
==== Front
BMC Public Health
BMC Public Health
BMC Public Health
1471-2458
BioMed Central London

20019
10.1186/s12889-024-20019-5
Research
The impact of diabetes mellitus on tuberculosis recurrence in Eastern China: a retrospective cohort study
Wang Yuting 1
Shi Jinyan 2
Yin Xiwen 1
Tao Bilin 1
Shi Xinling 1
Mao Xinlan 1
Wen Qin 1
Xue Yuan xueyuan80908@163.com

3
https://orcid.org/0000-0002-9151-284X
Wang Jianming jmwang@njmu.edu.cn

13
1 https://ror.org/059gcgy73 grid.89957.3a 0000 0000 9255 8984 Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Ave., Nanjing, 211166 China
2 Department of Clinical Laboratory, The Fourth People’s Hospital of Lianyungang, Lianyungang, 222000 China
3 grid.89957.3a 0000 0000 9255 8984 Department of Infectious Diseases, The Third People’s Hospital of Changzhou, Changzhou Medical Center, Nanjing Medical University, 300 Lanling North Road, Changzhou, 213001 China
18 9 2024
18 9 2024
2024
24 25346 8 2024
9 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

The comorbidity of tuberculosis (TB) and diabetes mellitus (DM) is a significant global public health issue. This study aims to explore the recurrence risk and related factors of active pulmonary TB, specifically focusing on the impact of DM.

Methods

A retrospective cohort study was conducted in Lianyungang City, Jiangsu Province, Eastern China by recruiting 12,509 individuals with newly diagnosed pulmonary TB between 2011 and 2019. The Cox proportional hazards models were performed to identify risk factors of recurrence and assess the association between DM and recurrence. The hazard ratio (HR) and 95% confidence interval (CI) were used to estimate the strength of the association.

Results

After a median follow-up period of 5.46 years, we observed 439 recurrent cases (incident recurrence rate: 6.62 per 1000 person-years). Males (HR: 1.30, 95% CI: 1.03–1.64), patients aged ≥ 60 years (HR: 1.39, 95% CI: 1.15–1.70), DM (HR: 2.40, 95% CI: 1.68–3.45), and etiologic positivity in the initial episode (HR: 2.42, 95% CI: 2.00-2.92) had a significantly increased risk of recurrence.

Conclusions

Recurrence of pulmonary TB patients who have completed treatment, especially those who also suffer from DM, should be a concern. Enhanced follow-up and targeted surveillance of these high-risk groups are needed.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12889-024-20019-5.

Keywords

Tuberculosis
Recurrence
Diabetes mellitus
Risk factors
Successful treatment
http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 81973103 Medical Research Project of Jiangsu Health CommissionZDB2020013 Nanjing Major Science and Technology Specific Project2021-11005 Postgraduate Research & Practice Innovation Program of Jiangsu ProvinceKYCX22_1822 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcBackground

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB), primarily spreading through the respiratory tract. It remains a serious threat to global public health, with mortality and disability rates exceeding acquired immune deficiency syndrome (AIDS). There was an estimation of 10.6 million new cases of TB and 1.3 million deaths worldwide in 2022 [1]. And the TB incidence has risen 3.9% from 2020 to 2022, reversing a 2% annual decline over the past two decades. The “End TB” strategy’s goals are still elusive.

Although the treatment success rate has reached over 85% for new TB cases in some countries [2], disease recurrence is still a critical burden of TB control. TB recurrence is defined as a second episode of TB occurring in patients who have completed a previous treatment or were considered cured [3]. Worldwide studies have reported recurrence rates ranging from 4.9 to 47% [4], contributing to an ongoing risk of pathogen transmission, increased mortality, and a substantial burden on the healthcare system.

The TB recurrence is influenced by many factors, with the patient’s immune status being particularly critical. TB patients with comorbidities such as diabetes and AIDS, which compromise immune function, typically experience more severe infections and slower recovery processes [5]. Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia due to deficiencies in insulin secretion, insulin action, or both [6]. The International Diabetes Federation reported that the estimated prevalence of DM among adults aged 20–75 years worldwide was 10.5% (537 million) in 2021 [7]. Since the global demographic transition, the burden of DM in TB-endemic countries has increased rapidly, raising widespread concern. A systematic review indicated that the prevalence of DM among TB patients ranged from 1.9 to 45% in different countries [8]. Diabetes impairs the immune system, making it more difficult for the human body to combat MTB infections. Therefore, people with DM have a 2–3 times higher risk of developing TB than the general population, and the duration of the disease is often prolonged [5]. Additionally, patients with DM face a higher risk of unfavorable treatment outcomes, including treatment failure, drug resistance, and TB-related mortality [9].

