Spotting the Silent Threat: Early Detection of Subclinical Tuberculosis in High-Risk Individuals

Abstract The dynamic spectrum of TB often results in underdiagnosis warranting the need for better diagnostics to accurately detect Mtb in diagnostically challenging cohorts. Household contacts of newly diagnosed TB patients who developed TB (Progressors) and those who remained healthy (Non-progressors) during a two-year follow-up cohort study were included. Mtb ccfDNA was detected in the plasma by targeting insertion sequences IS6110 and IS1081 using ddPCR. The assay yielded a sensitivity of 90·9% in detecting subclinical TB cases and 81·8% in possible TB cases. Further, the test detected Mtb ccfDNA in progressors even at six months prior to TB diagnosis at a sensitivity of 79·0%. In about 55·0% and 50·0% of cases Mtb ccfDNA could be detected as early as 12 months and 18 months prior to development of active disease, respectively. The test demonstrated excellent sensitivity (100·0%) in detecting extra-pulmonary TB cases up to six months prior to TB disease development. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by the Indian Council of Medical Research (Grant number:5/8/5/45/Adhoc/2022/ECD-1). EAD was supported by DST-INSPIRE fellowship. The CTRIUMPh cohort study was supported by the NIH/DBT Indo-US Vaccine Action Programme. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The parent study protocol received ethical approval from the Institutional Ethics Committees of the ICMR-National Institute for Research in Tuberculosis (ICMR-NIRT) in Chennai, India, Byramjee Jeejeebhoy Government Medical College (BJGMC) in Pune, India, and Johns Hopkins University (JHU) in Baltimore, USA. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present work are contained in the manuscript