stressors during hospitalization that compound the stress of acute illness and produce allostatic overload. This stress-induced dysfunction potentially contributes to a spectrum of generalized disease susceptibility and risk of adverse outcomes after discharge. Focused efforts to diminish patient exposure to hospital-related stressors during and after hospitalization might diminish the presence or severity of PHS. Viewing PHS from this perspective enables the development of hypothesis-driven risk-prediction models, encourages critical contemplation of traditional hospitalization, and suggests that targeted environmental interventions may significantly reduce adverse outcomes.

 

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic basis of HCM is much more complex than was originally thought, with more than 1,400 mutations in 11 sarcomeric protein genes now known to be associated with the disease. Most of these mutations are autosomal dominant.³

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Obstruction of the left ventricular outflow tract is thought to be the pivotal pathophysiologic process of HCM. Other abnormalities may include myocardial ischemia and diastolic dysfunction, believed to be related to narrowing of the intramural coronary arteries.⁴ Histopathologic study of heart muscle in HCM demonstrates disarray of the hypertrophied myocyte architecture with variable patterns of interstitial fibrosis.

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

The obstruction is usually due to a combination of systolic anterior motion of the mitral valve and accelerated blood flow around the hypertrophied septum, resulting in a pushing force that sweeps the mitral valve toward the septum (Figure 3).^5,6

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

HCM is a clinical diagnosis: currently, there is no test that can definitively confirm it. It is defined as left ventricular hypertrophy without dilated ventricular chambers that cannot be explained by another disease state, with hypertrophy defined as wall thickness of 15 mm or greater in adults.⁹ The differential diagnosis of HCM is summarized in Table 1.

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Patients with symptoms may present with progressive exertional dyspnea, chest pain, or syncope that may be related to left ventricular outflow tract obstruction, myocardial ischemia, arrhythmia, or heart failure. Left ventricular outflow tract obstruction, defined as a resting peak gradient of 30 mm Hg or higher, affects one-third of HCM patients. Another third have a dynamic, provoked gradient of 30 mm Hg or higher during the Valsalva maneuver, aerobic exercise, or pharmacologic provocation with amyl nitrate.¹¹ Identifying these patients at the time of diagnosis is important for prognostication, as discussed below.

Physical findings are nonspecific

Physical findings may be unremarkable, especially in patients without resting left ventricular outflow tract obstruction. When present, the physical findings are nonspecific and include systolic murmurs, bifid carotid pulse, a fourth heart sound, and a hyperdynamic precordium.

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

 

 

Laboratory testing for phenocopies of HCM

Laboratory testing should be done at index encounters for all patients suspected of having HCM, as testing can help identify patients with HCM phenocopies, ie, a group of rare but clinically important diseases that cause pathologic left ventricular hypertrophy that is not due to sarcomeric gene defects. Identifying these conditions early is pivotal, as their natural history, management, and prognosis are significantly different (Table 2).

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

 

 

Ambulatory electrocardiographic monitoring in all patients at diagnosis

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

Two models are widely available for risk stratification in HCM (Table 3). While the consensus is to implant a cardioverter-defibrillator for secondary prevention if a patient has a history of ventricular arrhythmia or cardiac arrest, the approach to primary prevention differs between these 2 models.

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

 

 

Medical management: Beta-blockers, then calcium channel blockers

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

 

 

Septal reduction therapy

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Papillary muscle reorientation surgery (Figure 6) has been shown in retrospective studies to reduce mobility of bifid hypermobile papillary muscles and alleviate left ventricular outflow tract obstruction.⁶² It should be considered in patients who have this problem, even if they have no left ventricular hypertrophy.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic basis of HCM is much more complex than was originally thought, with more than 1,400 mutations in 11 sarcomeric protein genes now known to be associated with the disease. Most of these mutations are autosomal dominant.³

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Obstruction of the left ventricular outflow tract is thought to be the pivotal pathophysiologic process of HCM. Other abnormalities may include myocardial ischemia and diastolic dysfunction, believed to be related to narrowing of the intramural coronary arteries.⁴ Histopathologic study of heart muscle in HCM demonstrates disarray of the hypertrophied myocyte architecture with variable patterns of interstitial fibrosis.

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

The obstruction is usually due to a combination of systolic anterior motion of the mitral valve and accelerated blood flow around the hypertrophied septum, resulting in a pushing force that sweeps the mitral valve toward the septum (Figure 3).^5,6

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

HCM is a clinical diagnosis: currently, there is no test that can definitively confirm it. It is defined as left ventricular hypertrophy without dilated ventricular chambers that cannot be explained by another disease state, with hypertrophy defined as wall thickness of 15 mm or greater in adults.⁹ The differential diagnosis of HCM is summarized in Table 1.

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Patients with symptoms may present with progressive exertional dyspnea, chest pain, or syncope that may be related to left ventricular outflow tract obstruction, myocardial ischemia, arrhythmia, or heart failure. Left ventricular outflow tract obstruction, defined as a resting peak gradient of 30 mm Hg or higher, affects one-third of HCM patients. Another third have a dynamic, provoked gradient of 30 mm Hg or higher during the Valsalva maneuver, aerobic exercise, or pharmacologic provocation with amyl nitrate.¹¹ Identifying these patients at the time of diagnosis is important for prognostication, as discussed below.

Physical findings are nonspecific

Physical findings may be unremarkable, especially in patients without resting left ventricular outflow tract obstruction. When present, the physical findings are nonspecific and include systolic murmurs, bifid carotid pulse, a fourth heart sound, and a hyperdynamic precordium.

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

 

 

Laboratory testing for phenocopies of HCM

Laboratory testing should be done at index encounters for all patients suspected of having HCM, as testing can help identify patients with HCM phenocopies, ie, a group of rare but clinically important diseases that cause pathologic left ventricular hypertrophy that is not due to sarcomeric gene defects. Identifying these conditions early is pivotal, as their natural history, management, and prognosis are significantly different (Table 2).

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

 

 

Ambulatory electrocardiographic monitoring in all patients at diagnosis

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

Two models are widely available for risk stratification in HCM (Table 3). While the consensus is to implant a cardioverter-defibrillator for secondary prevention if a patient has a history of ventricular arrhythmia or cardiac arrest, the approach to primary prevention differs between these 2 models.

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

 

 

Medical management: Beta-blockers, then calcium channel blockers

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

 

 

Septal reduction therapy

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Papillary muscle reorientation surgery (Figure 6) has been shown in retrospective studies to reduce mobility of bifid hypermobile papillary muscles and alleviate left ventricular outflow tract obstruction.⁶² It should be considered in patients who have this problem, even if they have no left ventricular hypertrophy.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

Hypertrophic cardiomyopathy (HCM) is a complex disease. Most people who carry the mutations that cause it are never affected at any point in their life, but some are affected at a young age. And in rare but tragic cases, some die suddenly while competing in sports. With such a wide range of phenotypic expressions, a single therapy does not fit all.

HCM is more common than once thought. Since the discovery of its genetic predisposition in 1960, it has come to be recognized as the most common heritable cardiovascular disease.¹ Although earlier epidemiologic studies had estimated a prevalence of 1 in 500 (0.2%) of the general population, genetic testing and cardiac magnetic resonance imaging (MRI) now show that up to 1 in 200 (0.5%) of all people may be affected.^1,2 Its prevalence is significant in all ethnic groups.

This review outlines our expanding knowledge of the pathophysiology, diagnosis, and clinical management of HCM.

A PLETHORA OF MUTATIONS IN CARDIAC SARCOMERIC GENES

The genetic basis of HCM is much more complex than was originally thought, with more than 1,400 mutations in 11 sarcomeric protein genes now known to be associated with the disease. Most of these mutations are autosomal dominant.³

The genetic differences within HCM result in varying degrees and locations of left ventricular hypertrophy. Any segment of the ventricle can be involved, although HCM is classically asymmetric and mainly involves the septum (Figure 1). A variant form of HCM involves the apex of the heart (Figure 2).

