Asthma Incidence and Risk Factors in Tuberculosis Survivors: A Longitudinal Analysis of National Health Data

Abstract

Tuberculosis remains a leading cause of morbidity and mortality worldwide, with approximately 10.8 million incident cases reported in 2023 [1]. Even after completing treatment, a substantial proportion of TB survivors experience chronic respiratory sequelae, including bronchiectasis and chronic obstructive pulmonary disease (COPD) [2]. However, the potential risk of asthma following TB has been less investigated and remains inconclusive.

The effect of TB on asthma development can be hypothesized in two opposing ways. Immunologically, TB infection induces a predominantly Th1-driven response, which may theoretically have an inverse relationship with asthma, typically characterized by allergen-triggered Th2-driven inflammation [3]. Conversely, another plausible hypothesis is that structural lung damage, airway remodelling, and airflow obstruction resulting from TB infection could predispose individuals to asthma development [2, 4]. In line with these opposing mechanisms, previous studies have reported inconsistent results, mostly derived from cross-sectional designs that limit the ability to establish a temporal relationship [4, 5]. Therefore, we conducted a nationwide longitudinal cohort study to clarify whether TB survivors are at increased risk of incident asthma and to identify associated risk factors.

We used linked data from the Korea Disease Control and Prevention Agency TB registry and the National Health Insurance Service (NHIS). Among newly registered TB cases aged ≥ 20 years between 2013 and 2017, TB survivors were 1:1 matched by age and sex with controls and followed until asthma diagnosis, death, or December 31, 2021. Pulmonary TB was identified using ICD-10 codes A15–A16 (excluding A17–A19) and TB-specific NHIS codes (V206, V246, V000). Asthma was defined as ≥ 3 outpatient visits or ≥ 1 hospitalization with codes J45 or J46. Hazard ratios (HRs) for asthma incidence were estimated using the Cox proportional hazards regression model, adjusting for age, sex, body mass index (BMI), smoking status, alcohol consumption, income level, residential area and Charlson Comorbidity Index (CCI). Stratified analyses were conducted for all variables. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Detailed methodology is available in the Open Science Framework repository (https://doi.org/10.17605/OSF.IO/285RA).

A total of 28,384 individuals were included (14,192 in each group). Mean age was 51.1 ± 14.9 years, and 68.3% were male. Compared to matched controls, TB survivors had a higher prevalence of underweight (11.4% vs. 3.3%), smoking, heavy drinking and comorbidities including COPD, bronchiectasis, and a CCI score ≥ 3 (all p < 0.001). In contrast, hypertension and dyslipidemia were more frequent in the control group. During a median follow-up of 5.1 years (interquartile range, 3.8–6.5), 2768 participants (1632 TB survivors and 1136 controls) developed asthma, corresponding to incidence rates of 23.1 versus 15.5 per 1000 person-years. TB survivors had a significantly higher risk of incident asthma than controls (adjusted HR [aHR], 1.26; 95% confidence interval [CI], 1.16–1.38) (Figure 1). This association was consistent across most subgroups (p for interaction > 0.05), except for patients with bronchiectasis and those with a Charlson comorbidity index score ≥ 3 (Figure 1). Among TB survivors, independent risk factors for incident asthma included age ≥ 60 years (aHR, 2.16; 95% CI, 1.94–2.41), female sex (aHR, 1.17; 95% CI, 1.02–1.35), obesity (aHR, 1.25; 95% CI, 1.10–1.44), low income (aHR, 1.35; 95% CI, 1.21–1.52), heavy smoking (≥ 20 pack-years; aHR for former smokers, 1.36; 95% CI, 1.14–1.64; and aHR for current smokers 1.20; 95% CI, 1.01–1.43), COPD (aHR, 1.33; 95% CI, 1.18–1.49) and CCI ≥ 3 (aHR, 1.40; 95% CI, 1.26–1.57). Detailed results are available in the Open Science Framework repository (https://doi.org/10.17605/OSF.IO/285RA).

Our study provides longitudinal evidence that adult TB survivors have a 26% higher risk of incident asthma than matched controls. Notably, this finding challenges the conventional hypothesis that the Th1-dominant response induced by TB infection strictly protects against the development of asthma, a typically Th2-driven disease. Although previous studies have suggested this association, most were limited by small samples, cross-sectional designs, or a focus on younger populations [4-6]. In contrast, our study overcomes these limitations by utilizing a large, population-based adult cohort with accurately verified pulmonary TB, a relatively long-term follow-up period, and comprehensive adjustment for potential confounders. Furthermore, the association remained remarkably consistent across various clinical subgroups, including age, sex, body mass index and smoking history. The observed association may be explained by a combination of structural and immunological changes, or alternatively by shared susceptibility factors affecting both TB and asthma. Chronic inflammation and aberrant healing processes following TB infection can lead to excessive airway remodelling, fibrosis and small airway narrowing. Additionally, altered immune regulation, such as the presence of elevated interleukin-4 and interleukin-13 levels in the post-TB airway, may create a pro-asthmatic inflammatory environment [2, 4, 7].

Nevertheless, this study has several limitations. First, asthma and comorbidities were identified using ICD codes, potentially leading to misclassification. Second, residual confounding cannot be fully excluded. Finally, the lack of biomarker or spirometry data and the use of a single Korean population may limit generalizability. In addition, given the observational nature of this study, causal inference cannot be established, and the possibility of shared underlying risk factors cannot be excluded.

In conclusion, TB survivors had an increased risk of asthma, suggesting the importance of long-term respiratory follow-up and management, especially in those with risk factors.

H.L. and D.W.S. are guarantors of manuscripts. H.L., D.W.S. and J.G.J. contributed to the conception and design of study. K.N.L. and K.H. performed the data analysis. J.G.J., K.N.L., K.H., H.J.Y., S.-H.K., D.W.S., and H.L. were involved in interpretation of the data. J.G.J. and H.L. wrote the initial draft of the manuscript. All authors made a critical revision of the manuscript. All of the authors read and approved of the final manuscript.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2025-00557268).

This study was approved by the Institutional Review Board (IRB) of Yeungnam University (IRB approval no. 2025-08-005). As the study utilized de-identified, publicly available data in compliance with confidentiality and data protection guidelines, the requirement for written informed consent was waived.

The authors declare no conflicts of interest.

The data that support the findings of this study are available from the corresponding author upon reasonable request.