China has suffered double threats from TB and DM. In 2022, there were an estimated 748,000 new cases of TB, accounting for 7.1% of the global TB incidence burden [1]. In Lianyungang City, Jiangsu Province, the estimated incidence rate of TB was 21.83 per 100,000 population in the same year. China is also one of the countries with the highest burden of DM, with a 10.6% average prevalence rate in 2021 [10]. In a pilot project conducted in TB clinics and hospitals in China, the overall prevalence of DM among TB patients was 12.4% [11]. Another community-based cohort study reported that DM was present in 6.3% of TB patients [12]. Although it is generally established that DM could increase the risk of active TB and affect treatment outcomes, the association between DM and TB recurrence has not been well-explained. Here, we conducted a retrospective cohort study in a Chinese population to estimate the impact of DM on the risk of pulmonary TB recurrence.

Methods

Study design and study population

We conducted a retrospective cohort study in Lianyungang, a city located in the northeast of Jiangsu Province, eastern China, which covers an area of 7615.71 square kilometers and had an estimated 4,511,000 inhabitants in 2019. We recruited newly diagnosed pulmonary TB cases as the study subjects from January 1, 2011 to December 31, 2019. After excluding those who (a) died, (b) had failed treatment, (c) were transferred to multidrug-resistant (MDR) treatment, (d) experienced a change in diagnosis, or (e) were lost to follow-up, 12,735 subjects had a successful treatment outcome during the first disease episode. We followed them till December 31, 2020. Among them, 12,509 remained TB disease-free for at least 6 months after completing treatment and were thus involved in the final analysis of recurrence (Fig. 1). This study was approved by the Institutional Review Board (ethics committee) of Nanjing Medical University. Written informed consent was obtained from study participants. The study was conducted in accordance with the Declaration of Helsinki.

Data collection

We queried the TB Management Information System to collect data of patients with pulmonary TB, including demographic characteristics, clinical information, and laboratory tests. We also collected data on DM from the Diabetes Management Information System and the medical records from the Fourth People’s Hospital of Lianyungang. Two databases were matched by name, gender, date of birth, and address.

Measurement and definition

Pulmonary TB was diagnosed and treated according to the China National TB Program (NTP) guidelines. The diagnosis primarily based on etiological examinations, including bacteriological and molecular biological tests, combined with an assessment of epidemiologic history, clinical manifestations, chest imaging, auxiliary examinations, and differential diagnosis. Change in diagnosis occurred when a patient’s initial TB diagnosis was revised during treatment, prompted by new clinical or diagnostic evidence. Patients were considered “cured” if they had negative sputum smear results for two consecutive months during anti-TB treatment and remained negative after completing the treatment. Patients who completed treatment without indication of failure but did not have smear- or culture-negative results at the end of treatment were classified as “completed treatment”. These two categories were regarded as “treatment success”. We defined TB recurrence as a new episode in patients who remained TB disease-free for at least 6 months after the successful initial treatment [13]. The length of follow-up was the time interval from the end of treatment until recurrence or the censored date.

We defined the DM status using any one of the following criteria before pulmonary TB diagnosis: (a) fasting blood glucose (FBG) ≥ 7.0 mmol/L, glucose (GLU) ≥ 11.1 mmol/L, or glycated hemoglobin (HbA1c) ≥ 6.5%; or (b) confirmation of DM diagnosis through medical records.

China utilized a nationwide household registration system, where everyone was granted a registration status. We divided the subjects into local and non-local residents according to their registered residence status. Patient delay in seeking TB service was defined as the interval between the occurrence of pulmonary TB symptoms and the first time of seeking healthcare. Health system delay was defined as the interval between the first time of seeking healthcare and the formal diagnosis in health institutions.

