Tuberculosis (TB) remains one of the deadliest infectious diseases caused by a single agent. Although the introduction of effective anti-TB chemotherapy has led to a decrease in TB deaths, global TB deaths remain high. In 2021, an estimated 1.6 million TB deaths occurred worldwide, making it the 13th leading cause of death globally and the second leading cause of death from a single infectious agent, following coronavirus disease 2019 (COVID-19) [1]. In South Korea, the number of TB deaths in 2021 was 1,430 (2.8 per 100,000), showing a 5.5% increase compared to that in 2020 (1,356 persons, 2.6 per 100,000), ranking third among Organization for Economic Co-operation and Development (OECD) countries [2].

The risk of death in patients with multidrug/rifampin-resistant tuberculosis (MDR/RR-TB) is notably higher than that in patients with drug-susceptible TB [3–5]. Identifying the timing and predictors of death during treatment is essential to determine the optimal timing and target populations for effective interventions. Several studies have reported various risk factors associated with mortality in patients with MDR/RR-TB [6,7]. Considering the diverse situations in different countries, it is crucial to identify country-specific risk factors. While some studies have highlighted the risk factors for TB deaths in South Korea [8–11], the majority have focused on drug-susceptible TB and do not represent nationwide data.

To address this gap, we constructed an integrated TB database by linking three national databases [12] and reported the nationwide treatment outcomes of patients with MDR/RR-TB notified between 2011 and 2017 [13,14]. Our findings revealed that death during treatment constituted the largest proportion of unfavorable outcomes, presenting a new challenge in the management of MDR/RR-TB in South Korea [13]. Subsequently, we investigated the timing and predictors of death during treatment of patients with MDR/RR-TB in South Korea

This study aimed to investigate the timing and predictors of death during treatment among patients with MDR/RR-TB in South Korea. Approximately 10% of patients with MDR/RR-TB died during their treatment, and nearly half of these deaths occurred within 6 months of initiating MDR-TB treatment. This study also identified various predictors of death during treatment, encompassing demographic factors (old age and male sex), clinical factors (comorbidities), TB-specific factors (smear positivity, FQ resistance, and history of previous TB treatment), and socioeconomic factors (belonging to the lowest income class). This study emphasizes the need for an integrated and comprehensive strategy to reduce mortality in patients with MDR/RR-TB, particularly focusing on the early stages of treatment and vulnerable populations.

The study revealed that deaths occurred more frequently in the intensive phase, but were consistently observed throughout the entire treatment duration. TB-related deaths occurred earlier (median, 4.4 mo) compared to non-TB-related deaths (median, 6.1 mo). This aligns with the findings of a cohort study on drug-susceptible TB in South Korea that showed that many TB-related deaths occurred during the intensive phase [8]. Therefore, interventions aimed at reducing mortality should prioritize the early stages of treatment, emphasizing strategies such as early diagnosis and prompt initiation of appropriate treatment. This includes active case findings in high-risk populations and the expanded use of rapid molecular drug susceptibility testing (DST).

The distribution of the timing of deaths in this study also highlights the need for new treatment strategies beyond early detection and treatment. In a retrospective MDR/RR-TB cohort study using new drugs in South Korea [16], only age and low body mass index were found to be independent predictors of treatment outcomes, whereas traditional TB-specific factors (smear positivity, previous TB treatment, presence of cavity, drug resistance patterns) did not significantly predict treatment outcomes. This finding suggests that effective treatment with new drugs may mitigate the impact of TB-specific factors on treatment outcomes. However, despite achieving a high treatment success rate of 79.2%, the mortality rate remained high at 11.9% [16]. Therefore, simply incorporating new drugs into conventional longer regimens may not be sufficient to reduce mortality rates. Considering the cause and timing distribution of deaths shown in this study, the introduction of new, shorter regimens of 6–9 months [17,18] is expected to be an effective strategy to reduce mortality in patients with MDR/RR-TB.

