key: cord-0314452-9lxt016v authors: Li, M.; Guo, M.; Peng, Y.; Jiang, Q.; Xia, L.; Zhong, S.; Qiu, Y.; Su, X.; Zhang, S.; Yang, C.; Mijiti, P.; Mao, Q.; Takiff, H.; Li, F.; Chen, C.; Gao, Q. title: High proportion of tuberculosis transmission among social contacts in rural China: a 12-year prospective population-based genomic epidemiological study date: 2022-04-20 journal: nan DOI: 10.1101/2022.04.18.22273772 sha: fd872bd4bab66a2fda0ab9154e32e201c34c27e6 doc_id: 314452 cord_uid: 9lxt016v Background Tuberculosis (TB) is more prevalent in rural than urban areas in China, and delineating TB transmission patterns in rural populations could improve TB control. Methods We 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. Findings Of 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 within the relatives, 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 community 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. Interpretation A 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. Funding National Science and Technology Major Project of China Added value of this study 58 To our knowledge, ours is the first population-based genomic epidemiological study 59 to delineate TB transmission patterns in rural China. Close contacts have been shown 60 to be a high-risk group for TB transmission in other countries. In China, however, the 61 huge number of TB patients, limited resources for TB prevention and control and the 62 stigma associated with tuberculosis all contribute to a failure to identify and screen 63 many close contacts. As a consequence, close contacts have been calculated to 64 contribute only about 2% of the total TB burden. In this study, through the 65 investigation of genomic-clustered patients, we found at least 41·8% of clustered 66 patients were close contacts who comprised 9·9% of the total TB patients in the study. 67 Moreover, more than two-thirds of the close contacts were social contacts rather than 68 members of the immediate family. The composition of social contacts differed 69 between the two study sites due to differences in climate and lifestyle habits. The Implications of all the available evidence 78 Our study demonstrates that much of the transmission of TB in rural China was 79 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 20, 2022. ; https://doi.org/10.1101/2022.04.18.22273772 doi: medRxiv preprint among close contacts, especially social contacts. Therefore, strengthening and 80 improving proactive screening of close social contacts can identify more TB patients 81 and shorten the time to patient detection. We believe that this type of vigorous active 82 case-finding is essential for reducing TB transmission and the considerable TB burden 83 in China. Long-term prospective genomic epidemiological studies provide a useful 84 picture of TB transmission patterns that can help guide the design of strategies to 85 improve TB prevention and control. 86 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 20, 2022 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 12 Strains belonging to lineage 197 2 (L2), also termed the Beijing family, were divided into L2·3, representing "modern" 198 Beijing, and other sub-lineages considered "ancient" Beijing. 13 199 200 Drug-resistance profiles were predicted for 14 anti-TB drugs based on the mutations 201 reported to be associated with resistance, 14 using Whole-genome sequencing (WGS) 202 data as described previously. 15 Pan-susceptible TB was defined as susceptibility to the 203 four first-line drugs (isoniazid, rifampicin, ethambutol and pyrazinamide). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 20, 2022. In the analysis of risk factors for MDR-TB, the only association was a higher 274 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table S1 . Figure 5 shows examples of three of the largest clusters. The 313 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Finally, we used logistic regression to identify risk factors associated with clustering. 335 The univariate analysis found that occupation and the Beijing strain were significantly 336 associated with clustering, and both associations persisted in the multivariate analysis 337 ( The average time interval between the diagnosis of clustered student contacts was 351 much shorter than for non-student contacts. 352 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. contacts. 5, 25 In China, however, the importance of screening close contacts has been 361 underappreciated and its role in case finding has been limited. In China, only 2-3 362 close contacts per index case were identified and most of these were family members, 363 and it was therefore estimated that close contacts would contribute only about 1·0-3·3% 364 of the total TB patients. 26 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 20, 2022. ; https://doi.org/10.1101/2022.04.18.22273772 doi: medRxiv preprint identification of family contacts is generally straightforward, the definition and 392 identification of non-family contacts is difficult. In China, non-family contacts refer 393 mainly to classmates and colleagues. 27 However, in this study we found that many 394 patients with confirmed epidemiologic links were contacts either within the 395 community or contacts who shared the aggregated settings outside the community. 