Depression comorbid with tuberculosis and its impact on health status: cross-sectional analysis of community-based data from 48 low- and middle-income countries

Tuberculosis (TB) is one of the top 10 causes of deaths globally [1]. In 2015, there were 10.4 million new TB cases and 1.8 million deaths due to TB. Over 95% of TB cases and deaths occur in developing countries [1]. Depression often coexists with TB [2], and this comorbidity is associated with poor adherence to TB treatment and higher mortality [3]. Lack of adherence to anti-TB regimens may lead to higher risk for drug resistance, morbidity, and mortality, as well as community exposure to TB [4, 5].

In low- and middle-income countries (LMICs), the prevalence of depression is high and may be increasing [6]. A recent large prospective study from Korea found that depression at baseline is associated with a higher risk for incident TB [7]. Depression may lead to an increased susceptibility to TB by compromising immunity or through neglected self-care [8]. Thus, depression may be an unrecognized driver of the global TB and multidrug resistant TB (MDR-TB) epidemics [2]. However, the few previous studies on the association between depression and TB from LMICs have only been conducted in clinical settings with small sample sizes, and information from the general population is lacking. Furthermore, there is limited information on the joint effect of TB and depression on health status. We therefore assessed the association between TB and depression, and whether the co-occurrence of TB and depression confers a more pronounced decrement in health status and function compared to TB alone using community-based, predominantly nationally representative data from 48 LMICs that participated in the World Health Survey (WHS). Epidemiological data on the TB/depression comorbidity and its effect on health outcomes are crucial to provide a more accurate assessment of the public health significance of this comorbidity.

The analytical sample consisted of 242,952 individuals with a mean (SD) age of 38.4 (16.1) years and 50.8% were women (Table 1). The prevalence (95% CI) of TB was 1.7% (1.5–1.8%). All types of depression were more frequent among those with TB, with the difference being particularly pronounced for depressive episode (Fig. 1).

The prevalence of depressive episode among those with and without TB was 23.7% (95% CI 20.5–27.1%) and 6.8% (95% CI 6.5–7.1%), respectively (χ² test P < 0.001). The results of the multivariable multinomial logistic regression using the overall sample showed that TB is associated with a 1.98 (95% CI 1.47–2.67), 1.75 (95% CI 1.26–2.42), and 3.68 (95% CI 3.01–4.50) times higher odds for subsyndromal depression, brief depressive episode, and depressive episode, respectively (Table 2). Older age, female sex, lower levels of wealth, smoking, and diabetes were significant correlates of depressive episode.

The association between TB and depressive episode estimated by multivariable binary logistic regression by regions or country income levels are shown in Table 3. TB was associated with a depressive episode across regions and county income levels although the estimates for Europe did not reach statistical significance, possibly due to lack of statistical power (OR, 2.67; 95% CI 0.75–9.52; P = 0.1293).

Compared to those with no TB or depressive episode, depression alone, TB alone, and comorbid TB/depression were all significantly associated with worse health status scores in all domains. Comorbid TB/depression was associated with the largest decline (Table 4).

The results of the age-stratified analyses are shown in Additional file 1: Table S3. The decline in health status associated with depression alone and co-occurring TB/depression was similar across age groups, but that of TB alone was less pronounced in the oldest age group (i.e., ≥ 65 years). In order to assess whether the difference between TB alone and comorbid TB/depression is statistically significant, we also conducted the same analysis but changing the reference category to TB alone (overall sample). The b-coefficients (95% CIs) for comorbid TB/depression (vs. TB alone) were mobility 19.17 (14.52–23.81), self-care 18.46 (13.41–23.54), pain/discomfort 20.14 (16.23–24.04), cognition 15.61 (11.13-20.09), interpersonal activities 15.04 (10.13–19.96), and sleep/energy 19.67 (14.47–24.88) (all P < 0.0001). Overall, the interaction analysis showed that depression significantly amplifies the association between TB and difficulties in self-care but not with other health domains (Additional file 1: Table S4).

