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The Relationship of Asthma and Anxiety Disorders

From the Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington (W.J.K.); Department of Pediatrics, University of Washington, Seattle, Washington (L.R., P.L.); Center for Health Studies, Group Health Cooperative, Seattle, Washington (P.L.); Department of Psychiatry and Behavioral Sciences, Children’s Orthopedic Hospital, Seattle, Washington (E.M.)

Address correspondence and reprint requests to Wayne J. Katon, MD, Department of Psychiatry & Behavioral Sciences, Box 356560, University of Washington School of Medicine, 1959 NE Pacific St., Seattle, WA 98195-6560. E-mail: wkaton{at}u.washington.edu

	ABSTRACT

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OBJECTIVE: This article reviewed the child and adult medical literature on the prevalence of comorbid anxiety disorders in patients with asthma. Theoretical ideas regarding the relatively high comorbidity rates are presented along with a model describing putative interactions between anxiety disorders and asthma.

METHOD: A search of the literature from the last 2 decades using MEDLINE by pairing the word, "asthma," with the following words: "anxiety," "depression," "panic," and "psychological disorders." We located additional research by screening the bibliographies of articles retrieved in the MEDLINE search.

RESULTS: Both adult and child/adolescent populations with asthma appear to have a high prevalence of anxiety disorders. In child/adolescent populations with asthma, up to one third may meet criteria for comorbid anxiety disorders. In adult populations with asthma, the estimated rate of panic disorder ranges from 6.5% to 24%. However, most studies are limited by small samples, nonrepresentative populations, self-reported asthma status, and lack of controlling for important potential confounders such as smoking and asthma medications. There are also limited data on the impact of anxiety comorbidity in patients with asthma on symptom burden, self-care regimens (such as monitoring peak expiratory flow, taking medication, and quitting smoking), functional status, and medical costs.

CONCLUSIONS: There appears to be a high comorbidity of anxiety disorders in patients with asthma. The prevalence and longitudinal impact of anxiety comorbidity needs to be examined in a large population-based sample of children, adolescents, and adults with asthma. If a high prevalence of comorbid anxiety disorder is documented and if this comorbidity adversely affects the self-efficacy and self-care, symptom burden, and functioning in persons with asthma, then it will be important to develop treatment trials.

Key Words: asthma, • anxiety, • medical costs.

Abbreviations: ASI = Anxiety Sensitivity Index.

	INTRODUCTION

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Asthma is the most common chronic illness of childhood, with a prevalence of 7 to 10% (1–2). It is also among the 4 most common chronic disorders in adult populations, with a prevalence of approximately 5% (3). Morbidity and mortality due to asthma have increased in recent years, particularly among children and teenagers (4), suggesting the need for reassessing both control and prevention measures (5). The economic impact of asthma is considerable, with total expenditures in the United States for 1990 in excess of $6 billion (6,7). Researchers have observed substantial variation in asthma outcomes, including symptom burden (8), emergency department visits (9), and hospitalizations (10–12). The availability of efficacious treatments for asthma suggests that some proportion of poor outcomes is preventable (13). This conclusion has prompted health care providers and planners to focus special attention on children, adolescents, and adults at risk for poor asthma outcomes.

Numerous patient characteristics have been found to influence asthma outcomes, including age, poverty, gender, psychosocial factors, psychiatric disorders, and ethnicity (9,10,14,15). In addition, modifiable risk factors have been identified within the realms of patient and provider behavior, including decreasing exposure to tobacco smoke (16), regular use of inhaled anti-inflammatories (17), and provision of a written care plan (18). While co-existing medical conditions such as allergic rhinitis and sinusitis have been shown to play a role in determining asthma outcomes in adolescents and adults (19–25), comorbid psychiatric conditions have received relatively little attention.

	METHODS

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This paper reviews the evidence for the high prevalence of anxiety disorders, particularly panic disorder, in children, adolescents, and adults patients with asthma. We completed a literature review from the last 2 decades of research using MEDLINE by pairing the word "asthma" with the following words: anxiety, panic, psychological disorders, and depression. We also located research based on the bibliographies of the articles located with the MEDLINE search. We selected articles that: 1) were English-language only; 2) assessed the prevalence of anxiety symptoms or anxiety disorders in patients with asthma alone or in patients with asthma, emphysema, and chronic bronchitis; 3) assessed the prevalence of asthma and other respiratory illnesses in patients with panic disorder; and 4) were based on examining at least 30 subjects.

