Abstract
Background: Depressive and anxiety symptoms increase the risk of death in patients with Chronic Obstructive Pulmonary Disease (COPD), but the combined effects of the two factors are unknown. Purpose: To assess the possible interactive effects of depressive and anxiety symptoms on the death of patients with COPD. Methods: Prospective data for 7787 Chinese patients with COPD was analyzed and the deaths were recorded. Depressive and anxiety symptoms were evaluated using the Hospital Anxiety and Depression Scale. A product of depressive and anxiety symptoms was added to the logistic regression model to evaluate the multiplicative interaction, and relative excess risk of interaction (RERI), attributable proportion (AP) of interaction, and synergy index (S) were applied to evaluate the additive interaction of the two factors. Bootstrap was used to calculate 95% confidence intervals (CIs) of RERI, AP and S. RERI > 0, AP > 0, or S > 1 indicated biological interaction. Results: After 4 years’ follow-up, the cumulative mortality was 20.0%, and the percentages of deaths in patients with depressive and anxiety symptoms were 28.5% and 30.9%, respectively. When adjusting for variables such as age, sex, disease duration, marital status, income, education level, co-morbidity, smoke status, biomass smoke, 6MWD, MRC, BMI and FEV1. the RERI, AP, and S (with 95% CIs) resulted in depression and anxiety scores of 6.54 (1.23–13.79), 0.54 (0.18–0.83), and 2.64 (1.33–4.75) respectively. Conclusion: Interaction effects were found between depressive and anxiety symptoms on the death of patients with COPD. Patients with both depressive and anxiety symptoms have an increased risk of death from COPD.
Introduction
Chronic obstructive pulmonary disease (COPD) is progressive and defined by a limitation of airflow that is at least partially irreversible (Citation1), but it is not limited to the lung. It can also cause systematic manifestations that result in many co-morbidity disorders (Citation2, 3) such as depression and anxiety, which are two of the most common disorders in patients with COPD (Citation4). A systematic review and meta-analysis reported the prevalences of clinically significant anxiety and depression at approximately 36% and 40%, respectively (Citation5). Depression and anxiety are frequently reported as increasing mortality (Citation6–9), but the strength of this association and the issue of residual confounding variables (e.g., lifestyle factors and physical disease), remains controversial (Citation10, 11). The influence of depression and anxiety on the death of patients with COPD needs further investigation.
To the best of our knowledge, no studies have been done on the interaction of depression and anxiety on the mortality of patients with COPD. Hence, the aim of this cohort study was to investigate associations between individual and combined depressive or /and anxious symptoms loads (using the Hospital Anxiety and Depression Scale (HADS)) and mortality, and to examine the joint effects of depressive and anxious symptoms on mortality in patients with COPD in four-year period in China primary care, while adjusting for known risk factors, such as age, sex, education levels, smoking behavior, and the BODE index (Including: body-mass (B), the degree of airflow obstruction (O), dyspnea (D) and exercise capacity (E)).
Methods
Study design
From May 2008 to May 2012, a total of 8,217 subjects from all 14 rural communities of Xuzhou City in China, were enrolled in the study and followed up until either the time of their death or this study's deadline.
Baseline data had been previously obtained and described by Lou et al. (Citation12). General practitioner teams were then established to conduct at least one monthly face-to-face follow-up visit either at the patient's home or at the clinic. The frequency and nature of any adverse events were recorded during these interviews and throughout the follow-up process.
Study population
The selection of patients for this study has been previously described (Citation12). All of the patients with COPD were diagnosed with the standards set forth by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (Citation1), and exclusions were made using the criteria described in the follow to minimize selection bias by the County People's Hospital. Exclusion criteria included the presence of fever; active tuberculosis; changes in either radiographic images or medication within the four weeks immediately preceding recruitment; a primary diagnosis of asthma or obvious bronchiectasis; cystic fibrosis; interstitial lung disease; previous lung volume reduction surgery; lung transplantation; pneumonectomy; any uncontrolled or serious condition that could potentially affect the spirometry test; and a refusal to fill out psychological questionnaires. In the present study, the enrolled subjects completed baseline surveys and participated in the 4-year follow up process.
