Chronic obstructive pulmonary disease (COPD) exacerbations contribute significantly to morbidity and mortality. COPD is also associated with high levels of psychological distress, which has been linked with higher exacerbation rates. At a recent American Thoracic Society conference symposium titled “Depression and Obstructive Lung Disease: State of the Science and Future Directions” held in 2010 in New Orleans, clinicians and researchers identified a number of important research priorities related to psychiatric comorbidities, including the need to better understand their impact on COPD outcomes, such as exacerbations. This article reviews the current literature and quantifies the prospective impact of anxiety and depression on exacerbation risk in patients with COPD. The limitations of the existing literature and the perspectives for future research are addressed.
Chronic obstructive pulmonary disease (COPD) is characterized by recurrent episodes of symptom deterioration (i.e., exacerbations) that usually require some form of intervention (1–3). COPD exacerbations are responsible for a substantial health, financial, and human burden (e.g., frequent hospitalizations, increased medication consumption, functional impairment, and death) (4–7). Not only do patients have to deal with the physical consequences of the disease, but they must also deal with the psychological consequences of COPD. Previous research has shown that psychological distress is significantly elevated and common among patients with COPD, with up to 55% of patients suffering from a clinical diagnosis of anxiety and/or depression (7). Although the link between anxiety and depression and increased risk for cardiac events such as myocardial infarction has been well documented (8, 9), the literature assessing the impact of anxiety and depression on COPD-related morbidity (i.e., exacerbation risk) is limited and suffers from several limitations such as small sample sizes.
In the COPD literature, a wide range of screening and diagnostic tools has been used to assess psychological distress. They fall into two categories, that is, those that measured symptom severity, using self-report questionnaires, and those that evaluated psychiatric disorders, using structured clinical interviews (7). Experiencing symptoms of psychological distress can be acute and transient (e.g., feeling anxious before a maximal exercise test), but may become chronic and persist (e.g., feeling so fearful of having a panic attack and avoiding situations involving physical effort as a result). Clinical levels of psychological distress, that is, psychiatric disorders, can be diagnosed only on the basis of structured interviews that take DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria and levels of functional impairment into account (10). In the present article, we use the terms “anxiety” and “depression” with reference to either clinical levels of anxiety and depression, that is, psychiatric disorders, using structured interviews that took DSM-IV and levels of functional impairment into account, or elevated symptoms, using a validated questionnaire.
The latest Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 report provides a definition of a COPD exacerbation (11). COPD exacerbation can be symptom based, requiring a significant worsening of symptoms (i.e., a minimum of one or two symptoms for 24 to 48 h) from a previous state of functioning; or event based, requiring the administration of a therapeutic intervention (e.g., prescription of antibiotics and/or corticosteroids). An additional distinction can be made between exacerbations that were treated in-hospital, that is, in the emergency department (ED) or requiring hospitalization, or out-of-hospital, that is, in the patient's own environment via initiation of an action plan and/or after consultation with a physician or case manager.
As of April 2011, nine studies (12–20) have examined the prospective associations between clinical levels and symptoms of psychological distress, and exacerbation risk for patients with COPD (Table 1; see the appendix in the online supplement for the systematic literature search process). Of these nine studies, five (12–14, 18, 19) are of particular relevance regarding their sample size, or their measure of psychological distress and exacerbations. Their individual results are described in the following paragraphs.