	RESULTS

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Comorbidity of Asthma and Panic Disorder in Adult Populations
Several studies have examined the association between panic disorder and asthma as well as other respiratory illnesses in adults (26). Researchers’ interest in this association stems from overlapping symptoms these illnesses share such as sensations of being smothered, choking, hyperventilation-induced dyspnea, and increased anxiety. The prevalence of panic disorder in adults has been estimated as 1% to 3% in community populations (27) and 4% to 8% in primary care populations (26). Twelve cross-sectional studies in adult populations have suggested that the prevalence of panic disorder among patients with asthma ranges from 6.5% to 24% (28–39) (1 of these studies [33] examined patients referred for pulmonary testing for asthma or chronic obstructive lung disease; see Table 1). A recent study of a representative community sample of 3032 adults aged 25 to 74 years showed that self-reported respiratory disease was associated with a 70% greater likelihood of panic attacks [OR = 1.7 (1.2–2.4)] (38). A second large community sample of 4181 adults from Germany, which included physician confirmation of asthma using a physician interview, found that current severe asthma (ie, in last 4 weeks) was associated with a significantly increased likelihood of having any anxiety disorder [OR = 2.65 (1.35–5.18)] and panic disorder [OR = 4.61 (1.09–9.40)] (39). Lifetime severe asthma was also associated with an increased risk of having any anxiety disorder [OR = 2.09 (1.30–3.36)], panic disorder [OR = 2.61 (1.29–5.25)], social phobia [OR = 3.28 (1.42–7.59)], generalized anxiety disorder [OR = 5.51 (2.29–13.22)], and bipolar disorder [OR = 5.64 (1.95–16.35)] (39). Anxiety and depressive disorders are even more common in patients who present with severe life-threatening episodes of asthma as well as those hospitalized with acute asthma exacerbations (37).

There was only 1 longitudinal study in adults that examined whether high levels of baseline anxiety and depression were associated with an increased incidence of asthma. This study was also 1 of the only studies that examined the role of potential confounders such as smoking or preexisting pulmonary disease. In a large population-based longitudinal study of 5231 adults (aged 25 to 74 years) without asthma at baseline, Jonas and Wagener found that high levels of anxiety and depression were associated with an increased incidence of asthma in baseline nonsmokers as well as those without baseline respiratory symptoms and/or abnormal pulmonary function tests (43). This increased incidence of asthma in respondents with high baseline anxiety and/or depression was not found in respondents who were smokers or had preexisting respiratory symptoms or abnormal pulmonary function tests at baseline. The authors hypothesized that the baseline presence of smoking, respiratory symptoms, or abnormal pulmonary function tests may obscure the effects of anxiety and depression symptomatology on subsequent development of asthma (43).

Comorbidity of Asthma and Panic Disorder in Child/Adolescent Populations
Estimated prevalence rates of panic disorder and/or agoraphobia in adolescents in the community have varied between 0.6% to 4.7% (44,45). In children, it is important to recognize that panic disorder may be preceded by other anxiety disorders such as separation anxiety disorder, isolated panic attacks, generalized anxiety disorder, and overanxious disorder (46–48). There have been 7 prior studies reporting the prevalence of anxiety disorders conducted in children or adolescents with asthma (49–55) (Table 2) Kashani and colleagues compared 56 children and adolescents with asthma and 56 children and adolescent controls from the same outpatient pediatric clinic. They found a nonsignificant trend toward higher prevalence of psychiatric disorders in patients with asthma compared with controls (65% vs. 48%); parents rated children with asthma as having a significantly higher number of anxiety symptoms (49). Bussing and colleagues showed that 43.2% of 37 children with asthma in an outpatient pediatric practice met criteria for an anxiety disorder vs. 19.4% in 25 healthy controls (50). Two other case-control studies by Vila and colleagues showed a high prevalence rate of anxiety disorders based on the Kiddie Schedule for Affective Disorders and Schizophrenia in children with asthma and higher scores on anxiety scales in children with asthma compared with those with diabetes or no medical illness respectively (51,52). Vila et al reported that approximately one third of children with asthma met research criteria for 1 or more anxiety diagnoses in each of these 2 studies (51,52). A recent longitudinal study following children from age 3 to 21 found that an earlier experience with asthma predicted the development of agoraphobia and/or panic disorder by ages 18 to 21 (53). A secondary analysis of the Methods for Epidemiology of Child and Adolescents Mental Disorders Survey reported that respondents with asthma had an increased likelihood of any anxiety disorder [OR = 1.59 (1.1–2.1)], with significant increases in separation anxiety, overanxious disorder, and simple phobia (54). Goodwin and colleagues also reported from a large survey of youths aged 9 to 17 (the Methods for Epidemiology of Child and Adolescent Mental Disorders Study) that self-reported asthma was associated with a 2-fold increased likelihood of panic attacks [OR = 2.2 (3.1–4.0)] (55).