This study revealed various risk factors associated with deaths, including demographic, clinical, and socioeconomic factors, which align with the findings of previous studies [6]. The risk factors associated with a higher hazard ratio in this study were age and comorbidities. Age is likely to have a great impact on death during treatment, with patients aged ≥ 65 years contributing to 65% of total deaths. The risk of death increased proportionally with age, reaching a 68 times higher risk for patients aged ≥ 75 years than those ≤ 24 years. Risk factors associated with death during TB treatment varied by region [19]. HIV positivity is the primary risk factor for death in countries with a high incidence of TB and prevalence of HIV [7,19]. However, age and non-infectious comorbidities were the main risk factors for death in regions with a low incidence of TB and HIV [19–21], as shown in this study.

Older patients face a higher risk of both incidence of TB and TB-related death, primarily because of immunosenescence, comorbidities, and an increased susceptibility to adverse reactions during treatment [22,23]. Although TB in older patients has traditionally been considered a concern in developed countries [24], it has now evolved into a global challenge with increasing life expectancy [22]. Notably, South Korea, which has one of the fastest-growing older populations globally, has encountered challenges with TB in older population [25,26]. A tailored strategy that encompasses initiatives, such as the implementation of routine TB screening at aged-care facilities, the establishment of age-friendly infrastructure and services, and the integration of TB and non-communicable diseases services, has the potential to significantly improve TB management among older adults [27].

This study identified that comorbidities and the lowest income level as independent predictors of death, which was consistent with previous studies [28,29]. In contrast to age, comorbidities and socioeconomic factors may be modifiable. Various risk factors from demographic, clinical, and socioeconomic perspectives contribute to TB-related deaths, and these factors are interconnected. For example, lower socioeconomic groups face a higher risk of malnutrition, engage in less healthy behaviors (such as smoking and alcohol abuse), are less likely to seek healthcare, and are more likely to have comorbidities [28]. Therefore, a comprehensive and integrated approach is required to reduce mortality in patients with MDR/RR-TB.

The risk of death among TB patients has generally been higher in rural areas than in urban areas, likely due to differences in the accessibility and quality of health care [30]. The lower risk of death in non-metropolitan areas compared to metropolitan areas suggests that there may not be a significant disparity in healthcare access in South Korea. Furthermore, this suggests that high-risk groups, such as the homeless and single-room occupants with limited medical accessibility, may be more prevalent in metropolitan areas rather than in non-metropolitan areas.

To our knowledge, this is the first study to evaluate the timing and predictors of death in a nationwide MDR/RR-TB cohort in South Korea. The strength of this study is that it was a population-based study covering almost all MDR/RR-TB cases notified in South Korea. However, the retrospective nature of this study and its reliance on routinely collected health data introduced several limitations. First, the cause of death might not be accurate. In the KTBS, the cause of death was determined by an attending physician or TB nurse based on the death certificate. This was not been confirmed through autopsy or alternative methods, potentially leading to a reporting bias. However, this potential misclassification did not affect the study results because we analyzed the risk factors for all-cause death. A verification process to determine the exact cause of death and subsequent analysis of the predictive factors for TB-related death is necessary. Second, regimen-related factors and adverse drug reactions were not included in the assessment of risk factors for mortality. Third, this study did not adequately capture recent advancements in MDR-TB treatment. Several studies conducted in other countries have reported that the use of new drugs contributes to a reduction in TB deaths [31,32]. This study has limitations in determining the impact of new drugs on mortality because the use of the new drug was limited during the study period. Therefore, further studies using nationwide data are required.

In conclusions, this nationwide study highlighted the increased deaths during the intensive phase and identified high-risk groups, including older people and those with comorbidities or socio-economic vulnerabilities. A comprehensive strategy, including active case finding, early detection with molecular DST, introduction of new, shorter regimens, comorbidity management, and socioeconomic support, is crucial for reducing MDR/RR-TB mortality in South Korea.