Early Clearance of Mycobacterium Tuberculosis: The Infect Case Contact Cohort Study in Indonesia

Abstract

Introduction: Early clearance of M. tuberculosis is the eradication of infection before an adaptive immune response develops. We studied highly exposed Tuberculosis (TB) case contacts to identify host factors associated with early clearance. Methods: Indonesian household contacts of sputum smear positive TB cases were recruited. An Interferon Gamma Release Assay (IGRA) was performed at baseline and 14 weeks. Early clearance was defined as a persistently negative IGRA. Contacts were characterised with respect to demographic and clinical characteristics, index case exposure, and disease phenotype. Associations with a positive IGRA at each time point were estimated. Results: From 462 TB patients, 1347 households contacts (median age 27·9 years) were recruited. At baseline, 780 (57·9%) had a positive IGRA and 490 (36·3%) were IGRA negative. After 14 weeks, 116/445 (26·1%) initially IGRA negative contacts were IGRA converters and 317 (71·2%; 25·0% of all contacts) remained persistently IGRA negative. After accounting for measures of exposure and possible confounders, BCG vaccination was associated with reduced risk of a positive IGRA at baseline (relative risk [RR]=0·90; 95% CI 0·83 - 0.99; p=0·03), and a strongly reduced risk of IGRA conversion (RR=0·55; 95% CI 0·40 - 0·76; P<0·001). IGRA conversion was associated with diabetes mellitus (RR=1·90; 95% CI 1·02 - 3·51; p=0·04) and smoking (RR=1·66; 95% CI 1·10 - 2·49; p=0·02). Conclusions: Early clearance, defined as two negative IGRA tests 14 weeks apart, is found in a quarter of TB case contacts and is strongly associated with BCG vaccination. Further studies of the underlying immune mechanisms will inform strategies for enhanced protection against M. tuberculosis infection. Funding: AV was supported by a New Zealand Health Research Council Clinical Training Research Fellowship. Cohort recruitment was funded by the University of Otago and Mercy Hospital, Dunedin, New Zealand. Qiagen donated the QuantiFERON® test materials used in the study. Enrollment clinical management and laboratory examination of index cases was conducted in the TANDEM project, which is supported by the European Union’s Seventh Framework Programme (FP7/2007–2013) under Grant Agreement Number 305279. MGN was supported by a Spinoza grant from the Netherlands Organisation for Scientific Research. Declaration of Interest: The authors have no conflict of interests to declare Ethical Approval: The study was approved by the Health Research Ethics Committee Universitas Padjadjaran (14/UN6.C2.1.2/KEPK/PN/2014) and the Southern Health and Disability Ethics Committee New Zealand (13/STH/132).