Insights in Chest Diseases

Keywords

Anxiety; Depression; Chronic obstructive pulmonary disease (COPD)

Introduction

It was estimated that the prevalence of chronic obstructive pulmonary disease (COPD) will increase in forthcoming years and by 2020, will have become the third cause of mortality in the world [1]. It is a progressive disease which gradually declines the pulmonary capacity having a negative influence on the quality of life of patients [2]. The prevalence of anxiety and depression in these patients is greater than among the general population [3,4], nevertheless, various studies suggest that there is significant under-diagnosis [5]. Recently, the importance of psychiatric comorbidity (anxiety/depression) in COPD has been objectified and it has been suggested that it has a long-term negative effect on morbidity and mortality in these patients [4,6]. Divo et al. [7] reported that anxiety and depressive symptoms are associated with death. Vanfleteren et al. [8], identify a specific relationship with a different outcome (more myocardial infarction) and more symptoms (Dyspnea and use of rescue inhalers).

It is important to diagnose anxiety and depression in patients with COPD to be able to treat them correctly, improve their health [9] and their quality of life [5]. It has been pointed out that untreated anxiety/depression in patients with COPD could have negative repercussions on therapeutic compliance, thereby increasing the risk of exacerbation and of hospitalization [9,10]. This would be one of the reasons why previous studies have shown contradictory results on the impact of anxiety and depression on the hospitalization rates. The discrepancies among the studies are based on various reasons: Studies carried out in different countries with non-comparable health services; also differences in the kind of patient; and the methodology used to determine the anxiety/depression. There are different instruments for measuring anxiety and depression. One of them, particularly indicated for detecting anxiety-depression in patients with chronic diseases is the Hospital Anxiety and Depression Scale (HADS), which allows levels of anxiety and depression in these patients to be measured with an acceptable level of sensitivity and specificity [11].

The relationship between anxiety/depression with the exacerbation of COPD is not well defined and more research is needed to explain the pathways to exacerbation.

The objective of this study was to determine the prevalence of anxiety and depression at the beginning of the study in a cohort of patients diagnosed with COPD selected in Primary Care appointments, and to determine a possible association between anxiety and/or depression (diagnosed using HADS) and hospitalization for the exacerbation of the COPD.

Methods

A prospective cohort study was carried out to follow patients diagnosed with COPD originating from the Primary Care Centre of Mollerussa, Lleida (Spain) with a population of 37,462 inhabitants (2015). The Lleida’s Catalan Institute of Health Research Support Unit provided the list of patients who, in their computerized medical history were shown, in June 2012, as was diagnosed with COPD based on the GOLD definition [12] (ratio between post-bronchodilator FEV1/FVC<0.70). To estimate the prevalence of anxiety/depression with an accuracy (e) of 0.04, and an α error of 0.05 and an expected prevalence of 0.5 we selected a random sample of 512 patients with COPD. They were interviewed at the beginning of the study to collect information about the variables of interest (age, sex, smoking habit, family situation, level of studies, severity (GOLD), body mass index (BMI), previous admissions for exacerbation of the COPD, exacerbations treated on an outpatient basis during the last year, degree of dyspnoea, BODEx prognostic index, Charlson comorbidity index and quality of life measurement (EuroQol). Also, they were administered the HADS test [13] to determine whether the patient had anxiety and/or depression or not. The HADS test is considered to be an acceptable method to discriminate between healthy patients and those suffering from anxiety and depression [5].

The HADS is a questionnaire consisting of 14 items (7 to assess anxiety and 7 for depression) with scores ranging from 0 to 3 (possible values from 0 to 21 for each of the subscales). The test looks at the situation of the patient's last week and is designed to be administered to subjects with organic diseases. In addition to the quantitative valuation, it can be categorised and for the study, it was decided to use a value of 10 as a cut-off point between the presence or absence of anxiety and depression. Patients who had a positive HAD test were sent to their respective primary care physicians to assess starting a psycho-pharmacological treatment.