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

Obstruction of the left ventricular outflow tract is thought to be the pivotal pathophysiologic process of HCM. Other abnormalities may include myocardial ischemia and diastolic dysfunction, believed to be related to narrowing of the intramural coronary arteries.⁴ Histopathologic study of heart muscle in HCM demonstrates disarray of the hypertrophied myocyte architecture with variable patterns of interstitial fibrosis.

Only in the last decade has the significance of left ventricular outflow tract obstruction in HCM been truly appreciated. The degree of obstruction in HCM is dynamic, as opposed to the fixed obstruction in patients with aortic stenosis or congenital subvalvular membranes. Therefore, in HCM, exercise or drugs (eg, dobutamine) that increase cardiac contractility increase the obstruction, as do maneuvers or drugs (the Valsalva maneuver, nitrates) that reduce filling of the left ventricle.

The obstruction is usually due to a combination of systolic anterior motion of the mitral valve and accelerated blood flow around the hypertrophied septum, resulting in a pushing force that sweeps the mitral valve toward the septum (Figure 3).^5,6

A less common source of dynamic obstruction is the papillary muscles (Figure 4). Hypertrophy of the papillary muscles can result in obstruction by these muscles themselves, which is visible on echocardiography. Anatomic variations include anteroapical displacement or bifid papillary muscles, and these variants can be associated with dynamic left ventricular outflow tract obstruction, even with no evidence of septal thickening (Figure 5).^7,8 Recognizing this patient subset has important implications for management, as discussed below.

DIAGNOSTIC EVALUATION

The clinical presentation varies

HCM is a clinical diagnosis: currently, there is no test that can definitively confirm it. It is defined as left ventricular hypertrophy without dilated ventricular chambers that cannot be explained by another disease state, with hypertrophy defined as wall thickness of 15 mm or greater in adults.⁹ The differential diagnosis of HCM is summarized in Table 1.

Even if patients harbor the same genetic variant, the clinical presentation can differ widely. Although the most feared presentation is sudden cardiac death, particularly in young athletes, most patients have no symptoms and can anticipate a normal life expectancy. The annual incidence of sudden cardiac death in all HCM patients is estimated at less than 1%.¹⁰ Sudden cardiac death in HCM patients is most often due to ventricular tachyarrhythmias and most often occurs in asymptomatic patients under age 35.

Patients with symptoms may present with progressive exertional dyspnea, chest pain, or syncope that may be related to left ventricular outflow tract obstruction, myocardial ischemia, arrhythmia, or heart failure. Left ventricular outflow tract obstruction, defined as a resting peak gradient of 30 mm Hg or higher, affects one-third of HCM patients. Another third have a dynamic, provoked gradient of 30 mm Hg or higher during the Valsalva maneuver, aerobic exercise, or pharmacologic provocation with amyl nitrate.¹¹ Identifying these patients at the time of diagnosis is important for prognostication, as discussed below.

Physical findings are nonspecific

Physical findings may be unremarkable, especially in patients without resting left ventricular outflow tract obstruction. When present, the physical findings are nonspecific and include systolic murmurs, bifid carotid pulse, a fourth heart sound, and a hyperdynamic precordium.

It can be difficult to distinguish the murmur of left ventricular outflow tract obstruction in HCM from a murmur related to aortic stenosis by auscultation alone. The simplest clinical method for telling them apart involves the Valsalva maneuver: bearing down creates a positive intrathoracic pressure and limits venous return, thus decreasing intracardiac filling pressure. This in turn results in less separation between the mitral valve and the ventricular septum in HCM, which increases obstruction and therefore makes the murmur louder. In contrast, in patients with fixed obstruction due to aortic stenosis, the murmur will decrease in intensity owing to the reduced flow associated with reduced preload.

 

 

Laboratory testing for phenocopies of HCM

Laboratory testing should be done at index encounters for all patients suspected of having HCM, as testing can help identify patients with HCM phenocopies, ie, a group of rare but clinically important diseases that cause pathologic left ventricular hypertrophy that is not due to sarcomeric gene defects. Identifying these conditions early is pivotal, as their natural history, management, and prognosis are significantly different (Table 2).

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷

 

 

Ambulatory electrocardiographic monitoring in all patients at diagnosis

Ambulatory electrocardiographic monitoring for 24 to 48 hours is recommended for all HCM patients at the time of diagnosis, even if they have no symptoms. Any evidence of nonsustained ventricular tachycardia suggests a substantially higher risk of sudden cardiac death.^28,29

In patients with no symptoms or history of arrhythmia, current guidelines suggest ambulatory electrocardiographic monitoring every 1 to 2 years.^9,21

Two risk-stratification models

Two models are widely available for risk stratification in HCM (Table 3). While the consensus is to implant a cardioverter-defibrillator for secondary prevention if a patient has a history of ventricular arrhythmia or cardiac arrest, the approach to primary prevention differs between these 2 models.

The North American model was the first risk-stratification tool and considers 5 risk factors.⁹ However, if this algorithm were strictly followed, up to 60% of HCM patients would be candidates for cardioverter-defibrillator implantation.

The European model. This concern led to the development of the HCM Risk-SCD (sudden cardiac death), a risk-stratification tool introduced in the 2014 European Society of Cardiology HCM guidelines.³⁰ This web-based calculator estimates a patient’s 5-year risk of sudden cardiac death using a complex calculation based on 7 clinical risk factors. If a patient’s calculated 5-year risk of sudden cardiac death is 6% or higher, cardioverter-defibrillator implantation is recommended for primary prevention.

The HCM Risk-SCD calculator was validated and compared with classic risk factors alone in a retrospective cohort study in 48 HCM patients.³⁰ Compared with the North American model, the European model results in a lower rate of cardioverter-defibrillator implantation (20% to 26%).^31,32

Despite the better specificity of the European model, a large retrospective cohort analysis showed that a significant number of patients stratified as being at low risk for sudden cardiac death were ultimately found to be at high risk in clinical practice.³¹ Further research is needed to find the optimal risk-stratification approach in HCM patients at low to intermediate risk.

GENETIC TESTING, COUNSELING, AND FAMILY SCREENING

Genetic testing is becoming more widely available and has rapidly expanded in clinical practice. Genetic counseling must be performed alongside genetic testing and requires professionals trained to handle the clinical and social implications of genetic testing. With this in mind, genetic testing can provide a definitive means of identifying family members at risk of HCM.

Given the autosomal dominant nature of HCM, screening for HCM is recommended in all first-degree relatives of an affected patient. Genetic testing may be a means to achieve this if a pathogenic mutation has been identified in the affected patient. However, serial electrocardiographic and transthoracic echocardiographic monitoring is an acceptable alternative in those without a clear genetic mutation association or in those who do not want to undergo genetic testing. If these first-degree relatives who do not undergo genetic testing are adult athletes or adolescents, they should undergo surveillance monitoring, with echocardiography and electrocardiography, whereas adults not participating in athletics should be monitored every 5 years.^9,21

As genetic counseling and testing become more widely available, more patients are being found who harbor a mutation but have no phenotypic manifestations of HCM on initial presentation. Clinical expression varies, so continued monitoring of these patients is important. Expert guidelines again recommend serial electrocardiography, transthoracic echocardiography, and clinical assessment every 5 years for adults.⁹

Recent data suggest that up to 40% of HCM cases are nonfamilial, ie, their inheritance is sporadic with no known family history and no sarcomeric gene mutation evident on screening.^33,34 The clinical course in this subgroup seems to be more benign, with later clinical presentations (age > 40) and lower risk of major adverse cardiovascular events.

MANAGEMENT

Conservative management

Asymptomatic HCM can usually be managed with lifestyle modifications.