Assessment of anxiety and depression
Depressive and anxiety symptoms were measured using HADS (Citation13). This scale consists of 14 items: seven measure anxiety (HADS-A) and seven measure depression (HADS-D). The items are scored on a four-step scale ranging from 0–3 (zero means not at all and three, very much). The anxiety and the depression scale are scored by summing the patient's responses. Each score ranges from 0–21, with the higher scores indicating elevated anxiety or depression levels, and scores of ≥8 on a subscale should be taken as an indication of possible pathology (Citation13). The Chinese version of HADS has been developed and validated by previous studies (Citation14). In this study, patients who had a score of ≥8 for depression or anxiety were defined as being depressed or anxious. The patients who had a score of less than 8 were defined as being asymptomatic of either depression or anxiety. The patients independently completed HADS questionnaires under the observation of their health care practitioner. Completing all items on the HADS constituted a valid questionnaire. To ensure a 95% accuracy level, 10% of these questionnaires were randomly checked by the authors on a daily basis. If the accuracy level was less than 95%, all the questionnaires were re-investigated for that day. All data were imputed twice and a consistency test was run to ensure the completeness and accuracy of data entry.
Covariates
All participants completed questionnaires and underwent spirometry testing at baseline to determine relevant characteristics. The endpoint was recorded at the death of patients with COPD. The collection of general characteristics were the same as previously reported (Citation12). Upon admission, general characteristics such as age, sex, education level, marital status, smoking status (i.e., smoker or non-smoker), exposure to coal and/or biomass smoke, and household net income were recorded. Marital status was dichotomized in terms of living with a partner versus living without a partner. Patients without a partner included those patients who were widowed, divorced, or never married.
Subject weight and height were measured before pulmonary function tests and body mass index (BMI) results were calculated by dividing the weight in kilograms by the square of height in meters. Educational level was categorized as below high school, high school, and beyond high school. Cigarette smoking was defined as having smoked at least 100 cigarettes during one's lifetime or having smoked in the least 6 months (Citation15). Those patients who answered “yes” to smoking at least 100 cigarettes during their lifetime were asked whether they now smoke cigarettes every day, some days, or not at all.
Current smokers were defined as those who had smoked at this level and, at the time of the interview, reported smoking either every day or some days. Former smokers were defined as those who smoked at this level but currently did not smoke. Nonsmokers were defined as those who had smoked fewer than 100 cigarettes during their lifetimes. Participants who had cooked the equivalent of two meals per day for at least 6 months were defined as having been exposed to coal and/or biomass smoke. Those who did not cook were classified as not exposed to this smoke. The co-morbidities were collected from the patient's medical history records.
Assessment of pulmonary function
Spirometry and bronchodilator response tests were carried out by trained professionals according to the standardized guidelines of the American Thoracic Society (ATS) (Citation16). Patients carried out the pulmonary function test at the same time (±2 h) each day with drugs eluted. GOLD stages were defined as described in the updated GOLD strategy (Citation1).
Assessment of dyspnea
Dyspnea was measured using the Medical Research Council (MRC) dyspnea scale, which classifies breathlessness into six grades (0–5) according to the patient's self-perceived breathlessness during daily activities (Citation17).
Assessment of exercise capacity
The 6-minute walking distance test (6MWD) was carried out according to ATS guidelines. Each patient was instructed to walk as rapidly as possible on a solid floor, flat corridor for 6 minutes. The test was repeated twice with an interval of at least 30 minutes (Citation18), and the best walking distance was recorded
Definition of endpoint
The principle diagnosis on discharge from hospital was used to identify the endpoint event. These diagnoses were coded according to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). The end point of this study was defined as death during the follow-up period. Information on death came from the Chinese information system for disease control and prevention (V2.0), and the information for each deceased patient was verified by the authors.
Statistical analysis
All data were imputed by two professional staff using Epidata 3.0 and a double entry system. Verification was done afterwards to ensure the completeness and accuracy of data entry. The computer-based analysis program SPSS version 13.0 was used for all calculations. Differences in continuous variables were tested using the Student's t-test, and differences in categorical variables were assessed using Pearson's χ2 test. The associations between depressive symptoms, anxiety symptoms and the death of patients with COPD were determined using binary logistic regression.
The results were stratified into depression (having depressive symptoms versus not), anxiety (having anxiety symptoms versus not), and were adjusted for age (continuous), sex (males or females), educational level (less than high school, high school, or greater), marital status, co-morbidity (yes or no), exposure to coal and/or biomass smoke (yes or no), smoker (never, former and current), and the BODE index (continuous). A cross-product interaction term was included in the logistic regression model to assess multiplicative interactions. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the contrast statement in SPSS13.0. Variance was calculated using the Taylor series linearization method, which leads to an asymptotically unbiased estimate. All associations reported were statistically significant (p < .05) using two-tailed tests.
Biologic synergism refers to the increased likelihood of an individual becoming diagnosed with a disease when they are exposed to two or more risk factors but not when exposed to each factor alone. Biological interactions of evaluation should be based on the sum of the scale rather than by multiplying the scale (Citation19, 20). Therefore, we used three measures to estimate biological interactions: relative excess risk due to interaction (RERI), the attributable proportion due to interaction (AP), and the synergy index (S). The RERI measures the excess risk attributed to interaction relative to the risk without exposure. AP refers to the attributable proportion of the disease, which is caused by an interaction in subjects who have been exposed to both risk factors. S is the excess risk from exposure to both factors when there is a biological interaction relative to the risk from exposure to both but without interaction. In the absence of additive interactions, RERI and AP = 0 (Citation21). The current study refined the criteria as having either a statistically significant RERI > 0 or AP > 0 to indicate biological interactions.