Based on the Diagnosis Criteria for Pulmonary Tuberculosis of China (WS 288–2017), patients were classified as having etiologic positivity if they exhibited positive results in sputum smear, sputum culture, or Xpert MTB/rifampicin (RIF). The proportional method was used to perform drug susceptibility testing (DST) for the first-line anti-TB drugs of RIF and isoniazid (INH). Monodrug-resistant was defined as resistance to RIF or INH. MDR was defined as resistance to, at least, RIF and INH.

The two prevalent dosage forms of anti-TB drugs were combined drugs in blister packs and fixed-dose combinations (FDC). Combined drugs in blister packs referred to a packaging method where multiple anti-TB drugs were included in a single blister pack, with each drug still in its separate form (i.e., single drug formulations). FDC drug was a composite preparation (tablet or capsule) of multiple anti-tuberculosis medications formulated per specific dosage parameters. The FDC used in our study was a combination of INH, RIF, pyrazinamide, and ethambutol. Extended treatment time was defined if the anti-TB therapy lasted > 270 days [14].

Statistical analysis

Continuous variables were presented as median with interquartile range (IQR), while categorical variables were expressed as frequency (percentage). The Mann-Whitney test was used to compare continuous variables between pulmonary TB patients with and without DM. The Pearson Chi-square or Fisher’s exact test was applied to derive the P values for categorical variables. Incidence was expressed as new cases per 1000 person-years (PYs). Kaplan-Meier curves were plotted to illustrate the risk of recurrence and the log-rank test was used to compare the differences between groups. We utilized the Cox proportional hazards models to explore the risk factors for recurrent TB. Hazard ratios (HR) and 95% confidence intervals (95% CI) were used to estimate the strength of the association. A bidirectional stepwise method was applied to ascertain the optimal model. Furthermore, we performed a subgroup analysis to investigate the modification effect of age and gender. We added cross-product terms to the multivariable model, adjusting for other covariates, to assess the adjusted HR (aHR) of DM among different subgroups. All analyses were conducted using R software version 4.1.2, and results with P < 0.05 were deemed statistically significant.

Results

Demographic characteristics

From January 1, 2011, to December 31, 2019, there were 13,702 new cases of pulmonary TB registered in Lianyungang. After excluding patients who died (n = 179),were defined as treatment failure (n = 329), were transferred to MDR treatment (n = 154), had a revised diagnosis (n = 107), and were lost to follow-up (n = 198), a total of 12,735 patients were successfully treated, resulting in a treatment success rate of 92.9%. We further excluded 226 patients who were followed < 6 months and included 12,509 eligible individuals in the final analysis (Fig. 1).

Fig. 1 Flowchart of study participants with pulmonary tuberculosis enrolled in this study. MDR, multidrug-resistant

Among the 12,509 participants, 8902 (71.2%) completed their treatment, and 3607 (28.8%) were cured. The median age was 52 years (IQR: 28–65). The majority were males (73.7%), local residents (91.6%), and farmers (76.9%). At the baseline, 30% were classified with etiologic positivity for TB, while only 3.5% remained positive for sputum smear after the two-month intensive treatment period. There were 397 (3.2%) patients having the comorbidity with DM. Subjects with DM had a significantly longer median patient delay (25 vs. 19, P < 0.001), higher proportions of farmer careers (87.7% vs. 76.5%, P < 0.001), etiologic positivity (50.9% vs. 29.4%, P < 0.001), extended treatment time (27.2% vs. 15.9%, P < 0.001), and sputum smear positive at the end of two-month therapy (10.8% vs. 3.3%, P < 0.001) (Table 1).

Table 1 Baseline characteristics of the 12,509 participants stratified by diabetes status