Avoiding high-risk physical activities is the most important modification. All HCM patients should be counseled on the risk of sudden cardiac death and advised against participating in competitive sports or intense physical activity.³⁵ Aerobic exercise is preferable to isometric exercises such as weightlifting, which may prompt the Valsalva maneuver with worsening of left ventricular outflow tract obstruction leading to syncope. A recent study showed that moderate-intensity aerobic exercise can safely improve exercise capacity, which may ultimately improve functional status and quality of life.³⁶

Avoiding dehydration and excessive alcohol intake are also important in maintaining adequate preload to prevent an increasing left ventricular outflow tract gradient, given the dynamic nature of the left ventricular outflow tract obstruction in HCM.

 

 

Medical management: Beta-blockers, then calcium channel blockers

Beta-blockers are the first-line therapy for symptomatic HCM related to left ventricular outflow tract obstruction. Their negative inotropic effect reduces the contractile force of the ventricle, effectively reducing the pressure gradient across the outflow tract. Reduced contractility also means that the overall myocardial workload is less, which ultimately translates to a reduced oxygen demand. With their negative chronotropic effect, beta-blockers lower the heart rate and thereby lengthen the diastolic filling phase, allowing for optimization of preload conditions to help prevent increasing the left ventricular outflow tract gradient.^37,38

Beta-blockers can be titrated according to the patient’s symptoms and tolerance. Fatigue and loss of libido are among the most common side effects.

Nondihydropyridine calcium channel blockers can be a second-line therapy in patients who cannot tolerate beta-blockers. Several studies have shown improvement in surrogate outcomes such as estimated left ventricular mass and QRS amplitude on electrocardiography, but currently no available data show that these drugs improve symptoms.^28,39,40 They should be avoided in those with severe left ventricular outflow tract obstruction (gradient ≥ 100 mm Hg), as they can lead to critical outflow tract obstruction owing to their peripheral vasodilatory effect.

Dihydropyridine calcium channel blockers should be avoided altogether, as they produce even more peripheral vasodilation and afterload reduction than nondihydropyridine calcium channel blockers.

Disopyramide, a class IA antiarrhythmic, has been shown to effectively reduce outflow gradients and relieve symptoms. However, in view of its adverse effects, it is a third-line therapy, given to those for whom beta-blockers and calcium channel blockers have failed. Its most worrisome adverse effect is QT prolongation, and the QT interval should therefore be closely monitored at the start of treatment. Anticholinergic effects are common and include dry eyes and mouth, urinary retention, and drowsiness.

Disopyramide is usually used in combination with beta-blockers for symptom control as a bridge to a planned invasive intervention.⁴¹

Use with caution

Any medication that causes afterload reduction, peripheral vasodilation, intravascular volume depletion, or positive inotropy can worsen the dynamic left ventricular outflow tract obstruction in a patient with HCM and should be avoided.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and nitrates must be used with extreme caution in these patients.

Diuretics. Even restrained use of diuretics can cause significant hemodynamic compromise in patients with obstructive physiology. Therefore, diuretics should be used sparingly in these patients.

Digoxin should not be used for managing atrial fibrillation in these patients, as its positive inotropic effect increases contractility and increases the left ventricular outflow tract gradient.

Norepinephrine and inotropic agents such as dobutamine and dopamine should be avoided for the same reason as digoxin. In patients with circulatory shock requiring vasopressor support, pure alpha-agonists such as phenylephrine are preferred, as they increase peripheral resistance without an inotropic effect.

Anticoagulation for atrial tachyarrhythmias

The risk of systemic thromboembolic events is significantly increased in HCM patients with atrial fibrillation or flutter, regardless of their estimated risk using conventional risk-stratification tools such as the CHADS₂ score.^42–44 In accordance with current American Heart Association and American College of Cardiology guidelines, we recommend anticoagulation therapy for all HCM patients with a history of atrial fibrillation or flutter. Warfarin is the preferred anticoagulant; direct oral anticoagulants can be considered, but there are currently no data on their use in HCM.⁹

Standard heart failure treatments

End-stage systolic heart failure is a consequence of HCM but affects only 3% to 4% of patients.⁴⁵ While most randomized controlled trials of heart failure treatment have excluded HCM patients, current guidelines recommend the same evidence-based medical therapies used in other patients who have heart failure with reduced ejection fraction. This includes ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists if indicated.^9,21

Heart transplant should be considered in patients with class III or IV New York Heart Association functional status despite optimization of their HCM treatment regimen. Heart transplant outcomes for HCM patients are comparable to outcomes for patients who receive a transplant for non-HCM cardiovascular disease.^45,46

 

 

Septal reduction therapy

If medical therapy fails or is not tolerated in patients with severe symptoms, surgery can be considered for obstructive HCM.

Ventricular septal myectomy has been the long-standing gold standard of invasive therapy. Multiple studies have demonstrated long-term survival after myectomy to be equivalent to that in the general population and better than that of HCM patients who do not undergo this surgery.^47–50 Factors that may be associated with better surgical outcomes include age younger than 50, left atrial size less than 46 mm, and resolution of atrial fibrillation during follow-up.⁵¹

Septal reduction therapy may also be considered in patients at high risk of sudden cardiac death based on a history of recurrent ventricular tachycardia or risk-stratification models as described above. Retrospective analyses have shown that surgical myectomy can markedly reduce the incidence of appropriate implantable cardioverter-defibrillator discharges and the risk of sudden cardiac death.⁵²

Alcohol septal ablation is an alternative. This percutaneous procedure, first described in the mid-1990s, consists of injecting a small amount of alcohol into the artery supplying the septum to induce myocardial necrosis, ultimately leading to scarring and widening of the left ventricular outflow tract.⁵³

Up to 50% of patients develop right bundle branch block after alcohol septal ablation, and the risk of complete heart block is highest in those with preexisting left bundle branch block. Nevertheless, studies have shown significant symptomatic improvement after alcohol septal ablation, with long-term survival comparable to that in the general population.^53–56

Several meta-analyses compared alcohol septal ablation and septal myectomy and found that the rates of functional improvement and long-term mortality were similar.^57–59 However, the less-invasive approach with alcohol septal ablation comes at the cost of a higher incidence of conduction abnormalities and higher left ventricular outflow tract gradients afterward. One meta-analysis found that alcohol septal ablation patients may have 5 times the risk of needing additional septal reduction therapy compared with their myectomy counterparts.

Current US guidelines recommend septal myectomy, performed at an experienced center, as the first-line interventional treatment, leaving alcohol septal ablation to be considered in those who have contraindications to myectomy.⁹ The treatment strategy should ultimately be individualized based on a patient’s comorbidities and personal preferences following informed consent.

A nationwide database study recently suggested that postmyectomy mortality rates may be as high as 5.9%,⁶⁰ although earlier studies at high-volume centers showed much lower mortality rates (< 1%).^50–52,61 This discrepancy highlights the critical role of expert centers in optimizing surgical management of these patients. Regardless of the approach, interventional therapies for HCM should be performed by a multidisciplinary team at a medical center able to handle the complexity of these cases.

Additional surgical procedures

A handful of other procedures may benefit specific patient subgroups.

Papillary muscle reorientation surgery (Figure 6) has been shown in retrospective studies to reduce mobility of bifid hypermobile papillary muscles and alleviate left ventricular outflow tract obstruction.⁶² It should be considered in patients who have this problem, even if they have no left ventricular hypertrophy.

Apical myectomy has been shown to improve functional status in patients with isolated apical hypertrophy by reducing left ventricular end-diastolic pressure and thereby allowing for improved diastolic filling.⁶³

Mitral valve surgery may need to be considered at the time of myectomy in patients with degenerative valve disease. As in the general population, mitral valve repair is preferred to replacement if possible. 

Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal lung disease that generally affects older adults. It is characterized by a radiographic and histopathologic pattern of usual interstitial pneumonia (UIP) that has no other known etiology.

