Tuberculosis remains a major public health concern and a danger to global health. Multidrug-resistant tuberculosis (MDR-TB) is characterized by resistance to at least isoniazid and rifampicin (1). The burden of multidrug-resistant tuberculosis has been estimated in 410,000 cases in 2022 (2). In worldwide, MDR-TB affects 3.3% of individuals newly diagnosed with tuberculosis (TB) and is found in 18% of those with a history of prior TB treatment (3). Elevated rates of MDR-TB are particularly evident in Russia, as well as in several countries throughout Asia and Eastern Europe (4, 5). China ranks among the top seven nations globally in terms of the burden of MDR-TB, accounting for approximately two-thirds of MDR/RR-TB cases worldwide (6). Epidemiological studies indicate a clear association between MDR-TB and age, with young adults-especially those between 26 and 45 years old-showing increased susceptibility (7). Management of MDR-TB remains particularly challenging owing to complex drug regimens, side effects of second-line agents, and substantial treatment expenses. Therefore, understanding the risk factors associated with MDR-TB is of critical importance.

We know for instance that smoking is the leading risk factor for increased mortality among males (and risk of TB infection, active TB disease, and TB mortality when co-existing with TB) (8, 9). This is especially important among Asian and African countries with high rates of TB and smoking (10). Currently 80% of smokers reside in LMICs—where we see the highest rates of TB. There will continue to be promotions of cigarettes through various channels with for instance BAT generating sales of US$34billion in 2022 and Philip Morris US$31.8 billion (11).

The Global Adult Tobacco Survey (GATS) found that tobacco-related diseases claim over 7 million lives globally every year (12). There is considerable evidence indicating a link between tobacco smoking and TB infection, with smokers exhibiting twice the risk of TB infection and progression to active TB (13). Furthermore, cigarette smoking is not only strongly correlated with a heightened risk of TB but is also linked to the recurrence and severity of pulmonary TB (14, 15). The finding that the risk of TB could be reduced by nearly two-thirds upon quitting smoking underscores the critical role of smoking in the fight against TB (16). Nevertheless, many relevant studies were constrained by limited sample sizes and relied more on case–control designs rather than cohort studies. Moreover, the epidemiological evidence regarding this relationship has yet to be comprehensively synthesized.

Following inhalation, Mycobacterium tuberculosis mainly targets and multiplies inside alveolar macrophages (AMs). Exposure to tobacco smoke, however, triggers substantial phenotypic and metabolic changes in these immune cells, reducing their ability to phagocytose and weakening their anti-mycobacterial activity (17, 18). Moreover, smoking undermines host immunity through several mechanisms: (1) impairing mucociliary clearance, (2) inhibiting the secretion of TNF-α and IL-12, and (3) disturbing the process of granuloma formation (19–21). It is plausible that smoking-related systemic immunosuppression may facilitate infection with drug-resistant TB strains, including MDR-TB. Additionally, TB patients who smoke demonstrated poorer adherence to treatment and a reduced tendency to complete therapeutic regimens, thereby increasing the risk of acquired drug resistance (22, 23). Multivariate logistic regression analysis showed that the risk of developing MDR-TB in individuals with comorbidities was 9.17 times higher than in individuals without comorbidities (24).

While prior Global Burden of Disease (GBD) studies have identified smoking as a risk factor for MDR-TB, they have not fully assessed the overall burden attributable to smoking in MDR-TB cases. Therefore, mapping the global distribution of smoking-related MDR-TB burden is critical. Using publicly available GBD data, we quantify its evolving impact over three decades (1990–2021).

This study aimed to elucidate the burden of multidrug-resistant tuberculosis (MDR-TB) attributable to smoking through an empirical analysis of Deaths, DALYs, YLDs, and YLLs between 1990 and 2021. The observed upward trajectory in both the absolute number of cases and the ASR indicates a growing public health challenge, necessitating targeted interventions to control the incidence of drug-resistant TB and mitigate its escalating impact.

While areas currently bearing the heaviest disease burden deserve priority attention, equal emphasis should be placed on regions where cases have risen most sharply in recent years. The sharpest rises in ASRs for mortality, DALYs, YLDs, and YLLs from 1990 through 2021 occurred in Oceania and Central Asia. Increasing funding for MDR-TB programs linked to tobacco control in these two areas could prove beneficial.