Characteristics	Overall
(N = 12509)	Without diabetes
(N = 12112)	With diabetes
(N = 397)	P	
Age (years), median (IQR)	52.0 (28.0–65.0)	51.0 (28.0–65.0)	59.0 (52.0–66.0)	< 0.001	
Gender				0.004	
 Female	3287 (26.3)	3157 (26.1)	130 (32.8)		
 Male	9222 (73.7)	8955 (73.9)	267 (67.3)		
Local residence				0.325	
 Yes	11,464 (91.6)	11,106 (91.7)	358 (90.2)		
 No	1045 (8.4)	1006 (8.3)	39 (9.8)		
Occupational status				< 0.001	
 Student	606 (4.8)	606 (5.0)	0 (0.0)		
 Farmer	9615 (76.9)	9267 (76.5)	348 (87.7)		
 Worker	821 (6.6)	809 (6.7)	12 (3.0)		
 Unemployed or retired	1467 (11.7)	1430 (11.8)	37 (9.3)		
Case detection				0.011	
 Referral	6104 (48.8)	5910 (48.8)	194 (48.9)		
 Clinical consultation	6257 (50.0)	6059 (50.0)	198 (49.9)		
 Physical examination	116 (0.9)	115 (1.0)	1 (0.3)		
 Other	32 (0.3)	28 (0.2)	4 (1.0)		
Patient delay (days),

median (IQR)

	19.0 (10.0–34.0)	19.0 (10.0–34.0)	25.0 (13.0–59.0)	< 0.001	
Health system delay (days),

median (IQR)

	0.0 (0.0–2.0)	0.0 (0.0–2.0)	0.0 (0.0–2.0)	0.348	
Etiological test result				< 0.001	
 Negative	8751 (70.0)	8556 (70.6)	195 (49.1)		
 Positive	3758 (30.0)	3556 (29.4)	202 (50.9)		
2-month sputum smear				< 0.001	
 Negative	12,069 (96.5)	11,715 (96.7)	354 (89.2)		
 Positive	440 (3.5)	397 (3.3)	43 (10.8)		
Dosage form				0.092	
 Combined drugs in blister packs	8443 (67.5)	8191 (67.6)	321 (63.5)		
 Fixed dose combinations	4066 (32.5)	3921 (32.4)	76 (36.5)		
Treatment duration				< 0.001	
 ≤ 270 days	10,470 (83.7)	10,181 (84.1)	289 (72.8)		
 > 270 days	2039 (16.3)	1931 (15.9)	108 (27.2)		
Note IQR, interquartile range

Risk of pulmonary TB recurrence

With a median follow-up time of 5.46 years (IQR, 3.22–7.58), we observed 439 (3.5%) recurrent cases. The overall recurrence rate was 6.62 (95%CI: 6.02–7.26) per 1000 PYs. Patients with DM had a significantly higher recurrence rate (20.21 per 1000 PYs, 95% CI: 13.91–28.38) than those without DM (6.28 per 1000 PYs, 95% CI: 5.68–6.92). The recurrence rate for male patients with DM was 26.22 per 1000 PYs (95% CI: 17.42–37.89) (Table 2).

Table 2 Incidence of pulmonary tuberculosis recurrence by diabetes status

	Recurrent events	Observation time
(PYs)	Incidence per
1000 PYs (95%CI)	P	
All	439	66,314	6.62 (6.02, 7.26)	< 0.001	
 Without diabetes	406	64,681	6.28 (5.68, 6.92)		
 With diabetes	33	1633	20.21 (13.91, 28.38)		
Male				< 0.001	
 Without diabetes	320	47,916	6.68 (5.97, 7.45)		
 With diabetes	28	1068	26.22 (17.42, 37.89)		
Female				0.255	
 Without diabetes	86	16,765	5.13 (4.10, 6.34)		
 With diabetes	5	566	8.83 (2.85, 20.61)		
Age < 60 years				< 0.001	
 Without diabetes	214	40,907	5.23 (4.55, 5.98)		
 With diabetes	16	850	18.82 (10.75, 30.57)		
Age ≥ 60 years				< 0.001	
 Without diabetes	192	23,773	8.08 (6.97, 9.30)		
 With diabetes	17	783	21.71 (12.64, 34.76)		
Note PYs, person-years; CI, confidence interval

Of 439 recurrent patients, the median time between the end of treatment for the first episode and pulmonary TB recurrence was 1.81 years (IQR, 1.01–3.14). About three-quarters of recurrence (72.9%, 320/439) occurred three years after the successful initial treatment (Fig. 2). We further assessed the time intervals for pulmonary TB recurrence stratified by different groups. Figure 3 showed a strong association between the early recurrence and etiologic positivity in the initial episode (HR: 1.56, 95% CI: 1.29–1.90, P < 0.001). Meanwhile, patients with positive sputum smears at the end of two months of treatment developed recurrent pulmonary TB more quickly than those with negative results (HR: 1.74, 95% CI: 1.19–2.55, P = 0.004).