Once the initial information was collected in the 512 participants, including the HADS test, the patients were monitored over two years and the existence of severe exacerbation was determined (Hospitalization for exacerbation of the COPD). The sources of information were the register of hospital admissions in both reference hospitals (Hospital Universitario Arnau de Vilanova and Hospital Universitario de Santa María).

The study was approved by the ethical committee of the Institute of Research in Primary Health Care (IDIAP) of Barcelona (code P14/022).

All the participants gave their written informed consent.

Statistical Analysis

A descriptive analysis was made using absolute and relative frequencies for categorical data and using means and standard deviations for continuous variables. For each patient, the exposure was considered in the case of a positive HADS depression and/or HADS anxiety test. Then the patient had not exposed if neither diagnostic of anxiety nor depression. The main outcome was defined as at least one admission in the two hospitals of reference in the study area for exacerbation of the COPD (CIE-10: J44.1) over the next two years. The admissions were estimated also for each year. A bivariate analysis was performed of all the variables and the different outcomes. The differences in categorical data were tested using Fisher’s exact test and, for numerical variables, a non-parametric Mann-Whitney test was used. The effect of HADS depression and/or anxiety was assessed using logistic regression, and the crude effect and the adjusted effect for all outcomes were assessed. In all the analyses, p-values of lower than 0.05 were considered significant, and SPSS software was used.

Results

At the beginning of the study, the prevalence of anxiety/ depression was 15.6% (7.2% of isolated anxiety and 12.5% of isolated depression). Most of these patients (53.7%) unknown to be affected by anxiety and/or depression. The average age was 69.5 years (SD=12.2) and 26.8% were women. The average Body Mass Index (BMI) was 29.5. The average ratio between Forced Expiratory Volume in the First Second (FEV1) and Forced Vital Capacity (FVC) was 65.2. Smokers and ex-smokers represented 66.8% of the sample. Half (50.8%) the patients were suffering from grade 2 (moderate) COPD and 22.1% were severe or very severe. 42.8% of the patients had slight dyspnoea (Table 1).

Table 1: Baseline characteristics (variables) of COPD patients at the beginning of study.

A total of 79 patients (15.4%) required hospitalization in the two year of study. During the first year of follow-up, the global incidence of hospitalization was 8.2% and in the second year it was 11.3%. In patients with anxiety/depression, the incidence of hospitalization in the first year came to 17.5% and in the second year to 18.8% (Table 2). The incidence of hospitalization during the two years of the study was greater in patients with anxiety and depression (13.4% vs. 26.3%) (Table 2).

Table 2: Incidence of severe exacerbations (hospitalizations) during the two years of follow up.

The patients admitted had similar characteristics in each of the two years of the study. They had lower FEV1 (55.6 ± 15.5) and FEV1/FVC (63.9 ± 7.7). Patients who were admitted during the two years of study were the older ones mean age 73.8 (p=0.001); they had a greater prevalence of anxiety and depression (HADS) 26.6% (p=0.006); worse FEV1 (p=0.001); greater prevalence of ischaemic heart disease (p=0.001); more intense dyspnoea (p=0.001); greater scores on the Charlson index (p=0.001); lower subjective perception of their quality of life measured using the EuroQol 5D (p=0.001) and greater severity of the disease (p=0.001). The other variables are shown in Table 3. Diabetes and anaemia were the only variables that were associated with hospital admission in the second year of the study but not during the first year (Table 3).

Table 3: Characteristics in function of the outcome during the two years of follow up.

In the multivariate regression model, the diagnosis of anxiety/ depression (HADS) increased the risk of hospitalization to almost double (ORa=1.94) over the two years of the study (p<0.041). During the first year, the ORa rose to 2.65; p<0.010 and for the second year the ORa was somewhat lower 1.88 (p=0.07) (Table 4).

Table 4: Effect (crude and adjusted) of the HADS diagnostic (anxiety and/ or depression) on admission during the two years of follow up.

Discussion

The study has enabled us to estimate that anxiety/depression doubles the risk of hospitalization in patients with COPD in a health centre.