	DISCUSSION

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In summary, most of the adult and child studies of patients with asthma have shown an increased rate of comorbid anxiety disorders. However, there are important limitations in many of the studies. Only 6 of the studies examined more than 150 subjects (38,39,43,53–55). In the 6 larger studies, only 2 had physician verification of asthma (Dunedin study [53] and the German community study [39]). Only 1 of the larger studies (the German community study) controlled for asthma severity (39). This community study found a significantly higher likelihood of having 1 or more anxiety disorders in patients with severe compared with nonsevere asthma (39). Most studies did not attempt to control for all possible socioeconomic and clinical confounders (other medical comorbidities, severity of asthma, smoking). Only the Jonas and Wagener study controlled for smoking status (43). The 6 larger studies were from community samples, whereas all others were in nonrepresentative tertiary care populations. Many of the medications that are used to treat asthma, such as methylxanthines, beta-agonists, and corticosterioids, can provoke symptoms of anxiety, and none of the studies controlled for the level of use of these medications (although the German community study included use of medications in the diagnosis of severe asthma) (39).

Perhaps the most important critique was that only 1 study described how researchers attempted to discriminate between the potential overlapping symptoms of asthma and panic, such as shortness of breath (37). Even in this study, the methods depended on the patients describing panic symptoms at times other than during an asthma attack. However, patients may have difficulty discerning which episode is due to panic, asthma, or a combination of these 2 syndromes. One recent cross-sectional, case-control study showed that the symptoms that best discriminated between panic attacks and asthma attacks were wheezing, coughing, and mucous production (57). These symptomatic differences between a panic attack and asthma attack need to be tested in longitudinal samples.

In studies of patients with major depression and chronic medical illness, validation of the comorbid depression diagnoses has been aided by demonstrating that those patients with comorbid major depression and medical illness had increased symptom burden, additive functional impairment, lack of adherence to self-care regimens, and increased medical costs compared with patients with the medical illness alone, even after controlling for severity of that medical illness, other medical comorbidities, behavior risk factors such as smoking, and socioeconomic variables (58). Large-scale epidemiologic studies are needed for patients with asthma and panic disorder to help validate the co-occurrence of these 2 comorbid conditions by measuring the effect of comorbidity on symptom burden, functioning, adherence to asthma self-care regimens, and medical costs after controlling for asthma severity, other medical comorbidity, and asthma medications. Use of instruments like the Anxiety Sensitivity Index (ASI) (59) may also help validate the panic disorder diagnosis in patients with asthma. Carr and colleagues showed that 35% of patients with the highest tertile of scores on the ASI met criteria for comorbid panic disorder versus only 5% in the middle tertile and 0% in the lowest tertile (31).

Since both asthma and anxiety disorders tend to begin in childhood and adolescence, comorbidity of these illnesses may have marked effects on functioning and development. Therefore, studying the impact of DSM-IV disorders, including anxiety comorbidity as well as the chronology of illness, may be essential in designing treatment programs to improve outcomes for these patients.

Theories Regarding High Comorbidity Rates
Several theories have been proposed to attempt to explain the apparent increased risk of the development of panic disorder in patients with asthma and other respiratory illnesses. A cognitive explanation posits that longitudinal experience with respiratory diseases such as asthma may generate fearful or catastrophic beliefs about respiratory symptoms, which, in turn, provoke panic attacks (26,31,60). The finding in 1 study found that only asthmatic patients with high scores on the Anxiety Sensitivity Index (59) (which measures the tendency to respond to bodily sensations with fear) were prone to meet criteria for panic disorder is consistent with this theory (31).

Biologic theories posit that repetitive experiences with hypoxia and hypercapnia may also sensitize neural circuits that control fear responses, such as neurons in the amygdala and locus ceruleus, to overreact to either subsequent episodes of hypoxia and hypercapnia due to asthma or to fearful perceptions of conditioned stimuli such as the sensation of breathlessness (60,61). The evidence of an increased likelihood of anxiety disorders in patients with severe versus nonsevere asthma supports this theory (39). Laboratory studies have shown that when asked to breathe CO₂, adult subjects with and without panic disorder experience a similar obligatory increase in respiratory rate and tidal volume (ie, hyperventilation). This is well tolerated in controls (even among psychiatric patients with depression or obsessive compulsive disorder), but patients with panic disorder experience breathlessness and somatic discomfort accompanying this hyperventilation with the associated frightening cognitions that they routinely experience during panic attacks (61). This evidence suggests that adult panic patients do not have abnormalities in pulmonary, peripheral, or medullary chemo-receptors (since both patients with panic and controls have similar changes in respiratory measures), but suggests that central brain circuits are more important in the development of panic attacks (61).