Fig. 2 Kaplan-Meier survival estimates for pulmonary tuberculosis recurrence

Fig. 3 Cumulative percentage of recurrent pulmonary tuberculosis by etiological test result (A) and second-month sputum smear (B). The blue line represents patients with negative results, while the red line represents positive ones. CI, confidence interval; HR, hazard ratio

Risk factors associated with recurrent pulmonary TB

We performed a Cox proportional hazard model to identify the risk factors of pulmonary TB recurrence (Table 3). Univariate analyses showed that males, people aged ≥ 60 years, students, DM, clinical consultation, etiologic positivity, second-month sputum smear positive results, and the utilization of FDC medications were significantly associated with pulmonary TB recurrence. After adjusting for gender, age, local residence, occupation, DM comorbidity, case detection, etiological test result, second-month sputum smear, dosage form, and treatment duration, we observed that males (HR: 1.30, 95% CI: 1.03–1.64, P = 0.030), patients aged ≥ 60 years (HR: 1.39, 95% CI: 1.15–1.70, P = 0.001), DM (HR: 2.40, 95% CI: 1.68–3.45, P < 0.001), and etiologic positivity in the initial episode (HR: 2.42, 95% CI: 2.00-2.92, P < 0.001) remained significant. Students (HR: 0.44, 95% CI: 0.22–0.89, P = 0.022) and the utilization of FDC medications (HR: 0.77, 95% CI: 0.61–0.95, P = 0.018) showed a protective effect against recurrent pulmonary TB.

Table 3 Univariate and multivariate Cox regression of risk factors associated with recurrence

Characteristics	Recurrent events	Univariate analysis	Multivariate analysis	
HR (95% CI)	P	HR (95% CI)	P	
Overall	439					
Gender						
 Female	91	1		1		
 Male	348	1.36 (1.08, 1.71)	0.009	1.30 (1.03, 1.64)	0.030	
Age						
 < 60 years	230	1		1		
 ≥ 60 years	209	1.55 (1.29, 1.87)	< 0.001	1.39 (1.15, 1.70)	0.001	
Local residence						
 Yes	417	1				
 No	22	0.73 (0.47, 1.12)	0.149			
Occupational status						
 Farmer	364	1		1		
 Student	8	0.36 (0.18, 0.72)	0.004	0.44 (0.22, 0.89)	0.022	
 Worker	22	0.67 (0.43, 1.02)	0.064	0.75 (0.48, 1.16)	0.192	
 Unemployed or retired	45	0.86 (0.63, 1.17)	0.337	0.85 (0.62, 1.16)	0.300	
Diabetes status						
 No	406	1		1		
 Yes	33	2.96 (2.08, 4.21)	< 0.001	2.40 (1.68, 3.45)	< 0.001	
Case detection						
 Referral	192	1				
 Clinical consultation	244	1.24 (1.03, 1.50)	0.025			
 Physical examination	2	0.52 (0.13, 2.05)	0.348			
 Other	1	1.02 (0.15, 7.14)	0.986			
Etiological test result						
 Negative	227	1		1		
 Positive	212	2.49 (2.06, 3.00)	< 0.001	2.42 (2.00, 2.92)	< 0.001	
2-month sputum smear						
 Negative	410	1				
 Positive	29	2.07 (1.41, 3.02)	< 0.001			
Dosage form						
 Combined drugs in blister packs	332	1		1		
 Fixed dose combinations	107	0.80 (0.64, 0.99)	0.043	0.77 (0.61, 0.95)	0.018	
Treatment duration						
 ≤ 270 days	357	1				
 > 270 days	82	1.27 (1.00, 1.61)	0.053			
Note HR, hazard ratio; CI, confidence interval

We further analyzed 2809 subjects with DST data. Among those with DM, 15 (9.6%) were mono-drug resistant, compared to 256 (9.7%) of the patients without DM. In the multivariate model, the HR for mono-drug resistant was 2.45 (95% CI: 1.70–3.54, P < 0.001). When considering DST, DM remained significantly contributing to an increased risk of pulmonary TB recurrence (HR: 2.12, 95% CI: 1.33–3.38, P = 0.002) (Supplementary Table 1).