The prevalence of anxiety/depression at the beginning of the study was 15.6% similar to other studies [14,15]. The prevalence of depression determined in our research was 12.5%. The studies estimate a highly variable prevalence of depression in patients with COPD which varies between 6% and 50% [6,8,16,17]. Van Manen et al. determined that the prevalence of depression was greater in patients with more severe COPD and was double than for the general population [17]. Ng et al. determined that the prevalence of depression in hospitalised patients with COPD rose to 44% [16]. The prevalence of anxiety in the patients in the study was 7.2%, similar to most of the studies which vary between 10% and 15.8% and which triples the prevalence of anxiety among the general population [18].

The incidence of hospitalization during the two years of the study was greater in patients with anxiety and depression (13.4% vs. 26.3%), and in the multivariate regression model, the diagnosis of anxiety/depression (HADS) increased the risk of hospitalization by almost double (ORa=1.94) over the two years of the study (p<0.041). The risk of hospitalization associated to anxiety/ depression (HADS) was greater during the first year of follow-up (ORa=2.65) than the second year (ORa=1.88) and suggests the loss of predictive value of the test or the greater importance of other factors over time. Other studies have also found a higher rate of hospitalization in COPD patients with anxiety/depression [15,19]. In the study by Ng et al. [19], multivariate analyses showed that depression was significantly associated with mortality (hazard ratio, 1.93; 95% confidence interval, 1.04-3.58).

Some potential pathways could explain the relationship between anxiety, depression and COPD exacerbations. Dysregulation induced by chronic psychological stress may weaken immune functions and potentially increase vulnerability to respiratory infections and COPD exacerbations. Therefore, the fact that psychiatric disorders, and depression in particular, can induce immunodeficiency and increase the risk of post-infarction death, for e.g., de Jonge et al. [20] makes us believe that these disorders can have a prospective impact on COPD. However, the 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 and poor self-care behaviours; that is, unwillingness to engage in pulmonary rehabilitation, decreased physical activity, failure to quit smoking, poor eating habits, and poor medication adherence [21]. This, in turn, could increase a patient’s vulnerability to COPD exacerbations or “speed up” the progression of the disease.

The study identified other factors associated with a greater risk of hospitalization which should also be mentioned. Most patients in the study had a GOLD 2 level of COPD and almost half (42.8%) the patients referred to slight dyspnoea. These percentages are higher than in other studies [22], no doubt because the patients come from primary care where patients with less severe are monitored and therefore they are ones with fewer symptoms.

The patients admitted in a hospital had a lower FEV1 and FEV1/ FVC. López et al. considered the severity (GOLD) to be a very important factor on deciding whether to start a treatment for depression [23]. At the same time, the associated comorbidity was also more prevalent among COPD patients who are hospitalised, a finding previously described [24,25].

Hospitalised patients have a higher level of dyspnoea (Medical Research Council-MRC). This progressive limitation to the airflow in COPD leads to dyspnoea and difficulty in breathing. This situation is one of chronic stress for the patient that limits the activities of their everyday life and deteriorates their state of health. Therefore, it is not surprising that 50% of patients have anxiety/depression [23].

Patients who were admitted into hospital during the two years of the follow up had a worse prognosis, measured using the Charlson index, a worse perception of quality of life (EuroQol) and greater severity (GOLD). These results have been previously described by other authors, such as Hanania et al. [26], who determined that chronic diseases such as COPD can be accompanied by psychiatric disorders, in particular depression, which complicate and aggravate the prognosis and the quality of life. Other studies have also determined a relationship between a lower quality of life (EuroQol) [27], a higher frequency of hospitalization [28] and a poorer prognosis of the disease [29].

Diabetes and anaemia are the two variables that are associated with hospitalization in the second year of the study, but not the first. This could be explained partly due to the cohort effect, as over time the effect of inflammatory anaemia in the COPD would increase [30] and the effect of diabetes would increase due to the accumulative effect of treatment with systemic and/or inhaled corticoids. Therefore, the risk of developing “steroid-induced diabetes” varies between different studies, with Odds Ratios that vary between 1.36 and 2.31 [31,32].