Ethics permission
Ethical approval for the study was given by the Ethics Committee of the Xuzhou Center for Disease Control and Prevention, and the Regional Ethical Vetting Board in Xuzhou, China. Informed, written consent was obtained from all participants.
Results
General characteristics of participants
The distribution of the follow-up period was 3.82 ± 0.05 years. After 4 years of follow-up of the 8,217 recruited patients, 7,787 had completed endpoint follow-ups and 430 (5.2%) had been lost from the study. A total of 1,556 patients (18.9%) died during the study. The demographic characteristics of the 8,217 participants are described in .
Table 1. Characteristics of patients who did not complete the study vs. those who completed it
Difference in general characteristics between patients who completed the study and those who were lost
From it can be seen that there were no significant differences (p > 0.05) in any of the general characteristics between those who completed the study and those who did not.
General characteristics of those who completed the study
presents the general characteristics of our analyzed sample of 4,062 women and 3,725 men. The mean scores were 6.6 ± 4.3 on the HADS-D scale and 6.7 ± 4.5 on the HADS-A scale. Over one third of the patients (35.2%) tested above the standard cutoff score and was classified as having substantial depressive symptoms, and one fifth (19.8%) had substantial anxiety symptoms. For the 7,787 patients, the 1-year mortality was 151 (1.9%), the 2-year mortality was 351 (4.5%), the 3-year mortality was 447 (5.7%) and the 4-year mortality was 607 (7.8%) patients. The percentage of deaths was higher for patients with depressive symptoms (782/2,741 = 28.5%) than without (774/5,046 = 15.3%, chi square = 193.29, p < 0.0001). The percentage of deaths was also higher in patients with anxiety symptoms (476/1,541 = 30.9%) than without (1,080/6,246 = 17.3%, chi square = 142.94, p < 0.0001).
Table 2. Characteristics of the COPD patients (n = 7,787)
Difference between survivors and nonsurvivors
The significant differences between survivors and nonsurvivors were that survivors had low BODE indexes, low anxiety rates, lower smoking levels, were younger, but had higher annual net household incomes, higher education levels and more partners. Differences regarding sex or a history of exposure to coal and/or biomass smoke were not significant.
Biological interaction of depression and anxiety on death from COPD
shows the results from the multiple logistic regression models that adjusted for age, sex, education level, income, disease duration, and the BODE index. The interaction of the two symptoms was assessed using a combined effects method, with the p value of the interaction term indicating the statistical significance of multiplicative interactions.
Table 3. Odds ratios for the association between depressive symptom and death by anxious symptom among patients with COPD
Patients who had depressive and anxiety symptoms had a significantly increased risk of death compared with non-depressive individuals with or without anxiety symptoms (OR: 3.29, 95%CI: (2.87–3.89)). However, there was no multiplicative interaction of without depressive symptoms and without anxious symptoms on increasing the risk of death (p = 0.28).
RERI, AP and S were calculated as measures of additive interaction and presented in . The results show that there is a strong additive interaction between having depressive symptoms and having anxiety symptoms (RERI 6.54 (95% CI 1.23–13.79)). In other words, the OR of patients with COPD who have both depressive and anxiety symptoms is 6.54 times higher as a result of the additive interaction of the two symptoms than that of patients who have neither.
Table 4. Measures for estimation of biological interaction between depressive and anxious symptom for the risk of death in patients with COPD
Discussion
In our study, we observed that patients with COPD who had both depressive and anxiety symptoms were associated with a 6.54 times higher increased risk of death compared with patients who were not depressed or anxious. This significant additive interaction indicates that the increased risk of death as a result of having this combination of symptoms was more than the addition of risks attributed to the presence of either depression or anxiety on their own. Therefore, this significant interaction suggests that depressive symptoms may confer an extra risk of death for patients with COPD who also have anxiety symptoms. No significant additive interaction was found regarding patients with COPD who did not have either depressive or anxiety symptoms.
