High proportion of tuberculosis transmission among social contacts in rural China: a 12-year prospective population-based genomic epidemiological study
Authors: Li Meng , Guo Mingcheng , Peng Ying , Jiang Qi , Xia Lan , Zhong Sheng , Qiu Yong , Su Xin , Zhang Shu , Yang Chongguang , Mijiti Peierdun , Mao Qizhi , Takiff Howard , Li Fabin , Chen Chuang , Gao Qian 
Published: April 2022

SummaryBackgroundTuberculosis (TB) is more prevalent in rural than urban areas in China, and delineating TB transmission patterns in rural populations could improve TB control.MethodsWe conducted a prospective population-based study of culture-positive pulmonary TB patients diagnosed between July 1, 2009 and December 31, 2020 in two rural counties in China. Genomic clusters were defined with a threshold distance of 12-single-nucleotide-polymorphisms, based on whole-genome sequencing. Risk factors for clustering were identified by logistic regression. Transmission links were sought through epidemiological investigation of genomic-clustered patients.FindingsOf 1517 and 751 culture-positive pulmonary TB patients in Wusheng and Wuchang counties, respectively, 1289 and 699 strains were sequenced. Overall, 624 (31·4%, 624/1988) patients were grouped into 225 genomic clusters. Epidemiological links were confirmed in 41·8% (196/469) of clustered isolates, including family (32·7%, 64/196) and social contacts (67·3%, 132/196). Social contacts were generally with relatives, within the community or in shared aggregated settings outside the community, but the proportion of clustered contacts in each category differed between the two sites. The time interval between diagnosis of student cases and contacts was significantly shorter than family and social contacts, probably due to enhanced student contact screening. Transmission of multidrug-resistant strains was likely responsible for 81·4% (83/102) of MDR-TB cases, with minimal acquisition of additional resistance mutations.InterpretationA large proportion of TB transmission in rural China occurred among social contacts, suggesting that active screening and aggressive contact tracing could benefit TB control, but contact screening should be tailored to local patterns of social interactions.FundingNational Science and Technology Major Project of China, Natural Science Foundation of China, and Science and Technology Major Project of ShanghaiEvidence before this studyWe searched PubMed for genomic epidemiological studies of Mycobacterium tuberculosis published in English before April 2022 employing whole-genome sequencing, using the search terms “tuberculosis”, “transmission”, “population based”, and “whole-genome sequencing”. We identified only 11 studies in which whole-genome sequencing was used to investigate transmission of M tuberculosis at the population level. We also searched the China national knowledge infrastructure (CNKI) and WANFANG databases with the same search terms for papers published in Chinese, but did not identify any studies. The duration of most of the 11 studies we identified was less than 5 years. Seven studies conducted epidemiological investigations of genomic-clustered cases, but the proportion of cases with confirmed epidemiological links was very low. Therefore, no studies had sufficient evidence to identify populations and sites at high risk of TB transmission. Five studies were conducted in China but all were in urban areas and focused on MDR-TB patients and internal migrants. The pattern of TB transmission in rural China, where TB is more prevalent, had not been addressed.Added value of this studyTo our knowledge, ours is the first population-based genomic epidemiological study to delineate TB transmission patterns in rural China. Close contacts have been shown to be a high-risk group for TB transmission in other countries. In China, however, the huge number of TB patients, limited resources for TB prevention and control and the stigma associated with tuberculosis all contribute to a failure to identify and screen many close contacts. As a consequence, close contacts have been calculated to contribute only about 2% of the total TB burden. In this study, through the investigation of genomic-clustered patients, we found at least 41·8% of clustered patients were close contacts who comprised 9·9% of the total TB patients in the study. Moreover, more than two-thirds of the close contacts were social contacts rather than members of the immediate family. The composition of social contacts differed between the two study sites due to differences in climate and lifestyle habits. The average time interval between the diagnosis of clustered student contacts was shorter than for family or community contacts. In addition, transmission of MDR strains was likely responsible for 81·4% of MDR-TB cases, with minimal acquisition of additional resistance mutations. Our 12-year study identified patterns of TB transmission not identified by previous studies, demonstrating the value of long-term genomic epidemiological studies.Implications of all the available evidenceOur study demonstrates that much of the transmission of TB in rural China was among close contacts, especially social contacts. Therefore, strengthening and improving proactive screening of close social contacts can identify more TB patients and shorten the time to patient detection. We believe that this type of vigorous active case-finding is essential for reducing TB transmission and the considerable TB burden in China. Long-term prospective genomic epidemiological studies provide a useful picture of TB transmission patterns that can help guide the design of strategies to improve TB prevention and control.