The results would be generalizable because 77.9% of patients in the sample (From primary care consultations) have a mild or moderate level (GOLD) of the disease; therefore they represent the actual spectrum of the disease at population level. Therefore, the risk of hospitalization that is attributable to anxiety/depression is representative of the general population.

Limitations

Given the complex nature of COPD, the high number of risk factors associated with exacerbations [33] and the probable circular relationship between these variables and psychological stress, for example, when anxiety and depression, and COPD risk factors each contribute to mental and physical health decline, it would be difficult to isolate one particular causal factor. In the logistic regression model, we decided not to enter the variables associated with quality of life and co-morbidity due to their collinearity with anxiety and depression. In other studies, the association between anxiety and depression, and hospitalizations became nonsignificant when adjusting for this covariate [27].

As in other studies [15,19] anxiety and depression were measured with the HADS test, nevertheless there is a shortage of studies that have used a measure of anxiety and depression that has been validated in patients with COPD. A better knowledge of their screening properties would have given us a better idea of the outcome of this study.

Conclusion

The outcome of this study suggests that anxiety and depression may increase the risk of COPD hospitalization. Nevertheless, the relationship between these and other factors is complex, as it is influenced by the multiple manifestations of COPD including clinical presentation, biological and physiological processes, and patient-related outcomes.

Anxiety and depression should routinely be evaluated by clinicians to be able to offer the best therapeutic options for patients, including pulmonary rehabilitation, cognitive–behavioural therapy and pharmacotherapy. This will be an important advance in the direction of the promising Predictive, Personalized, Preventive, and Participatory (P4) medicine model [34].

