Pulmonary tuberculosis in diabetes: Exploring the intersection and impact on mental health

Abstract

There is a bidirectional association between type II diabetes mellitus (T2DM) and pulmonary tuberculosis (PTB), with each enhancing the risk of the other, thus increasing the burden of both drug-sensitive and drug-resistant forms of the disease. This dual burden also has a detrimental impact on patient's mental health. Although several recommendations have been made for bidirectional screening of diabetes and tuberculosis, implementation remains poor, resulting in increased morbidity and mortality among patients with this comorbidity. Mental health is often neglected, as clinical outcomes receive disproportionate focus, with limited attention to patients’ social and psychological well-being. According to the World Health Organization, health is defined as a state of physical, mental, and social well-being, and not merely the absence of disease or infirmity. The aim of this mini-review is to highlight the intersection of PTB and T2DM, specifically discussing the mental health outcomes of the co-burden.

Key Words: Mycobacterium tuberculosis; Multi-drug resistance; Diabetes; Depression; Quality of life

Core Tip: Pulmonary tuberculosis (PTB) and Diabetes Mellitus type 2 (T2DM) both significantly increase the risk of mental health disorders, particularly depression and anxiety. Mental health issues in PTB patients are often underdiagnosed and undertreated, which can negatively affect treatment outcomes. Early screening and integrated care for mental health within co-morbid PTB and T2DM treatment programs are crucial for patient recovery. Stigma, social isolation, and financial burdens contribute to the psychological distress experienced by PTB patients with T2DM. Multidisciplinary approaches involving mental health professionals are essential for the holistic management of PTB.

INTRODUCTION

The intersecting epidemics of infectious diseases such as pulmonary tuberculosis (PTB) and non-communicable diseases like type 2 diabetes mellitus (T2DM) present a significant global health challenge. Individuals with diabetes have a two- to four-fold increased risk of developing active tuberculosis (TB), and similarly, PTB leads to the development of newly diagnosed PTB, hence up to 30% of patients with TB may also have diabetes mellitus (DM)[1].

Diabetes further exacerbates TB outcomes, increasing the risk of treatment failure, relapse, and mortality. Patients with TB-DM comorbidity are also at a higher risk of developing drug-resistant TB, including multidrug-resistant (MDR), pre-extensively drug-resistant (pre-XDR), and XDR TB, which worsens treatment outcomes. Notably, drug resistance was more prevalent among patients with TB and DM (21.83%) than in those with TB without DM (16.96%)[2,3].

In individuals with TB, mental health issues—including depression, anxiety, psychosis, mood instability, social stigma, and reduced quality of life—are frequently observed[4,5].

MDR-TB, in particular, poses a significant challenge to global TB control efforts and represents a major health security concern. Even among survivors, MDR-TB can cause lasting physical, psychological, and social harm.

Compared with treatment for drug-sensitive TB, MDR-TB therapy is considerably longer and is associated with severe side effects, often resulting in reduced treatment adherence and poorer outcomes. The prolonged and toxic treatment regimens for MDR-TB can contribute to mental health deterioration and reduce health-related quality of life for both patients and caregivers[6]. The aim of this mini-review is to highlight the intersection of PTB and T2DM, specifically discussing the mental health outcomes of the co-burden. Additionally, we also endeavor to summarize the current evidence on the epidemiology, clinical interactions, and psychological outcomes of TB with T2DM as comorbidity, to highlight priorities for comprehensive care, evaluate future studies and to study the mental health impacts of TB-T2DM comorbidity. The psychological component of TB-DM comorbidity is a very under-researched and poorly addressed topic in clinical practice. Hence, with the help of our mini-review, we attempt to fill the gaps in evidence for the interaction between TB, T2DM, and mental health.

BURDEN OF DRUG-RESISTANT TB AND DIABETES: GLOBAL OVERVIEW

TB and DM are two of the world's greatest health concerns whose co-occurrence is a significant concern to public health. As per the World Health Organization (WHO) Global Tuberculosis Report 2023, in 2022, 10.6 million people developed TB, and 1.3 million people died from TB. Interestingly, in 2022, globally, there were 410000 new cases of rifampicin-resistant (RR) or MDR-TB and the treatment success was only 63%. India accounted for the highest number of drug-resistant TB cases in 2022, contributing approximately 27% of the global burden. The proportion of new TB cases with MDR/ RR-TB declined from 4.0% in 2015 to 3.3% in 2022, while the proportion among previously treated cases fell from 25% to 17% over the same period[7].