See related editorial

Accurate diagnosis of IPF is crucial. We recommend early referral to a center specializing in interstitial lung disease to confirm the diagnosis, start appropriate therapy, advise the patient on prognosis and enrollment in disease registries and clinical trials, and determine candidacy for lung transplant.

Primary care physicians are uniquely positioned to encounter patients with IPF, whether because of a patient complaint or as an incidental finding on computed tomography. The goal of this article is to delineate the features of IPF so that it may be recognized early and thus expedite referral to a center with expertise in interstitial lung disease for a thorough evaluation and appropriate management.

WHAT IS IDIOPATHIC PULMONARY FIBROSIS?

IPF is 1 of more than 150 interstitial lung diseases, conditions that share nonspecific symptoms such as dysp­nea and a dry cough with insidious onset, certain radiologic findings, and a restrictive ventilatory defect.¹ More specifically, IPF is categorized with the idiopathic interstitial pneumonias, which include idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, diffuse alveolar hemorrhage, cryptogenic organizing pneumonia, and acute interstitial pneumonia (Table 1).² Identification of the pattern of UIP, the hallmark of IPF, is integral to establishing the diagnosis, as is exclusion of other causes of interstitial lung disease—eg, connective tissue disease, medication reaction, inhalational exposure, pneumoconioses, and granulomatous diseases (both infectious and noninfectious).

MORE COMMON THAN ONCE THOUGHT

The true incidence and prevalence of IPF are difficult to assess. IPF is generally considered a rare disease, but it is more common than once thought. In 2011, Raghu et al³ estimated the prevalence in Medicare beneficiaries to be 495 cases per 100,000. Based on this estimate and the current US population, up to 160,000 Americans could have IPF.⁴ Raghu et al also showed that IPF more often affects adults over age 65, which suggests that as the US population ages, the incidence of IPF may rise. Studies have also reported an increased incidence of IPF worldwide.⁵

Further, with the rising use of low-dose computed tomography to screen for lung cancer, more incidental cases of IPF will likely be found.^6–8

Older data showed a lag from symptom onset to accurate diagnosis of 1 to 2 years.⁹ A more recent study found a lag in referral of patients with IPF to tertiary care centers, and this delay was associated with a higher rate of death independent of disease severity.¹⁰

TYPICALLY PROGRESSIVE, OFTEN FATAL

IPF is typically progressive and limited to the lungs, and it portends a poor prognosis. The median survival is commonly cited as 2 to 5 years from diagnosis, although this is based on older observations that may not reflect current best practice and newer therapies. More recent studies suggest higher survival rates if patients have preserved lung function.¹¹

As the name indicates, the etiology of IPF is unknown, but studies have indicated genetic underpinnings in a notable proportion of cases.¹² Regardless of the cause, the pathogenesis and progression of IPF are thought to be the result of an abnormal and persistent wound-repair response. The progressive deposition of scar tissue disrupts normal lung architecture and function, eventually causing clinical disease.¹³

 

SYMPTOMS AND KEY FEATURES

Patients with IPF typically present with the insidious onset of dyspnea on exertion, with or without chronic cough. Risk factors include male sex, increasing age, and a history of smoking. Patients with undiagnosed IPF who present with dyspnea and a history of smoking are often treated empirically for chronic obstructive pulmonary disease (COPD).

Rales are a common finding on auscultation in IPF, and this can lead to an exhaustive cardiac evaluation and empiric treatment for heart failure. Digital clubbing is also relatively common.¹⁴ Hypoxemia with exertion is another common feature that also often correlates with disease severity and prognosis. Resting hypoxemia is more common in advanced disease.

On spirometry, patients with IPF typically demonstrate restrictive physiology, suggested by a normal or elevated ratio of the forced expiratory volume in 1 second to the forced vital capacity (FEV₁/FVC) (> 70% predicted or above the lower limit of normal) combined with a lower than normal FVC. Restrictive physiology is definitively demonstrated by a decreased total lung capacity (< 80% predicted or below the lower limit of normal) on plethysmography. Impaired gas exchange, manifested by a decreased diffusing capacity of the lungs for carbon monoxide (DLCO) on pulmonary function testing, is also common. Because pulmonary perfusion is higher in the lung bases, where IPF is also predominant, the DLCO is often reduced to a greater extent than the FVC.

PROGNOSTIC INDICATORS

Clinicians typically view IPF as a relentless and progressive process, but its course is variable and can be uncertain in an individual patient (Figure 1).^15,16 Nevertheless, over time, most patients have a decline in lung function leading to respiratory failure. Respiratory failure, often preceded by a subacute deterioration (over weeks to months) or an acute deterioration (< 4 weeks), is the most common cause of death, but comorbid diseases such as lung cancer, infection, and heart failure are also common causes of death in these patients.^17,18

Predictors of mortality include worsening FVC, DLCO, symptoms, and physiologic impairment, manifested by a decline in the 6-minute walking test or worsening exertional hypoxemia.^19–22 Other common comorbidities linked with impaired quality of life and poor prognosis include obstructive sleep apnea, gastroesophageal reflux disease, and depression.^16,23 Retrospective studies suggest that most IPF patients die 2 to 5 years after symptom onset. With the lag from symptom onset to final diagnosis, the average life expectancy is as little as 2 years from the time of diagnosis.^9,18,24,25

Two staging systems have been developed to predict short-term and long-term mortality risk based on sex, age, and physiologic parameters.^23,24 The GAP (gender, age, physiology) index provides an estimate of the risk of death for a cohort of patients: a score of 0 to 8 is calculated, and the score is then categorized as stage I, II, or III. Each stage is associated with 1-, 2-, and 3-year mortality rates, with stage III having the highest rates. The GAP calculator (www.acponline.org/journals/annals/extras/gap) provides an estimate of the risk of death for an individual patient. The application of these tools for the management of IPF is evolving; however, they may be helpful for counseling patients about disease prognosis.

CLUES TO DIAGNOSIS

Histologic patterns

UIP is a histologic pattern observed on surgical lung biopsy specimens, characterized by fibrosis and a “honeycomb” pattern alternating with areas of normal lung parenchyma in a patchwork pattern (Figure 2). These abnormalities are usually subpleural and worse in the lower lobes. Inflammation is not typically seen.

UIP on histologic study is also seen in fibrotic lung diseases other than IPF, including connective tissue disease-associated interstitial lung disease, inhalational or occupational interstitial lung disease, and chronic hypersensitivity pneumonitis.^26–29 Consequently, the diagnosis of IPF requires exclusion of other known causes of UIP.

According to the 2011 guidelines,¹⁶ the histology of interstitial lung disease can be categorized as definite UIP, probable UIP, or possible UIP, or as an atypical pattern suggesting another diagnosis. If no definite cause of the interstitial lung abnormality is found, the level of certainty of the histopathologic pattern of UIP helps formulate the clinical diagnosis and management plan.

Clues on computed tomography

The UIP nomenclature also describes patterns on high-resolution computed tomography (HRCT). HRCT is done without contrast and produces thin-sliced images (usually < 1.5 mm) in inspiratory, expiratory, and prone views; this allows detection of air trapping, which may indicate an airway-centric alternative diagnosis.

On HRCT, UIP appears as reticular opacities, often with traction bronchiectasis or bronchiolectasis, usually with a basilar and peripheral predominance. Honeycombing is a key feature and appears as clustered cystic spaces with well-defined walls in the periphery of the lung parenchyma. Ground-glass opacities are not a prominent feature of UIP, and although they do not exclude a UIP pattern, they should spur consideration of other diagnoses.¹⁶ Reactive mediastinal and hilar lymphadenopathy is another common feature of UIP.