The analysis demonstrated a significant gender dichotomy in the tuberculosis burden attributable to tobacco use, with males exhibiting considerably higher rates than females. This disparity is potentially attributable to a combination of pathogenic mechanisms: Endogenous hormonal variations, specifically the putative role of female sex hormones in potentiating more robust immune responses to cytotoxic challenges. A heightened prevalence of modifiable risk factors (e.g., smoking) and a documented lower engagement with healthcare services among male populations. As can be seen from the results, the death burden of disease is relatively higher in all age groups 30–39. Individuals in young and middle adulthood usually have a fully developed and potent immune system. When Mycobacterium tuberculosis enters the body, the immune system responds with an intense assault to isolate and eradicate the pathogen. This reaction results in widespread inflammation and tissue death. Secondly, Owing to the aforementioned factors (e.g., fatigue and pressure), the immune function of young and middle-aged individuals becomes compromised, causing latent tuberculosis bacteria in the body to become active again and trigger ‘endogenous reactivation’—the main cause of adult tuberculosis. Studies have pointed out that smoking impairs the autophagy function of macrophages, and autophagy is essential for the removal of Mycobacterium tuberculosis. Autophagy defects caused by smoking may make it more difficult for macrophages to resist Mycobacterium tuberculosis infection, thereby increasing the risk of tuberculosis (32).

As of 2021, Lesotho exhibits the highest MDR-TB burden connected to smoking, while regions in Europe, the Americas, and Oceania report comparatively lower burdens. Concerning the distribution of MDR-TB cases by region, our results indicated that Lesotho, Uzbekistan, and Kyrgyzstan experienced the highest mortality rates. Lesotho, a small and landlocked nation encircled by South Africa, has a mortality rate of 650 per 100,000 population, with an estimated 11.8% of cases classified as MDR/RR-TB across both newly diagnosed and previously treated individuals. It is widely recognized that the high mortality rate results from the combined effects of tuberculosis, HIV, food scarcity, and poverty in Lesotho (33, 34). Uzbekistan ranks among the 30 countries worldwide burdened with high rates of MDR/RR-TB (35). Similarly, The Kyrgyz Republic is one of the high priority countries for MDR-TB, in 2021, 46% of the estimated 10.6 million people with TB were missed by health systems (known as “missed TB cases”) (36, 37). These areas have documented the highest TB incidence rates, which can largely be linked to economic challenges and undernutrition. Therefore, it is essential for these nations to emphasize the strategic allocation of healthcare resources, with particular attention to impoverished areas, efforts to combat hunger, and the development of social safety nets aimed specifically at assisting low-income families afflicted by TB.

Additionally, we implemented ARIMA and ES prediction models to estimate the impact of MDR-TB over the forthcoming 30 years. Projections indicate that by 2037, the mortality rate from MDR-TB linked to smoking among males is expected to decline, which implies effective control measures against smoking. Multiple factors contribute to the prevalence of MDR-TB, with five primary risk factors accounting for many TB cases globally: undernutrition, HIV infection, alcohol use disorder, diabetes, and smoking. Consequently, it is vital to acknowledge MDR-TB as a fundamental aspect in the realm of TB prevention and control. Attention should be directed not only toward minimizing TB incidence but also toward initiatives aimed at reducing the transition of drug-susceptible TB cases into drug-resistant variants.

To account for regional variations, governments should enact localized anti-smoking measures, such as hiking tobacco duties—a proven method to decrease demand (38, 39). As earnings increase, especially in developing nations, adapting tax systems is vital to sustain their efficacy. Whilst over 70 countries now have policies to ban smoking in public places, workplaces and public transport, Total bans seem to have a greater impact than partial bans (40). There can be concerns regarding how the laws are applied in practice, e.g., (41) as also seen in South Africa during the COVID-19 pandemic leading also to increase buying of cigarettes illicitly. In addition-return to previous practices as laws are relaxed (42–47). Potential ways forward include the use of NRT to help make quitting permanent-however, such policies are variably introduced across LMICs in view of cost/co-payment concerns (48).

Our findings provide valuable evidence to refine tobacco control policies and optimize healthcare delivery for vulnerable MDR-TB populations. It also emphasized how gender and age differences affect disease burden, underscoring the importance of targeted prevention strategies, thereby supporting the health-related Sustainable Development Goals. However, several methodological limitations should be considered when interpreting these results. Firstly, Reliance on self-reported smoking status from public repositories may result in prevalence underestimation, with particular under ascertainment among female populations. Secondly, the available datasets are limited to conventional tobacco formulations, omitting contemporary nicotine delivery systems such as electronic cigarettes, despite mounting evidence of their clinical consequences. Lastly, this investigation was constrained to evaluating active smoking-attributable MDR-TB burden due to unavailability of epidemiological data regarding passive smoke exposure, alternative nicotine consumption modalities, or electronic delivery systems.

This research highlights significant worldwide decreases in the impact of MDR-TB linked to smoking, mainly driven by high-SDI areas implementing effective public health initiatives. Nevertheless, inequalities persist, especially in lower-SDI regions, among males, and within older age groups (ages 40–60), who encounter greater burdens due to increased smoking prevalence and restricted healthcare availability. To tackle these disparities, it is essential to develop targeted interventions tailored to specific regions to further mitigate the effects of smoking-related MDR-TB. Enhancing tobacco control, improving access to healthcare, and adopting gender-sensitive strategies are vital for attaining fair advancements in global tuberculosis health.