We conducted a subgroup analysis to investigate the association between DM and pulmonary TB recurrence, focusing on gender and age (Fig. 4). Our findings revealed no significant correlation between DM and pulmonary TB recurrence in the female subgroup (aHR: 1.21, 95% CI: 0.47–3.12, P = 0.689). In contrast, the aHR was 2.80 (95% CI: 1.89–4.15, P < 0.001) among males, suggesting a substantial relationship between DM and pulmonary TB recurrence in this subgroup. The P-value for the interaction between gender and DM was 0.138, indicating no significant modification of the association incurred by gender. Regarding age, participants aged < 60 years had an aHR of 2.80 (95% CI: 1.68–4.68, P < 0.001), while those aged ≥ 60 years exhibited an aHR of 2.10 (95% CI: 1.25–3.53, P = 0.005). The P-interaction of 0.563 implied that age did not substantially modify the association between DM and pulmonary TB recurrence.

Fig. 4 Subgroup analysis of the association between diabetes and pulmonary tuberculosis recurrence. Data were analyzed using the Cox regression model adjusted for gender, age, local residence, occupation, case detection, etiological test result, second-month sputum smear, dosage form, and treatment duration. aHR, adjusted hazard ratio; CI, confidence interval; DM, diabetes mellitus

Discussion

After a median follow-up period of 5.46 years, we observed 439 recurrent cases, with an incident recurrence rate of 6.62 per 1000 PYs and the recurrence rate was higher in patients with DM. Nearly three-quarters of recurrence (72.9%) occurred within three years after the initial treatment.

Previous study defined TB recurrence as individuals developing active TB again after a successful treatment [15]. This definition might inadvertently include patients not wholly cured from their initial episode, leading to an overestimation of recurrence rate. To reduce the possibility of misclassification, we excluded “recurrent cases” occurred within 6 months after the initial treatment.

The incidence rates of TB recurrence vary greatly depending on the study site. A recent systematic review involving 145 studies reported that the pooled recurrence rate was 22.6 per 1000 PYs [16], which was higher than that reported in our study. We revealed a recurrence rate of 6.62 per 1000 PYs, which was slightly lower than the rate (7.55 per 1000 PYs) in Shanghai, China [17]. These discrepancies across studies could be attributed to the heterogeneity of regional distribution, study design, sample size, and definition of TB recurrence. In addition, we found that the treatment success rate for pulmonary TB in Lianyungang was 92.9%, higher than the 84.9% observed in Shanghai [17], and also above the average treatment success rate (90%) for new pulmonary TB cases in China. This indicates that the majority of pulmonary TB patients in Lianyungang completed their treatment according to the China NTP guidelines, which may contribute to a reduced risk of endogenous relapse.

Among the 439 recurrent patients in our study, 72.9% experienced recurrence within three years after initial treatment. Similarly, a retrospective cohort study in Sichuan, China reported a three-year recurrence rate of 73.4% [13]. Therefore, it should be cautious that TB patients who have completed treatment should be regularly monitored to detect recurrence at an early stage and disrupt transmission. Moreover, we found that pulmonary TB patients with etiologic positivity and positive second-month sputum smear in the initial episode were more prone to early recurrence. Thus, it is crucial to intensify follow-up for these specific patients and, when necessary, appropriately extend the treatment duration, thereby reducing the risk of TB recurrence.

TB recurrence can result from either an endogenous reactivation of the initial MTB infection (i.e., relapse) or an exogenous reinfection with a distinct MTB strain. Previous studies in China indicated that 58.2–69.0% of recurrent TB cases emanated from relapse rather than exogenous reinfection [18]. However, our study could not confirm this finding due to the non-routine collection of sputum samples, which prevented us from obtaining MTB isolates necessary for genotyping to distinguish between relapse and reinfection. Divergent mechanisms explain early recurrence for each type. For endogenous relapse, it is postulated that latent infection was not eradicated after initial anti-TB treatment. Colangeli et al. suggested that early stages of latent TB infection (LTBI) show high mutation rates, which decrease over time [19]. For exogenous reinfection, Suzanne et al. observed that the TB reinfection rate after treatment was approximately sevenfold the incidence rate in the general population [20]. This observation highlighted that the immunity generated by the primary infection did not confer sufficient defense against subsequent infections.