When evaluating results of HRCT for UIP, the radiologist categorizes the pattern as definite UIP, possible UIP, or inconsistent. The definite pattern meets all the above features and has none of the features suggesting an alternative diagnosis (Figure 3). The possible pattern includes all the above features with the exception of honeycombing. If the predominant features on HRCT include any atypical finding listed above, then the study is considered inconsistent with UIP. If the pattern on HRCT is considered definite, evaluation of pathology is not necessary. If the pattern is categorized as possible or is inconsistent, then surgical lung biopsy-confirmed UIP is necessary for the definitive diagnosis of IPF.

However, evidence is emerging that in the correct clinical scenario, possible UIP behaves similarly to definite UIP and may be sufficient to make the clinical diagnosis of IPF even without surgical biopsy confirmation.³⁰

 

A DIAGNOSTIC ALGORITHM FOR IPF

Given the multitude of interstitial lung diseases, their complexities, and the lack of a gold standard definitive diagnostic test, the diagnosis of IPF can be difficult, requiring the integration of clinical, radiologic, and, if necessary, pathologic findings.

Multiple pathologic processes can appear as UIP on imaging or lung biopsy, and these pathologic processes must be ruled out before diagnosing IPF. To aid in ruling out other conditions, the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association formulated joint evidence-based guidelines for the diagnosis and treatment of IPF.¹⁶ The guidelines include an algorithm as an aid to the systematic evaluation. We propose a new algorithm (Figure 4) that is slightly but not insignificantly different from the algorithm in the joint guidelines.

Demographic features

The patient’s demographic features and risk factors dictate the initial clinical suspicion of IPF compared with other interstitial lung diseases. The incidence of IPF increases with age, and IPF is more common in men. A history of smoking is another risk factor.³¹ A 45-year-old never-smoker is much less likely to have IPF than a 70-year-old former smoker, and a 70-year-old man is more likely to have IPF than a woman of the same age. Thus, the finding of interstitial lung disease in a patient with a demographic profile that is not typical (ie, a younger woman who never smoked) should prompt an exhaustive investigation for another diagnosis such as hypersensitivity pneumonitis or connective tissue disease.

Key elements of the history

After considering the demographic profile and risk factors, the next step in the evaluation is a thorough and accurate medical history. This should include assessment of the severity of dyspnea and cough, signs and symptoms of connective tissue disease (eg, arthralgias, sicca symptoms, Raynaud phenomenon, difficulty swallowing), and gastroesophageal reflux disease, which can be associated with connective tissue disease and, independently, with IPF.

It is also important to identify any environmental exposures that suggest pneumoconiosis or chronic hypersensitivity pneumonitis. The most common risk factors for hypersensitivity pneumonitis are birds and bird feathers, molds, fungi, hot tub use, and some industrial chemicals.³²

A medication history is important. Many medications are associated with interstitial lung disease, but amiodarone, bleomycin, methotrexate, and nitrofurantoin are among the common offenders.³³

A thorough family history is necessary, as there are familial forms of IPF.

Focus of the physical examination

The physical examination must include careful auscultation for rales. While rales are not specific for IPF, they are the most common pulmonary abnormality. Detailed skin, musculoskeletal, and cardiovascular examinations are also important to evaluate for rheumatologic signs, clubbing, or evidence of heart failure or pulmonary hypertension.

Laboratory tests

Laboratory testing should include a serologic autoantibody panel to evaluate for connective tissue diseases that can manifest as interstitial lung disease, including rheumatoid arthritis, dermatopolymyositis, scleroderma, Sjögren syndrome, and undifferentiated or mixed connective tissue disease. Typical preliminary laboratory tests are antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein. Others may include anticyclic citrullinated peptide (anti-CCP), anti-Scl-70, anti-RNP, anti-SS-A, anti-SS-B, and anti-Jo-1.¹⁶ The breadth of the panel should depend on patient demographics and findings in the history or physical examination that increase or decrease the likelihood of a connective tissue disease.

Lung function testing

Assessing the patient’s pulmonary physiology should include spirometry, DLCO, and body plethysmography (lung volumes). In most cases, IPF manifests with restrictive physiology. Once restrictive physiology is confirmed with a low total lung capacity, FVC testing can be used as a longitudinal surrogate, as it is less expensive and easier for the patient to perform. In general, a lower total lung capacity or FVC indicates more severe impairment.

The DLCO serves as another marker of severity but is less reliable due to baseline variability and difficulties performing the maneuver.

A 6-minute walk test is another crucial physiologic assessment tool that can quantify exertional hypoxemia and functional status (ie, distance walked), and can assist in prognosis.

Imaging

Most patients undergo chest radiography in the workup for undiagnosed dyspnea. However, chest radiography is not adequate to formulate an accurate diagnosis in suspected interstitial lung disease, and a normal radiograph cannot exclude changes that might reflect early phases of the disease. As the disease progresses, the plain radiograph can show reticulonodular opacities and honeycombing in the peripheral and lower lung zones (Figure 3).³⁴

The decision whether to order HRCT in the workup for a patient who has dyspnea and a normal chest radiograph is challenging. We recommend cross-sectional imaging when physiologic testing shows restriction or low DLCO, or when there is a high index of suspicion for underlying lung disease as the cause of symptoms.

Expert consultation can aid with this decision, especially when the underlying cause of dyspnea remains unclear after initial studies have been completed. Otherwise, HRCT is an essential test in the evaluation of interstitial lung disease.

Bronchoscopy’s role controversial

If the pattern on HRCT is nondiagnostic, then surgical biopsy is necessary, and the diagnosis of IPF requires a histologic pattern of UIP as described above.^16,35

Although bronchoscopy can be valuable if an alternative diagnosis such as sarcoidosis or chronic hypersensitivity pneumonitis is suspected, the role of bronchoscopic biopsy in the workup of IPF is controversial. The patchy nature of UIP does not lend itself to the relatively small biopsy samples obtained through bronchoscopy.^36,37

Surgical biopsy options

The favored biopsy approach is surgical, using either an open or a video-assisted thoracoscopic technique. The latter is preferred as it is less invasive, requires a shorter length of hospital stay, and allows a faster recovery.³⁸ Bronchoscopic cryobiopsy, currently under investigation, is a potentially valuable tool whose role in diagnosing IPF is evolving.

Frequently, neither HRCT nor surgical lung biopsy demonstrates UIP, making the definitive diagnosis of IPF difficult. Moreover, some patients with nondiagnostic HRCT results are unable to tolerate surgical lung biopsy because of severely impaired lung function or other comorbidities.

The role of multidisciplinary discussions

When surgical lung biopsy is not possible, current practice at leading centers uses a multidisciplinary approach to allow for a confident diagnosis.^30,39 Discussions take place between pulmonologists, pathologists, radiologists, and other specialists to collectively consider all aspects of a case before rendering a consensus opinion on the diagnosis and the management plan. If the discussion leads to a consensus diagnosis of IPF, then the patient’s clinician can move forward with treatment options. If not, the group can recommend further workup or alternative diagnoses and treatment regimens. The multidisciplinary group is also well positioned to consider the relative risks and benefits of moving forward with surgical lung biopsy for individual patients.

This approach illustrates the importance of referring these patients to centers of excellence in diagnosing and managing complex cases of interstitial lung disease, including IPF.⁴⁰

 

TREATMENT OF IPF

Antifibrotic therapy

Antifibrotic therapy is a choice between pirfenidone and nintedanib.

Pirfenidone, which has an undefined molecular target, was approved based on the results of 3 trials.^41,42 Pooled analyses from these trials showed a reduction in the decline from baseline in FVC percent predicted and improved progression-free survival.⁴³ Pooled and meta-analyses of pirfenidone clinical trials have shown a mortality benefit, although no individual study has shown such an effect on mortality rates.⁴⁴

The major adverse effects of pirfenidone are gastrointestinal distress and photosensitivity rash.