According to the International Diabetes Federation, the number of individuals with diabetes is projected to rise by about 50% globally between 2019 and 2045. International Diabetes Federation Diabetes Atlas 2023 reports that 537 million adults in the world have diabetes, and in the near future the cases will rise to 643 million by 2030 and 783 million by 2045. The burden of diabetes is growing fast in the most heavily affected countries with high TB prevalence, including South-East Asia and sub-Saharan Africa. In high TB burden countries, the expected increase is approximately 99%. Diabetes triples the risk of developing TB, and poor glycemic control adversely affects TB treatment outcomes, including delayed sputum culture conversion, increased relapse rates, treatment failure, and elevated morbidity and mortality. In 2015, diabetes was estimated to account for 10.6% of global TB-related deaths[8].

In 2017, 425 million people globally had diabetes, a figure expected to rise to 629 million by 2045—an increase of 48%. This rise will likely fuel further increases in both TB incidence and drug-resistant TB. Alarmingly, regions with the highest TB burden—such as India, Africa, and Southeast Asia—are also projected to experience the largest increases in diabetes prevalence, with estimated increases of 163% in Africa and 84% in Southeast Asia.

To address this dual epidemic, the WHO introduced the Collaborative Framework for Care and Control of Tuberculosis and Diabetes. This framework aims to guide national programmes, clinicians, and healthcare providers in implementing integrated care models for both TB and diabetes at organizational and clinical levels. The framework emphasizes the importance of glycemic control and routine diabetes screening as essential components of comprehensive TB patient care[9].

BURDEN OF TB AND DIABETES: INDIAN SCENARIO

According to the WHO Global Report 2023, 1.417 million people in India are suffering from pulmonary TB. India ranks among the top 20 high-burden countries for TB, TB/human immunodeficiency virus, and MDR-TB, as per the global lists used by WHO during 2016-2020. India also appears among the top 30 countries in terms of absolute numbers and rates of MDR/RR-TB, based on incidence estimates for 2019. As per the Global Health Report, the total incidence of TB in India is approximately 2820000 cases (199 per 100000 population), while the incidence of MDR/RR-TB is approximately 110000 cases (8 per 100000 population). The proportion of MDR/RR-TB among newly diagnosed TB cases is 2.5%, and 13% among previously treated cases.

By 2040, the percentage of MDR-TB among incident cases of drug-sensitive pulmonary TB is projected to increase, reaching 12.4% (95% prediction interval: 9.4-16.2%) in India. Additionally, the proportion of pre-XDR and XDR pulmonary TB among incident MDR pulmonary TB cases is predicted to increase, reaching 8.9%-10% by 2040[8].

MENTAL HEALTH IMPACTS OF TB

There is a bidirectional relationship between TB and mental health issues. The presence of mental health issues worsen the outcomes in TB, and vice versa[9]. TB is recognized as a high-risk condition for developing mental health disorders[10]. As a highly stigmatized condition, individuals suffering from TB often experience significant discrimination, which adversely affects their mental health. Both TB and mental illness independently have a profound effect on an individual's overall well-being, and when they co-exist, the impact becomes more intense. Mental illness increases the risk of non-adherence to treatment, adversely affecting health-related outcomes[11]. Evidence also suggests that conditions such as depression and schizophrenia increase the risk of acquiring TB[12]. Factors such as poor self-care, living in unhygienic conditions, inadequate nutrition, poverty, and compromised immune function—all commonly associated with mental illness—may further elevate this risk.

TB, being a chronic debilitating health condition, causes significant discomfort and disability, which adversely affects mental health. Long-term treatment and adverse effects of antitubercular medications further exacerbate mental health burden[13]. Several antitubercular drugs interact with psychotropic medications (e.g., rifampicin-a, cytochrome P450 inducer, decreases the therapeutic levels of antipsychotic-medications). Isoniazid is a monoamine oxidase and cytochrome P450 enzyme inhibitor and is linked with neuropsychiatric side effects like irritability, depression, and psychosis potentially leading to poor symptom control in patients with comorbid mental illnesses[14]. Cycloserine, a second-line antitubercular drug widely utilized in MDR-TB regimens, is well known to cause psychosis, extreme anxiety, mood lability, and suicidal thoughts Moreover, medications such as cycloserine, and isoniazid may induce psychosis and depression[15]. Older age and a history of mental illness are important risk factors for developing comorbid psychiatric conditions in TB patients. Substance use disorders, such as alcohol use disorder, are also frequently observed among people with TB, particularly those living in poverty.