References

1. López-Campos JL, Tan W, Soriano JB (2016) Global burden of COPD. Respirology 21: 14-23.
2. Celli BR, MacNee W, ATS/ERS Task Force (2004) Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 23: 932-946.
3. Dahlén I, Janson C (2002) Anxiety and depression are related to the outcome of emergency treatment in patients with obstructive pulmonary disease. Chest 122: 1633-1637.
4. Jennings JH, Digiovine B, Obeid D, Frank C (2009) The association between depressive symptoms and acute exacerbations of COPD. Lung 187: 128-135.
5. Rubio MC, Rodríguez Hermosa JL, Nebreda MJ (2009) Anxiety and COPD. Arch Bronconeumol 45: 51-53.
6. Almagro P, Calbo E, Ochoa de Echagüen A, Barreiro B, Quintana S, et al. (2002) Mortality after hospitalization for COPD. Chest 121: 1441-1448.
7. Divo M, Cote C, de Torres JP, Casanova C, Marin JM, et al. (2012) Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 186: 155-161.
8. Vanfleteren LEGW, Spruit MA, Groenen M, Gaffron S, van Empel VPM, et al. (2013) Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 187: 728-735.
9. Kunik ME, Roundy K, Veazey C, Souchek J, Richardson P, et al. (2005) Surprisingly high prevalence of anxiety and depression in chronic breathing disorders. Chest 127: 1205-1211.
10. Gudmundsson G, Gislason T, Janson C, Lindberg E, Suppli Ulrik C, et al. (2006) Depression, anxiety and health status after hospitalisation for COPD: a multicentre study in the Nordic countries. Respir Med 100: 87-93.
11. Wilkinson MJ, Barczak P (1988) Psychiatric screening in general practice: comparison of the general health questionnaire and the hospital anxiety depression scale. J R Coll Gen Pract 38: 311-313.
12. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, et al. (2007) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 176: 532-555.
13. Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67: 361-370.
14. González-Gutiérrez MV, Guerrero Velázquez J, Morales García C, Casas Maldonado F, Gómez Jiménez FJ, et al. (2016) Predictive Model for Anxiety and Depression in Spanish Patients with Stable Chronic Obstructive Pulmonary Disease. Arch Bronconeumol 52: 151-157.
15. Xu W, Collet JP, Shapiro S, Lin Y, Yang T, et al. (2008) Independent effect of depression and anxiety on chronic obstructive pulmonary disease exacerbations and hospitalizations. Am J Respir Crit Care Med 178: 913-920.
16. Ng TP, Niti M, Tan WC, Cao Z, Ong KC, et al. (2007) Depressive symptoms and chronic obstructive pulmonary disease: effect on mortality, hospital readmission, symptom burden, functional status, and quality of life. Arch Intern Med 167: 60-67.
17. van Manen JG, Bindels PJ, Dekker FW, IJzermans CJ, van der Zee JS, et al. (2002) Risk of depression in patients with chronic obstructive pulmonary disease and its determinants. Thorax 57: 412-416.
18. Brenes GA (2003) Anxiety and chronic obstructive pulmonary disease: prevalence, impact, and treatment. Psychosom Med 65: 963-970.
19. Cao Z, Ong KC, Eng P, Tan WC, Ng TP (2006) Frequent hospital readmissions for acute exacerbation of COPD and their associated factors. Respirology 11: 188-195.
20. de Jonge P, Rosmalen JGM, Kema IP, Doornbos B, van Melle JP, et al. (2010) Psychophysiological biomarkers explaining the association between depression and prognosis in coronary artery patients: a critical review of the literature. Neurosci Biobehav Rev 35: 84-90.
21. Burgess A, Kunik ME, Stanley MA (2005) Chronic obstructive pulmonary disease: assessing and treating psychological issues in patients with COPD. Geriatrics 60: 18-21.
22. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, et al. (2004) The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 350: 1005-1012.
23. Lopez F, Pineda MCJ (2007) Ansiedad y depresión en la EPOC. Rev Clin Esp 2: 53-57.
24. Alcázar B, García-Polo C, Herrejón A, Ruiz LA, de Miguel J, et al. (2012) Factors associated with hospital admission for exacerbation of chronic obstructive pulmonary disease. Arch Bronconeumol 48: 70-76.
25. Montserrat-Capdevila J, Godoy P, Marsal JR, Barbé F (2015) Predictive Model of Hospital Admission for COPD Exacerbation. Respir Care 60: 1288-1294.
26. Hanania NA, Müllerova H, Locantore NW, Vestbo J, Watkins ML, et al. (2011) Determinants of depression in the ECLIPSE chronic obstructive pulmonary disease cohort. Am J Respir Crit Care Med 183: 604-611.
27. Almagro P, Barreiro B, Ochoa de Echaguen A, Quintana S, Rodríguez Carballeira M, et al. (2006) Risk factors for hospital readmission in patients with chronic obstructive pulmonary disease. Respiration 73: 311-317.
28. Miravitlles M, Ferrer M, Pont A, Zalacain R, Alvarez-Sala JL, et al. (2004) Effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a 2 year follow up study. Thorax 59: 387-395.
29. Domingo-Salvany A, Lamarca R, Ferrer M, Garcia-Aymerich J, Alonso J, et al. (2002) Health-related quality of life and mortality in male patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 166: 680-685.
30. Juárez MC, de Miguel J, Castuera AP, de OC (2013) Anemia en pacientes ingresados por una exacerbación de EPOC. Influencia sobre el pronóstico de la enfermedad. Rev Patol Respir 16: 37-41.
31. Gulliford MC, Charlton J, Latinovic R (2006) Risk of diabetes associated with prescribed glucocorticoids in a large population. Diabetes Care 29: 2728-2729.
32. Blackburn D, Hux J, Mamdani M (2002) Quantification of the Risk of Corticosteroid-induced Diabetes Mellitus among the Elderly. J Gen Intern Med 17: 717-720.
33. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, et al. (2010) Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 363: 1128-1138.
34. Bousquet JS, Anto JM, Sterk PJ, Adcock IM, Chung KF, et al. (2011) Systems medicine and integrated care to combat chronic noncommunicable diseases. Genome Med 3: 43.