Carbon dioxide challenge studies in children with anxiety disorders have shown more respiratory abnormalities than in adult populations. Recent studies of children with anxiety disorders (social phobia, generalized anxiety disorder, separation anxiety, panic disorder) have shown greater changes in somatic symptom reporting during inhalation of CO₂-enriched air relative to the nonpsychiatrically ill comparison group (62,63). The severity of somatic symptoms was positively correlated with respiratory rate increases in measures such as tidal volume, minute ventilation, end-tidal CO₂, and irregularity in respiratory rate during room-air breathing. Children of parents with panic disorder compared with children of normal controls have also been found to have a higher resting respiratory rate as well as significantly more respiratory irregularities (including measures of tidal volume, minute ventilation, minute ventilation/end-tidal CO₂, minute ventilation/end tidal O₂ and tidal volume/inspiratory time), even when children with current anxiety disorders were excluded (63). This suggests that in children, respiratory abnormalities may be a more sensitive marker than symptom severity for anxiety disorder diatheses. In children, perturbations in respiratory function may represent risk factors for panic and other anxiety disorders as opposed to only a sequelae of panic attacks (64). Children with anxiety and asthma may have additive respiratory abnormalities, which may create a vicious cycle of anxiety and fear that provokes increased respiratory abnormalities, which, in turn, precipitates fear that is set off by both biologic and cognitive factors.

Physiologic studies of children with asthma vs. healthy controls have suggested that experimental stress modestly increases airway resistance in both cases and controls (63). However, children with asthma begin with higher intrinsic airway resistance, so increases in resistance result in a higher absolute level of compromise compared with healthy controls (65). The increased reactivity to life stressors often seen in patients with anxiety disorders may be associated with more frequent perturbations in airway resistance with common stressors, which may in turn stimulate neural circuits associated with fear responses.

A theoretical model illustrated in Figure 1 describes the potential adverse impact of comorbid anxiety/depressive disorders in patients with asthma and includes some of the potential effects on developmental tasks during childhood and adolescence. Anxiety and depressive illness as well as perceived asthma severity (symptom burden, functional impairment) may undermine self-efficacy, decrease internal locus of control, and decrease self-esteem. Both anxiety and asthma symptoms frequently lead to fearful cognitions (ie, catastrophizing) (26,31,60) and a sense of being out of control and needing help and support. Because children with asthma have a higher level of intrinsic airway resistance, negative stressors, and mood states may be much more likely to result in significant airway changes in resistance undermining self-confidence in learning to master these situations (65). These underlying frightening cognitions and decreased confidence and sense of control to manage illness symptoms may be associated with decreased active behavioral self-management strategies such as taking medication regularly, monitoring peak expiratory flow, and quitting smoking. Decreased self-management may then worsen asthma symptom burden, increase medical utilization and costs, and lead to increased functional impairment. Anxiety and depressive disorders may also directly affect perception of symptoms and be associated with increased medical costs and adverse asthma outcomes that impair functioning may precipitate anxiety and depressive disorders (66). A recent study showed that urban children with asthma who scored higher on a measure of psychological distress had more hospitalizations, more days of wheezing, and lower functional status than those scoring lower on distress (14). Finally, anxiety/depression and asthma may both individually and, when comorbid, additively impair key developmental tasks of adolescence (as shown in Figure 1) (67,68).

View larger version (49K): [in this window] [in a new window]   Figure 1. Adverse impact of anxiety/depressive disorder and asthma comorbidity.

	CONCLUSIONS

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Both asthma and anxiety disorders have a high prevalence in child, adolescent, and adult populations, and increasing evidence suggests that these disorders frequently co-occur. It is important for future studies to document the extent of comorbidity and whether comorbid anxiety disorders are associated with decreased self-efficacy and self-care, higher symptom burden, decreased functioning, and increased medical costs. If a high comorbid rate is documented, future studies need to be planned to enhance understanding regarding the biologic and cognitive mechanisms that might explain this association. Treatment studies also will be important to develop in order to test whether cognitive-behavioral and medication treatments of anxiety disorders improve both psychiatric and medical outcomes.

	ACKNOWLEDGMENTS

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Supported by National Institute of Mental Health Grants MH01643 and MH67587.

Received for publication June 2, 2003.

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