We found that TB is associated with the entire depression spectrum in the overall sample, and that the association between TB and depressive episode is comparable across regions and country income levels. Furthermore, the co-occurrence of depression and TB was associated with a major decrement in all health domains assessed compared to TB alone, with this additive effect being particularly pronounced for difficulties in self-care. The strengths of the study include the large sample size and use of predominantly nationally representative data from approximately one-fourth of the countries in the world obtained by standardized questionnaires across all countries. To the best of our knowledge, this is the first general population study on TB and depression. Furthermore, it is one of the very few studies assessing the association between TB and depression severity, and is the first to assess the joint effect of TB and depression on a variety of health conditions (i.e., mobility, self-care, pain/discomfort, cognition, interpersonal activities, sleep/energy). The finding that there may be a synergistic effect between TB and depression in terms of some health outcomes (i.e., self-care) is novel.

The association between TB and depression may be bidirectional [7, 25]. Depression itself may compromise immunity, leading to an increased risk for TB [8], while increased inflammation in TB may increase risk for depression [26]. Alternatively, depression may be a psychological reaction to the symptoms of TB (e.g., chronic cough, fatigue, weight loss) or associated disability [27], while hypoxia in chronic pulmonary diseases may induce depression [28]. It is also possible that patients with TB are perceived as a source of contagion in the community, which may lead to discrimination, stigma, social isolation, and rejection, and may predispose individuals to a higher risk for depression [27, 29]. Further, some anti-TB drugs can induce depression [27]. Finally, common risk factors, such as compromised immunity, stress, and malnutrition, may underlie the association [8, 26, 30, 31]. Regardless of whether depression and TB are etiologically related, the mere co-existence can complicate the diagnosis and management of these conditions, while it is also possible that they mutually influence each other and lead to the exacerbation of the other, altering the clinical course [27].

Other factors which were identified as significant correlates of a depressive episode in our study included sociodemographic factors (older age, female sex, lower levels of wealth), smoking, and diabetes. Previous studies have also found these factors to be associated with depression [32‐36]. In particular, diabetes is known to increase risk for TB [37], and may be an important risk factor for TB in LMICs [10] as there is an upward trend in diabetes prevalence mainly driven by changes in lifestyles and diet in this setting [38]. On the other hand, diabetes and depression are often comorbid and common pathophysiological mechanisms (e.g., stress, inflammation) may underlie this co-occurrence [39].

In our study, compared to TB occurring in isolation, co-existing TB/depression was associated with decrements in all health domains assessed, while a significant interaction was observed for difficulties in self-care. These results are in line with a small cross-sectional study from Turkey showing that psychiatric comorbidity is associated with a higher rate of disability among TB patients [40]. Depression may lead to poor adherence to anti-TB drugs, and thereby exacerbate the symptoms of TB and its associated disability. Indeed, a prospective study from Peru showed that co-occurring TB/depression leads to lower adherence to TB treatment and higher mortality when compared to TB without depression [3]. The fact that a significant interaction was observed for self-care may imply that there is a synergistic effect between TB and depression. It may be hypothesized, for example, that depression leads to poor TB treatment adherence and exacerbation of symptoms, which in turn may lead to a worsening of depression. However, the precise underlying mechanisms or the reason why an interaction was only observed for self-care is unclear and warrants further investigation. Finally, delayed diagnosis of TB in people with depression may also partly explain our findings. It has been reported that delayed detection of physical diseases may be common in individuals with depression [41]. Thus, it may be that, when individuals with prior depression are diagnosed with TB, their TB symptoms are more severe compared to those without prior depression. Lack of motivation or social support and cognitive impairment, which may affect decision-making [42], might limit access to healthcare among depressed individuals, leading to delayed diagnosis and treatment initiation for TB.