TB VIS-À-VIS MENTAL HEALTH AND DIABETES

The prevalence of diabetes is high in countries where TB is a major public health concern (WHO)[16]. Both TB and diabetes independently affect mental health, and their coexistence exacerbates this impact. Diabetes is a known risk factor for TB-related mortality, relapse, and complications[17]. A significant proportion of patients with TB report symptoms of depression and anxiety[18]. According to the Centre for Disease Control and Prevention, approximately 25% of people with TB also have diabetes. The risk of developing TB increases with longer duration of diabetes[1]. Additionally, age and body mass index (BMI) are independent risk factors for the development of diabetes in patients with TB[19]. Patients with diabetes often exhibit a higher prevalence of depression, anxiety, burnout, and stress[20]. The presence of mental illness is likely to worsen the course of both TB and diabetes, creating a vicious cycle where each condition intensifies the severity of the other, especially with regard to mental health. The comorbidity of TB and T2DM is increasingly recognized as a driver of mental health disorders, particularly depression, anxiety, and psychotic symptoms (Table 1)[21,22]. Few studies have exclusively studied TB with comorbid DM (TB-DM) patients and found a high prevalence of depression up to 77%[23]. TB-DM patients with depression had lower BMI, lower monthly income, and had higher levels of liver enzymes compared to those without depression. Another study from India has reported high prevalence of mental health symptoms in TB-DM patients, such as fatigue, lack of sleep, negative thoughts and social reclusion[24].

Table 1 Prevalence of mental health disorders in tuberculosis patients.

Mental health disorder	Prevalence in DSTB patients	Prevalence in MDR-TB patients	Ref.
Depression	25%-50%	50%-70%	Huque et al[11], 2020; Srinivasan et al[21], 2021
Anxiety	20%-40%	40%-60%	Alene et al[3], 2018
Suicidal ideation	5%-10%	10%-20%	WHO[22], 2017; Srinivasan et al[21], 2021
Psychosis	< 5%	5%-10%	Doherty et al[5], 2013

WHO: World Health Organization; TB: Tuberculosis; MDR: Multidrug resistant; DSTB: Drug sensitive tuberculosis.

Plausible mechanism for adverse mental health outcomes

Several biological and psychosocial mechanisms contribute to this association such as systemic inflammation and neuroinflammation, leading to elevated pro-inflammatory cytokines (interleukin 6, tumor necrosis factor-alpha) in both TB and T2DM which can cross the blood-brain barrier, promoting neuroinflammation and contributing to the development of depression and anxiety[25,26].

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation, which occurs due to Chronic stress from both infection (TB) as well as metabolic disease, leading to HPA axis overactivation, resulting in increased cortisol levels and hence causing depressive symptoms[21].

Hyperglycemia and glycation end-products in T2DM promotes oxidative stress, neuronal damage, and reduce neurotrophic support, increasing vulnerability to mood disorders[27].

Antitubercular medications such as isoniazid, cycloserine, and rifampicin can directly induce neuropsychiatric side effects, including depression, psychosis, and mood lability[28].

TB patients with T2DM face social stigma, economic hardship, job loss, and social isolation, which further exacerbate psychological distress and increase the risk of suicidal ideation[29,30].

These interacting mechanisms create a vicious cycle where mental health disorders worsen disease management, while disease progression exacerbates mental health burden hence again leading to a bidirectional relationship (Figure 1).

Figure 1 Pathogenetic mechanism of mental illness in co-existing pulmonary tuberculosis and diabetes mellitus. ¹Derived from systemic inflammation cause by Diabetes and tuberculosis. ²Isoniazide, Cycloserine. HPA: Hypothalamic pituitary axis; IL-6: Interleukin 6; TNF: Tumor necrosis factor.