Although there is an ongoing debate about the association between depression and death in patients with COPD (Citation10, 11, Citation22), many studies have consistently found that depression is associated with an increased risk of death. For example, Mykletun et al. (Citation8) reported that over a period of 3–6 years, depression was associated with a 1.52 times (95% CI: 1.35–1.72) higher risk of death after adjusting for confounders than in patients who were not depressed. In support of this, we also found a 1.76 times higher adjusted risk of death. With regard to the association between anxiety and death in patients with COPD, our result was not consistent with that of Mykletun et al. (Citation8). They reported that a more complex, U-shaped relationship existed between anxiety symptoms and mortality with the highest mortality rate occurring in patients who had low anxiety symptom loads. Our results showed the opposite: the highest mortality rate occurred in patients who had high anxiety symptom loads.
Patients with COPD who are very depressed are also more anxious (Citation23). Patients with COPD who are anxious are often also depressed: the magnitude of depression-related symptoms was estimated to account for 66% of the variance in the measurement of anxiety-related symptoms (Citation24). There is a positive correlation between depression and anxiety (Citation25), yet these disorders are often untreated or undertreated in patients with COPD (Citation26), and this has major implications regarding patient compliance with medical treatment, increased frequency of hospital admissions, prolonged hospital stays, and increased consultations with primary care physicians (Citation27, 28).
Depressed patients with a chronic medical illness are usually sicker than their non-depressed counterparts (Citation29, 30) and have lower treatment adherence (Citation31). Lack of treatment is also associated with premature death (Citation32, 33). Patients with anxiety and depression are often reluctant to engage in pulmonary rehabilitation, have decreased physical activity levels, fail to quit smoking, have poor eating habits, and poor medication adherence (Citation34). This, in turn, could have an interaction impact on the patient, increase their vulnerability to the disease, “speed up” its progression, and lead to an increased risk of death in patients with COPD.
Strengths
The present study has several design strengths. The sample was large and comprehensively evaluated. The participation rate was reasonable considering the scale of the study. Ascertainment of mortality was complete and unlikely to have been influenced by exposure status. An extensive list of physical symptoms and disorders was included and weighted for their associations with mortality. Despite the risk of “overadjustment,” these covariates still accounted for less than 4% of the association between depressive and anxiety symptoms and mortality. The inclusion of age, sex, disease duration, marital status, income, education level, co-morbidity, smoking status, biomass smoke exposure, 6MWD, MRC, BMI and FEV1 in interaction models further attenuated this association, but in the fully adjusted model, it remained highly significant and of reasonable strength.
Limitations
We did not consider the effect of genetic factors or lifestyle on death. Depression levels during follow-up were not systematically collected in patients who died and the depression status in some patients might have changed during the follow-up period. Although we used a reliable and valid measure of anxiety and depression, our measure was not a clinical diagnosis of a generalized anxiety and/or depression disorder. Other confounders, such as hypoxemia, hypercapnia, and the use of beta agonists for therapy, could not be adjusted for. These findings were only derived from a Chinese cohort and need to be replicated in other ethnic populations.
Implications
Despite the above limitations, we believe that our results have significance for public health. In fully adjusted models, we estimated that 54% of the deaths of patients with COPD can be explained by an interaction occurring between having depressive and anxiety symptoms. The finding supports the notion that the burden of death in depressive patients with COPD may be increased by anxiety. Given the difficulty in treating depression or anxiety in certain patients with COPD, recommendations to prevent these disorders emerging would be an inexpensive and practical means of reducing death from COPD.
| Abbreviations | ||
| COPD: Chronic obstructive pulmonary disease | = | |
| HADS: Hospital Anxiety and Depression Scale | = | |
| GOLD: Global Initiative for Chronic Obstructive Lung Disease | = | |
| BODE: Body mass index = B, airflow Obstruction = O, Dyspnea = D and Exercise capacity = E. BMI = body mass index | = | |
| ATS: American Thoracic Society | = | |
| MRC: Medical Research Council | = | |
| 6MWD: 6-minute walking distance test | = | |
| RERI: Relative excess risk due to interaction | = | |
| AP: The attributable proportion due to interaction | = | |
| S: The synergy index | = | |
Declaration of Interest Statement
Funding: The research was funded by the Science and Technology projects of Xuzhou City in 2007 (XM07C037). The researchers were independent from funders. The study funders had no influence on the design of the study, data collection, analysis, interpretation of data, writing of the report, or the decision to submit the article for publication. The authors declare that they have no competing interests.
Trial registration: Chinese Clinical Trials Registration (ChiCTR-TRC-12001958). PL participated in writing the manuscript. YN conceived the study, participated in its design, wrote the paper, and was involved in data collection and analysis. PC carried out the literature search and wrote the manuscript. PZ and JY conceived the study, participated in its design, and wrote the manuscript. NZ and NC contributed to the conception of the study, participated in its design, and contributed to drafts of the manuscript. LZ, HW, and JZ were lead authors in the original review, contributed to the conception of the study, participated in its design, and contributed to drafts of the manuscript. All authors read and approved the final manuscript.
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