Previous studies have shown that treating the psychological aspects of TB may lead to better clinical outcomes. For example, a prospective controlled trial in India showed that psychotherapy during TB treatment leads to higher adherence, treatment, and cure rates [43]. Furthermore, a psychological support group intervention for patients with MDR-TB in Peru showed that such an intervention can improve treatment adherence and completion [44]. Additionally, the formation of ‘TB clubs’ in Ethiopia increased treatment completion rates and reduced the stigma associated with TB [45]. Recently, a randomized controlled trial in Ethiopia showed that psychological counseling and educational intervention can substantially improve treatment adherence rates in TB [46].

A multi-faceted approach is likely to be relevant in addressing comorbid depression and TB in LMICs. First, previous studies from LMICs have shown that the treating doctor is often not aware of co-existing psychiatric morbidity in TB patients [47]. Thus, training of medical professionals and students on the psychological aspects of TB may lead to early detection and better management of psychiatric complications, and ultimately to a better clinical outcome of TB. Next, a close collaboration between TB and mental health specialists would be important for the early detection and treatment of depression in TB. Previous studies have shown that training of non-mental health specialists in LMICs may only have a limited impact on depression detection rates [48]. Thus, screening for depression may be a cost-effective strategy to improve detection rates of depression in TB. However, symptoms specific to depression (e.g., low mood, anhedonia) and symptoms of depression that overlap with TB (e.g., fatigue) should be distinguished. Some studies have assessed the validity of depression screeners such as the Center for Epidemiological Studies Depression scale or the General Health Questionnaire 12 among TB patients [40, 49]. These studies found that these screening tools can be used among TB patients to detect depression but that there may be a disease-specific optimal cut-off. Future studies on the validity and reliability of such screening tools are warranted, as only scarce data from limited populations are currently available. Finally, patient education and community awareness regarding facts and myths of TB may also be important [50], as discrimination and stigma can be underlying causes of depression in TB.

Our results should be interpreted in the light of several limitations. First, we lacked information on HIV, which is known to be associated with higher risk for TB [1] and depression [51]. Thus, some of the association may be attributable to comorbid HIV. However, this may not have been a major limitation as our region-wise analysis showed that TB is associated with depression even in areas with very low HIV prevalence (e.g., the Americas). Second, our study was based on the symptoms of TB rather than a laboratory confirmed diagnosis. Although we used the identical definition for TB used in previous publications [10‐12], it is possible that some level of symptom overlap may exist between respiratory diseases such as pneumonia, bronchitis, and chronic obstructive pulmonary disease, which may also cause cough of long duration and hemoptysis. Thus, our estimates may partially be representing the association between these conditions and depression. Furthermore, the potential misclassification may have led to an underestimation of the association between TB and depression. However, it is reassuring that the prevalence of depression in TB was within the previously reported range of estimates among patients with confirmed TB [2]. Additionally, we are not aware of any other population-based data with such a large number of LMICs that can be used to investigate the TB–depression relationship. Third, high-risk groups, such as the institutionalized and homeless, were not included in our study and thus our findings are not generalizable to this population. Finally, the direction of causality cannot be established due to the cross-sectional design.

In conclusion, individuals with TB have higher odds for depression, and the co-occurrence of TB and depression is associated with decrements in health. Screening for and addressing depression in individuals with TB may lead to better clinical outcomes. However, mental health services and specialists are limited in low-resourced settings where the highest burden of TB is located. Increased recognition of co-existing depression in TB patients by health professionals and the use of non-specialist health workers trained in mental healthcare, especially in resource-limited settings, may be key. However, given that healthcare workers are at increased risk of occupationally acquired TB in LMICs [52], sound infection control measures should be implemented to protect these individuals, yet this is a particular challenge in LMICs due to financial constraints. Finally, simultaneously addressing the mental and physical aspects of TB may lead to reduction in TB transmission [53], and also possibly in TB mortality and MDR-TB. This is an area for future research.