研究背景

         我国的结核病防控取得了显著的成效，但庞大的结核潜伏感染人群给结核病防控带来很大挑战。阐明结核潜伏感染发病的流行病学特征对及时调整不同地区结核病防控策略具有重要科学意义。另外，由于机体慢性炎症反应是多种疾病的诱因，考虑到中国结核潜伏感染负担较重，结核杆菌感染后宿主体内持续存在的免疫激活状态对健康产生的潜在负面影响不容忽视，探索结核潜伏感染对其他健康问题的影响将对优化结核潜伏感染管理政策和开展共病联合干预提供重要的科学依据。

研究方法

         2013年，研究团队针对我国农村四个研究现场21832名5周岁及以上常住人口利用γ-干扰素释放试验（interferon-γ release assay, IGRA）开展了结核潜伏感染检测，并对结核潜伏感染阳性人群开展两年、五年随访，探索活动性肺结核的流行特征。2023年，研究团队针对所有参与基线调查的研究对象开展十年随访，通过问卷调查获得研究对象既往十年的疾病史，结合结核病信息管理系统、慢性病管理系统、死因登记系统的数据，观察基线结核潜伏感染阳性人群和基线结核潜伏感染阴性人群十年随访期内不同疾病（肺结核、2型糖尿病（type 2 diabetes mellitus (T2DM)、心脑血管疾病、慢性呼吸系统疾病、癌症）的发病风险、全因死亡风险和因别死亡风险（死于心脑血管疾病、死于慢性呼吸系统疾病、死于癌症）。采用Cox等比例回归模型分析结核潜伏感染与不同健康结局发生的风险。采用亚组分析和敏感性分析进一步探索在不同特征人群中结核潜伏感染与不同健康结局的相关性。

研究结果

         参与基线调查的21832名研究对象中，剔除基线IGRA检测结果不确定者621名，共有21211名研究对象（基线结核潜伏感染阳性者4455名，基线结核潜伏感染阴性者16756名）纳入分析。

         十年随访期间，共计确诊181例活动性肺结核患者，发病密度为1.06/1000人年，基线结核潜伏感染阳性者的活动性肺结核发病风险（3.68/1000人年）是基线结核潜伏感染阴性者（0.35/1000人年）的7.17倍[95% CI (confidence interval)]: 5.02-10.24）。基线结核潜伏感染活动性肺结核发病风险的关联在不同亚组分析和敏感性分析的结果具有稳健性。结核潜伏感染是活动性肺结核新发病例的主要来源，并且结核潜伏感染的占比随着时间延长而降低。

         在结核潜伏感染与共病发病风险的关联研究中，基线结核潜伏感染阳性者T2DM发病密度为7.33/1000人年，高于基线结核潜伏感染阴性者的T2DM发病密度（4.63/1000人年），基线结核潜伏感染阳性者的T2DM发病风险比基线结核潜伏感染人群阴性者高20%（aHR (adjusted hazard ratio)=1.20, 95% CI: 1.03-1.41）；基线结核潜伏感染阳性者慢性支气管炎发病密度为1.00/1000人年，高于基线结核潜伏感染阴性者的慢性支气管炎发病密度（0.45/1000人年），基线结核潜伏感染阳性者的慢性支气管炎发病风险是基线结核潜伏感染阴性者的3.11倍（aHR=3.11, 95% CI: 1.12-8.62）；基线结核潜伏感染阳性者癌症发病率密度为5.23/1000人年，高于基线结核潜伏感染阴性者的癌症发病密度（2.86/1000人年），基线结核潜伏感染阳性者的癌症发病风险比基线结核潜伏感染阴性者高67%（aHR=1.67, 95% CI: 1.11-2.51）。

         在结核潜伏感染与死亡风险的关联研究中，Kaplan-Meier生存结果显示不同性别、BMI、研究地区及80岁以下人群中不同结核潜伏感染状态的全因死亡率存在统计学差异（P<0.05）。与基线结核潜伏感染阴性者相比，基线结核潜伏感染阳性者的全因死亡风险增加13%（aHR=1.13, 95% CI: 1.03-1.25），死于癌症的风险增加43%（aHR=1.43, 95% CI: 1.17-1.75）。

研究结论

         在我国农村地区，结核潜伏感染仍然是活动性肺结核新发病例的主要来源，作为降低结核病发病率的主要手段，结核病预防性干预是目前结核病预防与控制的重要组成部分。结核潜伏感染会增加2型糖尿病发病风险、慢性支气管发病风险、癌症发病风险、全因死亡风险和死于癌症的风险，该发现对未来探索结核潜伏感染与其他健康问题的联合干预和共病管理提供了新的视角。针对结核潜伏感染人群开展预防性治疗能否同时降低其他疾病负担、改善长期健康影响是下一步聚焦的重点方向。

Background

         Tuberculosis prevention and control has achieved remarkable results, but there are many challenges for tuberculosis prevention and control due to huge population of latent tuberculosis infection. Elucidating the epidemiological characteristics of latent tuberculosis infection (LTBI) is important for timely adjustment of tuberculosis prevention and control strategies in different regions. In addition, the chronic inflammatory response is the trigger of a variety of diseases. Considering the heavy burden of LTBI in China, the potentially negative impact of the persistent immune activation state in the host after Mycobacterium tuberculosis (MTB) infection on health cannot be ignored. Exploring the impact of LTBI on other health problems will provide important scientific basis for optimizing the management policy of LTBI and carrying out joint intervention of comorbidities.