Nintedanib is a triple tyrosine kinase inhibitor that broadly targets fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor receptors. Combined analysis of 2 concurrent trials⁴⁵ showed that nintedanib reduced the decline in FVC, similarly to pirfenidone. The major adverse event associated with nintedanib was diarrhea. Since it inhibits vascular endothelial growth factor, there is a risk of hematologic complications such as bleeding or clotting events.

Because pirfenidone and nintedanib can increase aminotransferase levels, regular monitoring is recommended.

To date, no trial has compared pirfenidone and nintedanib in terms of their efficacy and tolerability. Therefore, the choice of agent is based on the patient’s preference after a discussion of potential risks and expected benefits, a review of each drug’s side effects, and consideration of comorbid conditions and physician experience.

Patients need to understand that these drugs slow the rate of decline in FVC but have not been shown to improve symptoms or functional status.

Corticosteroids are not routine

Corticosteroids should not be used routinely in the treatment of IPF. Although steroids, alone or in combination with other immunosuppressive medications, were commonly used for IPF in the past, such use was not based on results of randomized controlled trials.⁴⁶ Retrospective controlled studies have failed to show that corticosteroids improve mortality rates in IPF; indeed, they have shown that corticosteroids confer substantial morbidity.^47,48 In addition, a randomized controlled trial combining corticosteroids with N-acetylcysteine and azathioprine was stopped early due to an increased risk of death and hospitalization.⁴⁹ Collectively, these data suggest that corticosteroids confer no benefit and are potentially harmful. Their use in IPF is discouraged, and the joint international guidelines recommend against immunosuppression to treat IPF.¹⁶

Other treatments

The guidelines offer additional suggestions for the management of IPF.

Preliminary evidence suggests that microaspiration associated with abnormal gastroesophageal acid reflux is a risk factor for IPF. As such, there is a weak recommendation for aggressive treatment of reflux disease.⁵⁰ However, because evidence suggests that proton-pump inhibitor therapy may be associated with adverse renal or central nervous system effects, this recommendation bears caution. It is hoped that ongoing studies will provide further insight into the role of acid-suppression in the management of IPF.^51,52

Further treatment recommendations include best supportive management such as supplemental oxygen, pulmonary rehabilitation, and vaccinations.

Prompt referral for lung transplant is imperative. IPF is now the most common indication for lung transplant, and given the poor overall prognosis of advanced IPF, transplant confers a survival benefit in appropriately selected patients.^53,54 Table 2 provides an evidence-based checklist for the workup and management of IPF.

ACUTE EXACERBATIONS OF IPF

The unpredictable nature of IPF can manifest in the form of acute exacerbations without an identifiable cause. The loosely defined diagnostic criteria for the diagnosis of acute exacerbations are a previous or new diagnosis of IPF, worsening or development of dyspnea in the last 30 days, and new bilateral ground-glass or consolidative changes with a background of UIP on HRCT.¹⁶

A new definition has been proposed⁵⁵ to facilitate research in the characterization and treatment of acute exacerbations of IPF. The new definition includes all causes of respiratory deterioration except for heart failure and volume overload. It is less strict about the 30-day time frame. This newer definition is based on the lack of evidence differentiating outcomes when an acute deterioration is associated with known or unknown etiologies.⁵⁵

The incidence of acute exacerbations is variable, with a 1- and 3-year incidence ranging between 8.6% and 23.9% depending on the criteria used.⁵⁶ In general, acute exacerbations carry a grim prognosis, with a median life expectancy of 2.2 months.⁵⁷

There is no approved therapy for exacerbations of IPF. Rather, treatment is mainly supportive with supplemental oxygen and mechanical ventilation. Current guidelines have a weak recommendation for the use of corticosteroids, but there are no recommendations regarding dose, route, or duration of therapy. Other treatments, primarily immunomodulatory agents, have been suggested but lack evidence of benefit.

Acknowledgments: Pathology images were provided by Carol Farver, MD, Pathology Institute, Cleveland Clinic. Radiology images were provided by Ruchi Yadav, MD, Imaging Institute, Cleveland Clinic.

Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal lung disease that generally affects older adults. It is characterized by a radiographic and histopathologic pattern of usual interstitial pneumonia (UIP) that has no other known etiology.

See related editorial

Accurate diagnosis of IPF is crucial. We recommend early referral to a center specializing in interstitial lung disease to confirm the diagnosis, start appropriate therapy, advise the patient on prognosis and enrollment in disease registries and clinical trials, and determine candidacy for lung transplant.

Primary care physicians are uniquely positioned to encounter patients with IPF, whether because of a patient complaint or as an incidental finding on computed tomography. The goal of this article is to delineate the features of IPF so that it may be recognized early and thus expedite referral to a center with expertise in interstitial lung disease for a thorough evaluation and appropriate management.

WHAT IS IDIOPATHIC PULMONARY FIBROSIS?

IPF is 1 of more than 150 interstitial lung diseases, conditions that share nonspecific symptoms such as dysp­nea and a dry cough with insidious onset, certain radiologic findings, and a restrictive ventilatory defect.¹ More specifically, IPF is categorized with the idiopathic interstitial pneumonias, which include idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, diffuse alveolar hemorrhage, cryptogenic organizing pneumonia, and acute interstitial pneumonia (Table 1).² Identification of the pattern of UIP, the hallmark of IPF, is integral to establishing the diagnosis, as is exclusion of other causes of interstitial lung disease—eg, connective tissue disease, medication reaction, inhalational exposure, pneumoconioses, and granulomatous diseases (both infectious and noninfectious).

MORE COMMON THAN ONCE THOUGHT

The true incidence and prevalence of IPF are difficult to assess. IPF is generally considered a rare disease, but it is more common than once thought. In 2011, Raghu et al³ estimated the prevalence in Medicare beneficiaries to be 495 cases per 100,000. Based on this estimate and the current US population, up to 160,000 Americans could have IPF.⁴ Raghu et al also showed that IPF more often affects adults over age 65, which suggests that as the US population ages, the incidence of IPF may rise. Studies have also reported an increased incidence of IPF worldwide.⁵

Further, with the rising use of low-dose computed tomography to screen for lung cancer, more incidental cases of IPF will likely be found.^6–8

Older data showed a lag from symptom onset to accurate diagnosis of 1 to 2 years.⁹ A more recent study found a lag in referral of patients with IPF to tertiary care centers, and this delay was associated with a higher rate of death independent of disease severity.¹⁰

TYPICALLY PROGRESSIVE, OFTEN FATAL

IPF is typically progressive and limited to the lungs, and it portends a poor prognosis. The median survival is commonly cited as 2 to 5 years from diagnosis, although this is based on older observations that may not reflect current best practice and newer therapies. More recent studies suggest higher survival rates if patients have preserved lung function.¹¹

As the name indicates, the etiology of IPF is unknown, but studies have indicated genetic underpinnings in a notable proportion of cases.¹² Regardless of the cause, the pathogenesis and progression of IPF are thought to be the result of an abnormal and persistent wound-repair response. The progressive deposition of scar tissue disrupts normal lung architecture and function, eventually causing clinical disease.¹³

 

SYMPTOMS AND KEY FEATURES

Patients with IPF typically present with the insidious onset of dyspnea on exertion, with or without chronic cough. Risk factors include male sex, increasing age, and a history of smoking. Patients with undiagnosed IPF who present with dyspnea and a history of smoking are often treated empirically for chronic obstructive pulmonary disease (COPD).

Rales are a common finding on auscultation in IPF, and this can lead to an exhaustive cardiac evaluation and empiric treatment for heart failure. Digital clubbing is also relatively common.¹⁴ Hypoxemia with exertion is another common feature that also often correlates with disease severity and prognosis. Resting hypoxemia is more common in advanced disease.