|1. N: Tot. (Women)|
|2. Setting||1. Mean Age (yr)|
|Study Author, Year (Ref.), Country||3. Length of Follow-up||2. Mean FEV1 (% of predicted)||Psychological Measure Used (Cutoff Points)||Exacerbation Definition||Association between Anxiety, Depression, and Exacerbations, as Reported by the Authors|
|Almagro et al., 2006 (17), Spain||1. 129 (9)||1. 72||Yesavage Scale (≥5)||Event-based: COPD-related hospitalization ≥ 24 h (excluding ED visit)||Adjusted OR for depression Hospitalization: NS (data not shown)|
|2. Inpatient (hospitalized)||2. 38%|
|3. 1 yr|
|Bula et al., 2001 (20), Switzerland||1. 52 (20)*||1. 82||GDS-short version (≥6)||Event-based: COPD-related hospitalization or ED visit||NA†|
|2. Inpatient (hospitalized)||2. NA|
|3. 6 mo|
|Carneiro et al., 2010 (15), Portugal||1. 45 (7)||1. 68||BDI-short version (continuous)||Event-based: COPD-related hospitalization or ED visit||Number of readmissions: R = 0.01; P = 0.09|
|2. Inpatient (hospitalized)||2. 45%||Number of hospital-stay days for COPD exacerbations: R = 0.51; P = 0.04|
|3. 66 wk|
|Chen et al., 2006 (16), Taiwan||1. 145 (39)*||1. 72||Zung Depression Scale (≥50)||Event-based: Unplanned COPD-related hospitalization or ED visit > 24 h||No association between depressive symptoms and readmissions|
|2. Inpatient (hospitalized)||2. 49%|
|3. 90 d|
|Fan et al., 2007 (13), United States||1. 610 (263)||1. 66||BDI-II (≥10 + quintile), STAI (continuous)||Event-based: COPD-related hospitalization or ED visit||Adjusted OR for depression and anxiety Inpatient: NS (data not shown)|
|2. Outpatient||2. 27%||Adjusted OR for depression (quintile ≥ 15)Inpatient: 1.54 (0.81–2.91)|
|3. 3 yr (1 yr for current analysis)|
|Gudmundsson et al., 2005 (18), Nordic countries||1. 406 (208)||1. 69||HADS (≥8)||Event-based: COPD-related hospitalization > 24 h||Adjusted HR for anxiety Hospitalization: 1.06 (0.79–1.14)|
|2. Inpatient (hospitalized)||2. 38%||Adjusted HR for depressionHospitalization: 1.09 (0.80–1.51)|
|3. 1 yr|
|Laurin et al., 2009 (12), Canada||1. 116 (56)||1. 66||ADIS-IV (NA)||Event-based: Worsening condition requiring changes in usual treatment||Adjusted RR for anxiety and/or depression|
|2. Outpatient||2. 43%||Out-of-hospital treated (in patient's environment)||Any first exacerbation: 1.56 (1.02–2.37)|
|3. 2.2 yr (1 yr for current analysis)||In-hospital treated (COPD-related hospitalization or ED visit)||First outpatient: 1.68 (1.08–2.59)|
|First inpatient: 1.36 (0.82–2.25)|
|Ng et al., 2007 (19), Singapore||1. 376 (56)||1. 73||HADS (≥8)||Event-based: COPD-related hospitalization||Adjusted HR for depressionHospitalization: 0.93 (0.68–1.28)|
|2. Inpatient (hospitalized)||2. 48%||Data not presented for anxiety|
|3. 1 yr|
|Xu et al., 2008 (14), China||1. 491 (153)||1. 6||HADS (8–10 = possible case; ≥11 = probable case)||Symptom-based: Worsening of ≥1 of 3 key symptoms ≥48 h||Adjusted IRR for probable depression|
|2. Outpatient||2. 47%||Symptom-based: 1.51 (1.01–2.24)|
|3. 1 yr||Event-based: Out-of-hospital treated (worsening of ≥1 key symptoms + change in ≥1 of 3 medications)||Event-based: 1.56 (1.02–2.40)|
|Inpatient: 1.72 (1.04–2.85)|
|Adjusted IRR for probable anxiety|
|In-hospital treated (COPD-related hospitalization, excluding ED visit)||Symptom-based: 1.47 (0.97–2.27)|
|Event-based: 1.26 (0.78–2.03)|
|Inpatient: 1.63 (0.88–3.03)|
Using the Hospital Anxiety and Depression Scale (HADS) among 491 Chinese outpatients with stable COPD, Xu and colleagues identified 10% of patients with anxiety and 23% of patients with depression (14). One year later, compared with those without depressive symptoms (HADSD ≤ 7), those with “possible depression” (HADSD = 8–10) had significantly more event-based exacerbations (≥2 exacerbations, 25 vs. 20%; P = 0.003), more symptom-based exacerbations (≥2 exacerbations, 46 vs. 38%; P = 0.04), more COPD hospitalizations (≥2 hospitalizations, 14 vs. 8%; P = 0.03), and longer hospital stays (mean days ± SD, 38 ± 37 vs. 26 ± 19; P = 0.05). Anxious patients (HADSA = 8–10) had significantly more symptom-based exacerbations (≥2 exacerbations, 43 vs. 40%; P = 0.003) and longer hospital stays (mean days ± SD, 49 ± 48 vs. 27 ± 21; P = 0.03) compared with nonanxious patients (HADSA ≤ 7). However, when looking at higher anxiety scores, there was no difference between patients with (“probable anxiety,” HADSA ≥ 11) and without anxiety. For patients with “probable depression” (HADSD ≥ 11), the results showed that they were at least 50% higher risk of having a symptom (adjusted incidence rate ratio [IRR], 1.51; 95% confidence interval [CI], 1.01 to 2.24) or an event-based exacerbation (adjusted IRR, 1.56; 95% CI, 1.02 to 2.40), respectively, compared with those without depression. They were also at higher risk of having a subsequent COPD hospitalization (adjusted IRR, 1.72; 95% CI, 1.04 to 2.85).