The relation between male gender and the recurrence of pulmonary TB in our study is consistent with previous findings. A survey in Hangzhou indicated that men demonstrated a higher susceptibility to TB recurrence, a trend aligning with initial TB infection patterns [3]. We supposed that factors known to exhibit gender disparity, including habits such as tobacco smoking and alcohol drinking, could serve as confounding variables. Smoking might potentially trigger recurrence among male patients with TB. Nicotine inhibits the macrophages’ ability to synthesize tumor necrosis factor-α, potentially aggravating disease severity, diminishing treatment efficacy, and increasing recurrence risk [2]. Further studies are needed to verify this claim.

Ruan et al. identified an increased risk of TB recurrence in patients aged ≥ 60 years [3], consistent with our findings. The elevated risk of recurrence in older people might result from an interaction of physiological and socio-environmental factors. Age-related immunological decline and multimorbidity may reduce treatment effectiveness and promote latent MTB strain reactivation. Cellular immunosenescence exacerbates this risk. Indirect evidence from mouse and computational models showed that susceptibility to MTB increased with age due to impaired recruitment protective CD4 + T-cells [21]. On the other hand, the demographic trend of aging populations results in a higher percentage of older TB patients. Also, low socioeconomic status and inadequate TB knowledge often lead to poor treatment adherence. The interplay of these intricate factors assumes a critical role in TB recurrence, particularly among the elderly.

We demonstrated an increased risk of pulmonary TB recurrence among patients with etiologic positivity in their initial episode. An 8-year study in the Republic of Estonia identified that sputum smear positivity was a risk factor for recurrence in MDR-TB or extensive drug-resistant TB(XDR-TB) cases [22]. Hesseling et al. found that smear grade could significantly predict the recurrence in drug-susceptible TB cases without human immunodeficiency virus (HIV) infection [23]. High mycobacterial loads reflect enhanced bacterial replication, extensive tissue damage, and impaired immune responses, creating an environment conducive to disease reactivation. Even after successful treatment, MTB organisms may persist in a dormant state, capable of reactivation and subsequent replication when the immune system is weakened. These findings highlight the importance of early diagnosis, adequate treatment, and close monitoring of TB patients with etiologic positivity to reduce the risk of recurrence.

The comorbidity of TB and DM is a cause for concern. A five-year prospective study in Yemen demonstrated that DM was an independent risk factor for TB recurrence [15]. A large-scale cohort study in South Korea also identified DM as a risk factor for TB recurrence and TB-related mortality [24]. However, findings from Iran and Brazil did not find a significant association [25, 26], potentially due to the heterogeneity of demographic characteristics for the study population.

Our subgroup analysis revealed a substantial association between DM and pulmonary TB recurrence among males. Men engage in a greater frequency of behaviors with inherent risks than women. The risky behaviors, in combination with impaired host immune function in DM patients, may contribute to the heightened severity of TB and diminished microbiological responses [27]. However, since we lacked information on glycemic control in our DM patient cohort, further research is necessary to ascertain whether the severity of DM affects gender-specific differences in TB recurrence.

DM heightens the risk of TB recurrence through intricate mechanisms. Hyperglycemia undermines both innate and adaptive immunity by impairing the function of critical cells such as monocytes/macrophages and neutrophils, resulting in deficiencies in bacterial recognition, phagocytic activity, and cell activation [28]. Additionally, hyperglycemia promotes chronic inflammation, decreasing immunomodulatory cytokines while increasing proinflammatory ones, which are essential for macrophage activation and the inflammatory response to TB. Another laboratory research revealed that alveolar macrophages from patients with diabetes exhibited a delayed innate immune response, subsequently leading to delayed initiation of the adaptive immune response necessary to restrict MTB replication [29].

On the other hand, the pharmacokinetics and pharmacodynamics of anti-TB drugs were altered in subjects with DM [30]. Charles et al. observed lower isoniazid plasma concentrations and a decreasing trend in rifampin exposure in Tanzanian TB-DM patients, suggesting that DM may account for drug exposure differences [31]. Accordingly, reduced exposure to anti-TB drugs may increase the risk of TB recurrence in individuals with DM.