Methods

         In 2013, we conducted latent tuberculosis infection detection using the interferon-γ release assay (IGRA) among 21832 residents aged 5 years and above in four rural study sites in China. Individuals identified as LTBI-positive were followed up for two and five years to explore the epidemiological characteristics of active pulmonary tuberculosis. In 2023, we performed a ten-year follow-up for all participants in the baseline survey. The histories of diseases over the previous decade were obtained through questionnaires, combined with data of the Tuberculosis Information Management System, the Chronic Disease Management System, the Mortality Registration System, to observe the risks of different diseases (pulmonary tuberculosis, type 2 diabetes mellitus (T2DM), cardio-cerebrovascular diseases, chronic respiratory diseases, cancer), the risk of death about all cause and specific cause (death from cardio-cerebrovascular diseases, death from chronic respiratory diseases and death from cancer) among baseline LTBI-positive and LTBI-negative populations during the ten-year follow-up period. The Cox proportional hazards regression model was used to analyze the risks of LTBI with different health outcomes. Subgroup analyses and sensitivity analyses were further conducted to explore the associations between LTBI and different health outcomes across populations with varying characteristics.

Results

         Among the 21832 participants in the baseline survey, 621 individuals with indeterminate results of IGRA in baseline were excluded, leaving 21211 participants for analysis, including 4455 LTBI-positive individuals and 16756 LTBI-negative individuals in baseline.

         During the 10-year follow-up period, a total of 181 cases of active pulmonary tuberculosis were confirmed, with an incidence density of 1.06 per 1000 person-years. The incidence risk of active pulmonary tuberculosis in LTBI-positive individuals (3.68 cases per 1000 person-years) was 7.17 times higher than that in LTBI-negative individuals in baseline (0.35 per 1000 person-years) (95% confidence interval (CI): 5.02–10.24). The association between LTBI and the risk of active pulmonary tuberculosis was robust across different subgroup analyses and sensitivity analyses. LTBI is the main source of new PTB cases, and the proportion of LTBI decreases with the prolongation of time.

         In the study between LTBI and the incidence risk of comorbidities, the incidence density of T2DM in the LTBI-positive population was 7.33 per 1000 person-years, which was higher than that in the LTBI-negative population (4.63 per 1000 person-years). The risk of T2DM in the LTBI-positive population was 20% higher than that in the LTBI-negative population (aHR=1.20, 95%CI: 1.03-1.41). The incidence density of chronic bronchitis in the LTBI-positive was 1.00 per 1000 person-years, which was higher than that in the LTBI-negative population (0.45 per 1000 person-years). The risk of chronic bronchitis in the LTBI-positive population was 3.11 times higher than that in the LTBI-negative population (aHR=3.11, 95%CI: 1.12-8.62). The incidence density of cancer in the LTBI-positive population was 5.23 per 1000 person-years, which was higher than that in the LTBI-negative population (2.86 per 1000 person-years). The risk of cancer in the LTBI-positive population was 67% higher than that in the LTBI-negative population (aHR=1.67, 95% CI: 1.11-2.51).

         In the study of LTBI and risk of death, Kaplan-Meier survival results showed statistically significant differences in all-cause mortality among different LTBI states in different gender, BMI, study sites and people younger than 80 years old (P<0.05). Compared with the LTBI-negative population, the risk of all-cause mortality in the LTBI-positive population increased by 13% (aHR=1.13, 95%CI: 1.03-1.25), and the risk of death from cancer increased by 43% (aHR=1.43, 95%CI: 1.17-1.75).

Conclusions

         LTBI is still the main source of active tuberculosis in rural China. Preventive measurement, as the main way to reduce the incidence of tuberculosis, is a crucial component of TB prevention and control. LTBI could increase the incidence risk of T2DM, chronic bronchi, cancer and the risk of all-cause mortality and the risk of death from cancer. Our finding provides a new perspective for exploring the joint intervention and comorbidity management of LTBI and other health problems in the future. Whether preventive treatment for people with LTBI can simultaneously reduce the burden of other diseases and improve the long-term health impact is the focus of future work.