When looking at psychiatric disorders (found in 49% of the sample), Laurin and colleagues found that among 110 outpatients with stable COPD, those with anxiety (e.g., social phobia, panic disorder, generalized anxiety disorder) and depressive (e.g., major depression, dysthymia) disorders had significantly higher annual rates of exacerbations (weighted mean = 3.81 in psychiatric vs. weighted mean = 2.73 in controls; F = 6.90, P = 0.009) (12). Patients with anxiety and/or depressive disorders were at 1.56 higher risk of having an exacerbation (95% CI, 1.02 to 2.37), especially those treated on an outpatient basis over an average of 2.2 years. This association was independent of numerous confounders.
In their National Emphysema Treatment Trial (NETT) study among 610 outpatients with COPD, Fan and colleagues (13) analyzed the impact of depression (found in 41% of patients) on exacerbations, using various cutoff scores via the Beck Depression Inventory (BDI). When depressive symptoms were evaluated continuously, they were found not to be associated with hospitalizations at 1 year after adjusting for covariates. When BDI scores were analyzed by quintile, the results revealed that patients with moderate depressive symptoms (≥15), compared with patients with low depressive scores (<5), were at higher risk of COPD-related hospitalizations and ED visits (odds ratio [OR], 2.49; 95% CI, 1.40 to 4.45). However, this association became nonsignificant after adjusting for sex, antidepressant use, disease severity, partial pressure of oxygen, prior COPD hospitalization, medical comorbidity, and dyspnea severity. When looking at mortality risk, these patients with moderate depressive symptoms had an increased risk of 3-year COPD mortality (adjusted OR, 2.74; 95% CI, 1.42 to 5.29). On the other hand, anxiety symptoms, measured with the State-Trait Anxiety Inventory, were not associated with COPD-related hospitalizations, ED visits, or 1- and 3-year mortality.
When analyzed continuously using the HADSD, any depressive symptoms (present in 44% of the sample) were not significantly related to COPD readmissions (adjusted hazard ratio [HR], 0.93; 95% CI, 0.68 to 1.28) among 376 patients with COPD hospitalized for an acute exacerbation (19). However, when patients with high levels of depressive symptoms (HADSD ≥ 8) were compared with patients with low levels, the results showed that they had a significantly higher total number of days spent in the hospital in the following year (14.2 and 11.2 d per patient per year, respectively; P = 0.04), even after adjusting for covariates (including comorbid anxiety). These patients also had a 1.93 higher risk of all-cause mortality (adjusted HR, 1.93; 95% CI, 1.04 to 3.58). On the other hand, high scores for anxiety (HADSA ≥ 8) were not independently associated with all-cause mortality (HR, 1.97; 95% CI, 0.96 to 4.02). No COPD-specific mortality data were presented.
No evidence of a significant association between 1-year readmissions and depressive (found in 29% of patients) or anxiety symptoms (found in 41% of patients, measured on the basis of HADS ≥ 8) was found in the study by Gudmundsson and colleagues (18). However, in these 406 consecutive patients hospitalized for an acute COPD exacerbation, those with poorer health status (as measured by the St. George's Respiratory Questionnaire) and higher anxiety symptoms (but not higher depressive symptoms) were at 1.36 higher risk of readmission at 1 year (adjusted HR, 1.36; 95% CI, 1.12 to 1.65). As such, anxiety may be a specific risk factor for exacerbations among patients with poorer health.
These studies emphasized the high level of anxiety and depression in patients with COPD. In the last three studies, the association between anxiety, depression, and hospitalizations generally became nonsignificant when adjusting for covariates. However, the results from these studies also highlighted the influence of the way the scores were analyzed, that is, continuously versus using different cutoffs.