On spirometry, patients with IPF typically demonstrate restrictive physiology, suggested by a normal or elevated ratio of the forced expiratory volume in 1 second to the forced vital capacity (FEV₁/FVC) (> 70% predicted or above the lower limit of normal) combined with a lower than normal FVC. Restrictive physiology is definitively demonstrated by a decreased total lung capacity (< 80% predicted or below the lower limit of normal) on plethysmography. Impaired gas exchange, manifested by a decreased diffusing capacity of the lungs for carbon monoxide (DLCO) on pulmonary function testing, is also common. Because pulmonary perfusion is higher in the lung bases, where IPF is also predominant, the DLCO is often reduced to a greater extent than the FVC.

PROGNOSTIC INDICATORS

Clinicians typically view IPF as a relentless and progressive process, but its course is variable and can be uncertain in an individual patient (Figure 1).^15,16 Nevertheless, over time, most patients have a decline in lung function leading to respiratory failure. Respiratory failure, often preceded by a subacute deterioration (over weeks to months) or an acute deterioration (< 4 weeks), is the most common cause of death, but comorbid diseases such as lung cancer, infection, and heart failure are also common causes of death in these patients.^17,18

Predictors of mortality include worsening FVC, DLCO, symptoms, and physiologic impairment, manifested by a decline in the 6-minute walking test or worsening exertional hypoxemia.^19–22 Other common comorbidities linked with impaired quality of life and poor prognosis include obstructive sleep apnea, gastroesophageal reflux disease, and depression.^16,23 Retrospective studies suggest that most IPF patients die 2 to 5 years after symptom onset. With the lag from symptom onset to final diagnosis, the average life expectancy is as little as 2 years from the time of diagnosis.^9,18,24,25

Two staging systems have been developed to predict short-term and long-term mortality risk based on sex, age, and physiologic parameters.^23,24 The GAP (gender, age, physiology) index provides an estimate of the risk of death for a cohort of patients: a score of 0 to 8 is calculated, and the score is then categorized as stage I, II, or III. Each stage is associated with 1-, 2-, and 3-year mortality rates, with stage III having the highest rates. The GAP calculator (www.acponline.org/journals/annals/extras/gap) provides an estimate of the risk of death for an individual patient. The application of these tools for the management of IPF is evolving; however, they may be helpful for counseling patients about disease prognosis.

CLUES TO DIAGNOSIS

Histologic patterns

UIP is a histologic pattern observed on surgical lung biopsy specimens, characterized by fibrosis and a “honeycomb” pattern alternating with areas of normal lung parenchyma in a patchwork pattern (Figure 2). These abnormalities are usually subpleural and worse in the lower lobes. Inflammation is not typically seen.

UIP on histologic study is also seen in fibrotic lung diseases other than IPF, including connective tissue disease-associated interstitial lung disease, inhalational or occupational interstitial lung disease, and chronic hypersensitivity pneumonitis.^26–29 Consequently, the diagnosis of IPF requires exclusion of other known causes of UIP.

According to the 2011 guidelines,¹⁶ the histology of interstitial lung disease can be categorized as definite UIP, probable UIP, or possible UIP, or as an atypical pattern suggesting another diagnosis. If no definite cause of the interstitial lung abnormality is found, the level of certainty of the histopathologic pattern of UIP helps formulate the clinical diagnosis and management plan.

Clues on computed tomography

The UIP nomenclature also describes patterns on high-resolution computed tomography (HRCT). HRCT is done without contrast and produces thin-sliced images (usually < 1.5 mm) in inspiratory, expiratory, and prone views; this allows detection of air trapping, which may indicate an airway-centric alternative diagnosis.

On HRCT, UIP appears as reticular opacities, often with traction bronchiectasis or bronchiolectasis, usually with a basilar and peripheral predominance. Honeycombing is a key feature and appears as clustered cystic spaces with well-defined walls in the periphery of the lung parenchyma. Ground-glass opacities are not a prominent feature of UIP, and although they do not exclude a UIP pattern, they should spur consideration of other diagnoses.¹⁶ Reactive mediastinal and hilar lymphadenopathy is another common feature of UIP.

When evaluating results of HRCT for UIP, the radiologist categorizes the pattern as definite UIP, possible UIP, or inconsistent. The definite pattern meets all the above features and has none of the features suggesting an alternative diagnosis (Figure 3). The possible pattern includes all the above features with the exception of honeycombing. If the predominant features on HRCT include any atypical finding listed above, then the study is considered inconsistent with UIP. If the pattern on HRCT is considered definite, evaluation of pathology is not necessary. If the pattern is categorized as possible or is inconsistent, then surgical lung biopsy-confirmed UIP is necessary for the definitive diagnosis of IPF.

However, evidence is emerging that in the correct clinical scenario, possible UIP behaves similarly to definite UIP and may be sufficient to make the clinical diagnosis of IPF even without surgical biopsy confirmation.³⁰

 

A DIAGNOSTIC ALGORITHM FOR IPF

Given the multitude of interstitial lung diseases, their complexities, and the lack of a gold standard definitive diagnostic test, the diagnosis of IPF can be difficult, requiring the integration of clinical, radiologic, and, if necessary, pathologic findings.

Multiple pathologic processes can appear as UIP on imaging or lung biopsy, and these pathologic processes must be ruled out before diagnosing IPF. To aid in ruling out other conditions, the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association formulated joint evidence-based guidelines for the diagnosis and treatment of IPF.¹⁶ The guidelines include an algorithm as an aid to the systematic evaluation. We propose a new algorithm (Figure 4) that is slightly but not insignificantly different from the algorithm in the joint guidelines.

Demographic features

The patient’s demographic features and risk factors dictate the initial clinical suspicion of IPF compared with other interstitial lung diseases. The incidence of IPF increases with age, and IPF is more common in men. A history of smoking is another risk factor.³¹ A 45-year-old never-smoker is much less likely to have IPF than a 70-year-old former smoker, and a 70-year-old man is more likely to have IPF than a woman of the same age. Thus, the finding of interstitial lung disease in a patient with a demographic profile that is not typical (ie, a younger woman who never smoked) should prompt an exhaustive investigation for another diagnosis such as hypersensitivity pneumonitis or connective tissue disease.

Key elements of the history

After considering the demographic profile and risk factors, the next step in the evaluation is a thorough and accurate medical history. This should include assessment of the severity of dyspnea and cough, signs and symptoms of connective tissue disease (eg, arthralgias, sicca symptoms, Raynaud phenomenon, difficulty swallowing), and gastroesophageal reflux disease, which can be associated with connective tissue disease and, independently, with IPF.

It is also important to identify any environmental exposures that suggest pneumoconiosis or chronic hypersensitivity pneumonitis. The most common risk factors for hypersensitivity pneumonitis are birds and bird feathers, molds, fungi, hot tub use, and some industrial chemicals.³²

A medication history is important. Many medications are associated with interstitial lung disease, but amiodarone, bleomycin, methotrexate, and nitrofurantoin are among the common offenders.³³

A thorough family history is necessary, as there are familial forms of IPF.

Focus of the physical examination

The physical examination must include careful auscultation for rales. While rales are not specific for IPF, they are the most common pulmonary abnormality. Detailed skin, musculoskeletal, and cardiovascular examinations are also important to evaluate for rheumatologic signs, clubbing, or evidence of heart failure or pulmonary hypertension.

Laboratory tests

Laboratory testing should include a serologic autoantibody panel to evaluate for connective tissue diseases that can manifest as interstitial lung disease, including rheumatoid arthritis, dermatopolymyositis, scleroderma, Sjögren syndrome, and undifferentiated or mixed connective tissue disease. Typical preliminary laboratory tests are antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein. Others may include anticyclic citrullinated peptide (anti-CCP), anti-Scl-70, anti-RNP, anti-SS-A, anti-SS-B, and anti-Jo-1.¹⁶ The breadth of the panel should depend on patient demographics and findings in the history or physical examination that increase or decrease the likelihood of a connective tissue disease.