IMPLICATIONS AND RISKS IN MANAGEMENT

Pathogenesis of TB in patients with diabetes

The emergence of MDR-TB in patients with diabetes may be driven by uncontrolled blood glucose levels, microbial genomic changes, and compromised immune function. DM increases the risk of MDR-TB due to impaired phagocytic activity, altered chemotactic response, enhanced production of reactive oxygen species, increased microbial proliferation, altered drug metabolism, and poor treatment adherence[31,32].

In patients with diabetes, inefficient innate immunity and hyperglycemia can lead to the accumulation of advanced glycation end-products, impairing phagocyte function and enhancing susceptibility to TB[33]. There are also reports of decreased phagocytosis and altered gene expression involved in antigen presentation and containment of Mycobacterium tuberculosis, including reduced release of anti-mycobacterial peptides. Peripheral blood monocytes in patients with diabetes express CCR2 at higher levels, which may affect cell trafficking. Since patients with T2DM have higher levels of the CCR2 ligand MCP-1 in their blood, these monocytes may be retained in circulation rather than migrating to infection sites in the lungs[34].

Treatment strategy

In general, patients with both TB and diabetes are not treated differently than those with only pulmonary TB[35]. However, stringent monitoring and control of glycemic levels are crucial. This includes regular assessment of random and fasting blood glucose and HbA1c every 3 months. Weekly strength-building counselling sessions should be provided to strengthen treatment adherence, encourage healthy dietary practices, promote adequate physical activity, and support mental health through interventions such as meditation[36].

Metformin and insulin do not interfere with antitubercular drugs. However, rifampicin-induced drug resistance has a particularly negative impact on treatment outcomes[21]. Rifampicin increases the hepatic metabolism of sulphonylureas—the most widely used oral hypoglycemic agents—leading to variability in drug levels and increased risk of hypo- or hyperglycemia.

Although no direct evidence supports the use of insulin specifically in TB patients with diabetes, some national treatment recommendations (such as those in Indonesia) highly recommend it. Insulin does not undergo hepatic metabolism and does not interact with rifampicin[22]. Nevertheless, challenges such as cost, storage, and availability limit its use in resource-constrained settings.

In patients with TB and T2DM, aggressive glycemic control[3,37,38], frequent follow-ups, and patient education are critical for optimal outcomes (Table 2).

Table 2 Suggested approach for challenges in the management of tuberculosis with comorbid diabetes mellitus.

Challenge	Suggested approach	Ref.
Delayed TB diagnosis in DM patients	Systematic TB screening in DM clinics	WHO 2023 Framework[37,38]
Poor TB treatment outcomes in DM	Aggressive glycaemic control; close follow-up during TB therapy	Huangfu et al[27], 2019
Drug-drug interactions affecting glycaemic control	Monitor blood glucose closely; adjust anti-diabetic medications	Restrepo[25], 2016
Rifampicin-induced hyperglycaemia	Increased SMBG (self-monitoring of blood glucose) during intensive phase	Restrepo[25], 2016
Lack of bi-directional screening at program level	Integrate DM screening in TB programs and TB screening in DM clinics	WHO 2023 Framework[37,38]
Poor patient adherence due to complex dual disease burden	Patient-centred care, education, counselling, and peer support	WHO 2023 Framework[37,38]
Lack of integrated clinical guidelines	Develop national guidelines on collaborative TB-DM management	WHO 2023 Framework[37,38]

TB: Tuberculosis; DM: Diabetes mellitus; WHO: World Health Organization.

SUGGESTED OUTCOMES

Poor glycemic control is associated with an increased risk of severe and advanced TB manifestations, including lung cavitations, positive sputum smear microscopy, slower sputum smear conversion, and delayed culture conversion[38,39]. These factors adversely affect treatment outcomes by delaying their completion, reducing cure rates, and increasing relapse rates in patients with pulmonary TB.

CONCLUSION

This mini-review highlights the significant epidemiological overlap between TB and T2DM, referencing their mutual impact on disease burden and outcomes. Increasing evidence also indicates that this comorbidity raises the risk of various psychopathologies, such as depression, anxiety, and psychosis, which remain inadequately managed in clinical practice. Models of integrated care that include routine mental health screening, strict glycemic control, and combined TB-DM management are necessary to improve overall outcomes. Future studies need to focus on investigating the mechanistic interactions between metabolic and psychiatric pathways and on assessing scalable interventions for the clinical and psychological complexity of TB-T2DM comorbidity.