396 Therefore, in addition to family contacts, we classified others as social contacts in the 397 hope of understanding where contacts occur and highlighting their relevance for TB 398 transmission in rural China. 399 400 We found that 67·3% of the transmission occurred among social contacts in rural 401 China, which was significantly higher than has been found in Vietnam, Zambia and 402 South Africa (15-50%). 28, 29 This suggests that active case-finding in rural China 403 should go beyond family contacts to include social contacts. In this study we proposed The purpose of active case-finding is to diagnose patients early and reduce 424 transmission. Importantly, we found that the time interval between TB diagnosis of 425 student patients and contacts was 3-4 times shorter than for family or community 426 contacts ( Figure 4B ). Students are a special group in China and receive special 427 attention from the government and society. Once a student patient is diagnosed with 428 TB, their classmates and even schoolmates will be screened. If a similar enhanced 429 screening strategy could be extended to other social contacts, patients might be 430 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 459 We declare no competing interests. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Data are n (%) unless otherwise specified. DR=drug resistance. MDR=multidrug resistance. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. PZA=pyrazinamide. MDR=multidrug resistance. FQ=fluoroquinolone. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 20, 2022. Due to the small number of relatives, they were not compared with the other categories. ** p<0.01, NS refers to no significance (given by Wilcoxon non-parametric rank sum test). (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 20, 2022. ; https://doi.org/10.1101/2022.04.18.22273772 doi: medRxiv preprint indicates the root and circles represent Mycobacterium tuberculosis isolates. M tuberculosis isolates are separated by lines with length representing genetic distance. Different colors of rectangle indicate resistance to different drugs. Two new MDR-TB patients were clustered with non-MDR-TB patients and were not included in the analysis. WHO. Global tuberculosis report 2020 What We Know About Tuberculosis Transmission: An Overview The global tuberculosis epidemic and progress in care, prevention, and research: an overview in year 3 of the End TB era The End TB Strategy: global strategy and targets for tuberculosis prevention Module 2: screeningsystematic screening for tuberculosis disease Recent transmission of Mycobacterium tuberculosis in China: the implication of molecular epidemiology for tuberculosis control Evaluation of the efectivenes of community-based pulmonary tuberculosis active case-finding among key populations: a multicenter prospective cohort study Tuberculosis prevalence in China, 1990-2010; a longitudinal analysis of national survey data Citywide Transmission of Multidrug-resistant Tuberculosis Under China's Rapid Urbanization: A Retrospective Population-based Genomic Spatial Epidemiological Study Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans Transmission of multidrug-resistant Mycobacterium tuberculosis in Shanghai, China: a retrospective observational study using whole-genome sequencing and epidemiological investigation A robust SNP barcode for typing Mycobacterium tuberculosis complex strains Southern East Asian origin and coexpansion of Mycobacterium tuberculosis Beijing family with Han Chinese Whole genome sequencing of Mycobacterium tuberculosis for detection of drug resistance: a systematic review A population-based genomic epidemiological study of the source of tuberculosis infections in an emerging city Transmission of tuberculosis and predictors of large clusters within three years in an urban setting in Tokyo, Japan: a population-based molecular epidemiological study A randomised controlled trial of stepwise sputum collection to increase yields of confirmed tuberculosis The effectiveness of contact investigation among contacts of tuberculosis patients: a systematic review and meta-analysis Long-term follow-up of contacts exposed to multidrug-resistant tuberculosis in HIV counseling and testing in tuberculosis contact investigations in the United States and Canada Tuberculosis Contact Investigations--United States Evaluation of tuberculosis contact investigations in Japan Risk and Timing of Tuberculosis Among Close Contacts of Persons with Infectious Tuberculosis Tuberculosis incidence among infected contacts detected through contact tracing of smear-positive patients Recommendations for investigating contacts of persons with infectious tuberculosis in low-and middle-income countries Analysis of TB case detection through investigation of close contacts of smear positive pulmonary tuberculosis patients Assessment of tuberculosis contact investigation in Shanghai, China: An 8-year cohort study Social contact patterns in Vietnam and implications for the control of infectious diseases Age-and Sex-Specific Social Contact Patterns and Incidence of Mycobacterium tuberculosis Infection Analysis of patients from active case finding in rural areas of Wusheng No reuse allowed without permission. 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