Finally, we performed a meta-analysis, using Review Manager Software 5.0 (21), with relative risk (RRs) and 95% confidence intervals for each effect (two-tailed), using dichotomous comparisons: that is, depressed or anxious versus nondepressed or nonanxious patients. The inconsistency of effects between study findings was measured using the I2 statistic (22). We contacted all the study's primary investigators by e-mail to provide missing information and any additional information necessary to compute RRs (for more details, see the appendix in the online supplement). When we pooled the results of the nine prospective studies, analyses revealed that patients with anxiety and/or depression were at greater risk for COPD-related exacerbations. More specifically, depression (RR, 1.12; 95% CI, 1.02 to 1.24; heterogeneity index, I2 = 0%) and comorbid depression and anxiety (RR, 1.18; 95% CI, 1.01 to 1.38; I2 = 0%) were associated with an increased risk for in-hospital–treated exacerbations in patients with severe COPD, whereas anxiety did not (RR, 1.05; 95% CI, 0.92 to 1.19; I2 = 0%). Depression and anxiety are common among patients with COPD (23) and when comorbid, tend to confer the greatest risk for exacerbations treated in an in-patient setting. Interestingly, the pooled analyses indicated a different pattern of risk for exacerbations treated in-hospital versus those treated out-of-hospital, that is, patients with anxiety were at greater risk for exacerbations treated out-of-hospital (RR, 1.23; 95% CI, 1.03–1.47; I2 = 0%), whereas those with depression were at higher risk for exacerbations treated in-hospital. However, it is difficult to determine a real difference in the pattern of risk because results looking at out-of-hospital–treated exacerbations included the findings of only two studies.
Given the complex nature of COPD (24), the high number of risk factors associated with exacerbations (25), and the probable circular relationship between these variables and psychological stress, for example, where anxiety and depression and COPD risk factors each contribute to mental and physical health decline (23), it would be presumptuous to isolate one particular causal factor. However, it is interesting to speculate on some potential pathways that could explain the relationship between anxiety, depression, and COPD exacerbations.
As seen in previous studies, both anxiety and depression are associated with activation of the hypothalamic–pituitary–adrenal (HPA) axis and increased systemic inflammatory responses (26–30) that could be responsible for an increased risk of exacerbations. In cardiovascular disease, it has been well documented that chronic activation of the sympathetic nervous system (SNS) and hyperactivity of the HPA axis (via inflammatory processes) can contribute to the development of many of the cardiovascular disease risk factors observed in depressed patients (31). Physiological dysregulation (e.g., activation of the SNS and HPA axis) induced by chronic psychological stress may weaken immune function (32) and potentially increase vulnerability to respiratory infections and COPD exacerbations. Therefore, the fact that psychiatric disorders, and depression in particular, can induce immunodeficiencies and increase the risk of postinfarction death, for example (33), makes us believe that these disorders can have a prospective impact on COPD. However, because of a lack of research among patients with COPD using reliable biomarkers for exacerbations, the precise nature of the biological mechanisms linking anxiety and depression to exacerbations remains unclear.
Patients with anxiety and depression often suffer from low self-confidence or self-efficacy, which may lead to worse disease-related coping (7, 34) and poor self-care behaviors, that is, unwillingness to engage in pulmonary rehabilitation, decreased physical activity, failure to quit smoking, poor eating habits, and poor medication adherence (35–37). This, in turn, could increase a patient's vulnerability to COPD exacerbations or “speed up” the progression of the disease. For example, it has been shown that having a low body mass index (<18.5 kg/m2) constitutes an important risk factor for in-hospital–treated exacerbations among patients with stable COPD (38). It is also possible that depression, which is often associated with feelings of hopelessness, helplessness, social isolation, low mobility, and decreased energy (10, 37, 39, 40), could reduce a patient's motivation to seek help, to report symptom deterioration, or to initiate their action plan, leading to more rapid disease progression and as such, greater risk for in-hospital–treated exacerbation. Alternatively, fear and worry associated with anxiety could amplify awareness of physical symptoms and increase symptom reporting in anxious patients (37), which may lead to higher rates of pharmacological interventions initiated on an outpatient basis. As such, this “early intervention” among anxious patients may have prevented or even avoided exacerbations requiring in-hospital treatment, which may explain why they do not appear to be at greater risk for these types of exacerbations.