Lung function testing

Assessing the patient’s pulmonary physiology should include spirometry, DLCO, and body plethysmography (lung volumes). In most cases, IPF manifests with restrictive physiology. Once restrictive physiology is confirmed with a low total lung capacity, FVC testing can be used as a longitudinal surrogate, as it is less expensive and easier for the patient to perform. In general, a lower total lung capacity or FVC indicates more severe impairment.

The DLCO serves as another marker of severity but is less reliable due to baseline variability and difficulties performing the maneuver.

A 6-minute walk test is another crucial physiologic assessment tool that can quantify exertional hypoxemia and functional status (ie, distance walked), and can assist in prognosis.

Imaging

Most patients undergo chest radiography in the workup for undiagnosed dyspnea. However, chest radiography is not adequate to formulate an accurate diagnosis in suspected interstitial lung disease, and a normal radiograph cannot exclude changes that might reflect early phases of the disease. As the disease progresses, the plain radiograph can show reticulonodular opacities and honeycombing in the peripheral and lower lung zones (Figure 3).³⁴

The decision whether to order HRCT in the workup for a patient who has dyspnea and a normal chest radiograph is challenging. We recommend cross-sectional imaging when physiologic testing shows restriction or low DLCO, or when there is a high index of suspicion for underlying lung disease as the cause of symptoms.

Expert consultation can aid with this decision, especially when the underlying cause of dyspnea remains unclear after initial studies have been completed. Otherwise, HRCT is an essential test in the evaluation of interstitial lung disease.

Bronchoscopy’s role controversial

If the pattern on HRCT is nondiagnostic, then surgical biopsy is necessary, and the diagnosis of IPF requires a histologic pattern of UIP as described above.^16,35

Although bronchoscopy can be valuable if an alternative diagnosis such as sarcoidosis or chronic hypersensitivity pneumonitis is suspected, the role of bronchoscopic biopsy in the workup of IPF is controversial. The patchy nature of UIP does not lend itself to the relatively small biopsy samples obtained through bronchoscopy.^36,37

Surgical biopsy options

The favored biopsy approach is surgical, using either an open or a video-assisted thoracoscopic technique. The latter is preferred as it is less invasive, requires a shorter length of hospital stay, and allows a faster recovery.³⁸ Bronchoscopic cryobiopsy, currently under investigation, is a potentially valuable tool whose role in diagnosing IPF is evolving.

Frequently, neither HRCT nor surgical lung biopsy demonstrates UIP, making the definitive diagnosis of IPF difficult. Moreover, some patients with nondiagnostic HRCT results are unable to tolerate surgical lung biopsy because of severely impaired lung function or other comorbidities.

The role of multidisciplinary discussions

When surgical lung biopsy is not possible, current practice at leading centers uses a multidisciplinary approach to allow for a confident diagnosis.^30,39 Discussions take place between pulmonologists, pathologists, radiologists, and other specialists to collectively consider all aspects of a case before rendering a consensus opinion on the diagnosis and the management plan. If the discussion leads to a consensus diagnosis of IPF, then the patient’s clinician can move forward with treatment options. If not, the group can recommend further workup or alternative diagnoses and treatment regimens. The multidisciplinary group is also well positioned to consider the relative risks and benefits of moving forward with surgical lung biopsy for individual patients.

This approach illustrates the importance of referring these patients to centers of excellence in diagnosing and managing complex cases of interstitial lung disease, including IPF.⁴⁰

 

TREATMENT OF IPF

Antifibrotic therapy

Antifibrotic therapy is a choice between pirfenidone and nintedanib.

Pirfenidone, which has an undefined molecular target, was approved based on the results of 3 trials.^41,42 Pooled analyses from these trials showed a reduction in the decline from baseline in FVC percent predicted and improved progression-free survival.⁴³ Pooled and meta-analyses of pirfenidone clinical trials have shown a mortality benefit, although no individual study has shown such an effect on mortality rates.⁴⁴

The major adverse effects of pirfenidone are gastrointestinal distress and photosensitivity rash.

Nintedanib is a triple tyrosine kinase inhibitor that broadly targets fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor receptors. Combined analysis of 2 concurrent trials⁴⁵ showed that nintedanib reduced the decline in FVC, similarly to pirfenidone. The major adverse event associated with nintedanib was diarrhea. Since it inhibits vascular endothelial growth factor, there is a risk of hematologic complications such as bleeding or clotting events.

Because pirfenidone and nintedanib can increase aminotransferase levels, regular monitoring is recommended.

To date, no trial has compared pirfenidone and nintedanib in terms of their efficacy and tolerability. Therefore, the choice of agent is based on the patient’s preference after a discussion of potential risks and expected benefits, a review of each drug’s side effects, and consideration of comorbid conditions and physician experience.

Patients need to understand that these drugs slow the rate of decline in FVC but have not been shown to improve symptoms or functional status.

Corticosteroids are not routine

Corticosteroids should not be used routinely in the treatment of IPF. Although steroids, alone or in combination with other immunosuppressive medications, were commonly used for IPF in the past, such use was not based on results of randomized controlled trials.⁴⁶ Retrospective controlled studies have failed to show that corticosteroids improve mortality rates in IPF; indeed, they have shown that corticosteroids confer substantial morbidity.^47,48 In addition, a randomized controlled trial combining corticosteroids with N-acetylcysteine and azathioprine was stopped early due to an increased risk of death and hospitalization.⁴⁹ Collectively, these data suggest that corticosteroids confer no benefit and are potentially harmful. Their use in IPF is discouraged, and the joint international guidelines recommend against immunosuppression to treat IPF.¹⁶

Other treatments

The guidelines offer additional suggestions for the management of IPF.

Preliminary evidence suggests that microaspiration associated with abnormal gastroesophageal acid reflux is a risk factor for IPF. As such, there is a weak recommendation for aggressive treatment of reflux disease.⁵⁰ However, because evidence suggests that proton-pump inhibitor therapy may be associated with adverse renal or central nervous system effects, this recommendation bears caution. It is hoped that ongoing studies will provide further insight into the role of acid-suppression in the management of IPF.^51,52

Further treatment recommendations include best supportive management such as supplemental oxygen, pulmonary rehabilitation, and vaccinations.

Prompt referral for lung transplant is imperative. IPF is now the most common indication for lung transplant, and given the poor overall prognosis of advanced IPF, transplant confers a survival benefit in appropriately selected patients.^53,54 Table 2 provides an evidence-based checklist for the workup and management of IPF.

ACUTE EXACERBATIONS OF IPF

The unpredictable nature of IPF can manifest in the form of acute exacerbations without an identifiable cause. The loosely defined diagnostic criteria for the diagnosis of acute exacerbations are a previous or new diagnosis of IPF, worsening or development of dyspnea in the last 30 days, and new bilateral ground-glass or consolidative changes with a background of UIP on HRCT.¹⁶

A new definition has been proposed⁵⁵ to facilitate research in the characterization and treatment of acute exacerbations of IPF. The new definition includes all causes of respiratory deterioration except for heart failure and volume overload. It is less strict about the 30-day time frame. This newer definition is based on the lack of evidence differentiating outcomes when an acute deterioration is associated with known or unknown etiologies.⁵⁵

The incidence of acute exacerbations is variable, with a 1- and 3-year incidence ranging between 8.6% and 23.9% depending on the criteria used.⁵⁶ In general, acute exacerbations carry a grim prognosis, with a median life expectancy of 2.2 months.⁵⁷

There is no approved therapy for exacerbations of IPF. Rather, treatment is mainly supportive with supplemental oxygen and mechanical ventilation. Current guidelines have a weak recommendation for the use of corticosteroids, but there are no recommendations regarding dose, route, or duration of therapy. Other treatments, primarily immunomodulatory agents, have been suggested but lack evidence of benefit.

Acknowledgments: Pathology images were provided by Carol Farver, MD, Pathology Institute, Cleveland Clinic. Radiology images were provided by Ruchi Yadav, MD, Imaging Institute, Cleveland Clinic.