Given the increased risk of TB recurrence in patients with DM, we recommend that TB and DM be managed within an integrated system to ensure comprehensive monitoring and treatment. TB patients with DM should have their blood glucose levels regularly monitored during anti-TB treatment to maintain optimal glycemic control, and they should receive more frequent follow-up after completing treatment to promptly identify and address any signs of TB recurrence.

In the current study, students had a significantly lower risk of pulmonary TB recurrence compared to farmers. This disparity may be related to higher educational attainment and greater access to healthcare resources among students. The student population demonstrated enhanced health awareness and higher compliance with follow-up visits. Additionally, supportive environments such as schools played a crucial role in promoting treatment adherence.

We found that utilizing FDC medications was associated with a reduced pulmonary TB recurrence risk, which seemed intriguing. FDC therapy has been endorsed by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD) since 1994. FDC administration potentially enhances TB treatment by simplifying treatment regimens, improving treatment adherence, preventing inappropriate drug selection, and decreasing likelihood of drug-resistant mutations in MTB [32, 33]. In comparison, combined drugs in blister packs, although more flexible in administration, may lead to missed doses for some patients due to its non-intermittent treatment schedules.

Our study has several limitations. Firstly, incomplete data on glycemic control and DM treatment hinders a comprehensive understanding of the potential links, while the intermittent recording of blood glucose levels may lead to underestimation of undiagnosed DM cases. Further studies should investigate the relationship between blood glucose fluctuations and pulmonary TB recurrence in patients with diabetes, thereby providing a more robust scientific rationale. Secondly, critical confounding variables associated with pulmonary TB recurrence, such as body mass index, smoking status, and HIV infection, were not systematically recorded. Lastly, limited access to DST data could introduce selection bias.

Conclusion

Our large population-based study with a long-term follow-up period provides valuable insights into pulmonary TB recurrence in settings with similar TB burdens. We found that recurrence hazards are significantly higher for males, patients aged ≥ 60 years, patients with diabetes, and patients with etiologic positivity in their first episode. This highlights the need for dedicated and proactive supervision from healthcare personnel to strengthen follow-up and monitoring management among high-risk populations. We recommended that all pulmonary TB patients with initial etiologic positivity undergo sputum smear examinations after treatment to ensure a successful cure. Notably, our most striking finding demonstrates that patients with DM have almost 2.5 times the hazard of pulmonary TB recurrence compared to those without DM. This emphasizes the importance of implementing a bidirectional screening policy for TB and DM. We suggest that, in the future, patients with TB and DM be managed within an integrated system with blood glucose testing included in the baseline assessment for TB patients. Future studies should aim to collect more comprehensive DM-related data to further explore the interaction between DM and TB recurrence.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

Not applicable.

Author contributions

Y.W., J.S., and X.Y.: Conceptualization, Methodology, Data Collection, Data Collation, Software, Formal analysis, Writing - Original Draft, Visualization. B.T., X.S., X.M., and Q.W.: Data Collation, Resources, Writing - Review & Editing, Supervision. Y.X. and J.W.: Conceptualization, Resources, Writing - Review & Editing, Visualization, Supervision, Project administration, Funding acquisition.

Funding

This work was supported by the National Natural Science Foundation of China (81973103), Medical Research Project of Jiangsu Health Commission (ZDB2020013), Nanjing Major Science and Technology Specific Project (2021–11005), and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX22_1822). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was approved by the Institutional Review Board (ethics committee) of Nanjing Medical University. Written informed consent was obtained from study participants. The study was conducted in accordance with the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Abbreviations

aHR adjusted hazard ratio

AIDS Acquired immune deficiency syndrome

CI Confidence interval

DM Diabetes mellitus

DST Drug susceptibility testing

FDC Fixed-dose combinations

HIV Human immunodeficiency virus

HR Hazard ratio

INH Isoniazid

IQR Interquartile range

IUATLD International Union against Tuberculosis and Lung Disease

LTBI Latent TB infection

MDR Multidrug-resistant

MTB Mycobacterium tuberculosis

NTP National TB Program

PYs Person-years

RIF Rifampicin

TB Tuberculosis

WHO World Health Organization

XDR Extensive drug-resistant

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yuting Wang, Jinyan Shi and Xiwen Yin contributed equally to this work.
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