Although there is some evidence to suggest that anxiety and depression may influence the course of COPD, the relationship between these factors is complex as it is influenced by the multiple manifestations of COPD including clinical presentation, biological and physiological processes, and patient-related outcomes. Articles have pointed out the need to phenotype COPD and exacerbations by multidimensional assessment, to identify patterns of disease activity and exacerbation “behavior” within individuals and groups of patients (41–44). As in the recent ECLIPSE cohort study (43), it would be interesting, in the future, to identify which combinations of disease attributes are associated with anxiety and depression, and which ones confer greatest risk for exacerbations, to better identify prognostic subgroups among patients with COPD.
A limitation of the current literature in this area is the lack of studies that used a measure of anxiety and depression that was validated in patients with COPD. A better knowledge of their screening properties, that is, their sensitivity and specificity, would have given us a better idea of the most appropriate instruments. Authors should be aware of the specificity and limitations of each instrument and their cutoff scores in COPD samples when interpreting the results of studies in disease-specific populations (45). Indeed, the appropriateness of a classification based on a one-point difference for a noncase to become a case and vice versa is questionable. This may be especially true because the classification accuracy of a cutoff score recommended by the initial validation studies of a questionnaire may be substantially affected by the cultural origin, sex, and disease status of the participants (46, 47). The use of questionnaires that are well justified and specifically validated in the study population is imperative. Future studies should clearly justify their choice of self-report questionnaire, present their psychometric properties, and attempt to validate any cutoff scores for use in the population under study. If a questionnaire is scored continuously, future studies should conduct analyses using scores in their continuous form, as cutoff scores established in one population (e.g., a community sample) may not be relevant to another (e.g., COPD sample).
Moreover, few studies detailed the exacerbation definition used, including the way overlapping exacerbations were dealt with to ensure the independence of events. Future studies should thus include an independent committee to review all individual events and ensure they all meet preselected criteria. In addition, the variability in individual patient follow-up periods should be accounted for by reporting the weighted number of events per patient-year to avoid a bias estimate of mean exacerbation rates. In addition, even if out-of-hospital–treated events tended to occur more frequently than hospitalizations (1), they are rarely assessed. The exclusion of such events—which account for a significant proportion of COPD morbidity and treatment costs (1)—likely provides an inaccurate, or at the very least, incomplete picture of COPD morbidity in relation to anxiety and depression.
The current literature provides some acceptable evidence suggesting an increased risk for exacerbations in patients with COPD who are suffering from anxiety and/or depression. However, because of the limited sample sizes and the weaknesses of each individual study included, the conclusions drawn from a pooled analysis needed to be interpreted with caution. The need for further well-conducted prospective studies powered to look at the specific and independent impact of anxiety and depression on COPD exacerbations is therefore still apparent. The role of cognitive, behavioral, and physiological processes in conferring risk for COPD exacerbations also requires more investigation (48). Anxiety and depression should routinely be evaluated by clinicians to be able to offer the best therapeutic options for patients, including pulmonary rehabilitation, cognitive–behavioral therapy, and pharmacotherapy. This will be an important advance in the direction of the promising Predictive, Personalized, Preventive, and Participatory (P4) medicine model (49).
The authors are grateful to all primary authors of the studies included in the present manuscript for their collaboration in providing additional data and details about their results, as well as all researchers who sent the authors more details on their study.
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*Both authors contributed equally to first authorship of the manuscript and can be considered as co–first authors.
Supported by postdoctoral scholarships from the Fonds de la Recherche en Santé du Québec (FRSQ) (C.L. and G.M.), FRSQ Research Scholar awards (S.L.B. and K.L.L.), and a CIHR New Investigator Award (S.L.B.).
Author Contributions: Substantial contributions to conception and design (C.L., G.M., S.L.B., K.L.L.), acquisition of data (C.L., G.M.), analysis (C.L., G.M., S.L.B., K.L.L.), interpretation of data (C.L., G.M., S.L.B., K.L.L.), drafting of the article and revisiting critically (C.L., G.M., S.L.B., K.L.L.), and final approval (C.L., G.M., S.L.B., K.L.L.).
This article has an online supplement, which is available from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201105-0939PP on January 12, 2012