Date Published: July 18, 2019
Publisher: Public Library of Science
Author(s): Vidya Mave, Padmapriyadarshini Chandrasekaran, Amol Chavan, Shri Vijay Bala Yogendra Shivakumar, Kavitha Danasekaran, Mandar Paradkar, Kannan Thiruvengadam, Aarti Kinikar, Lakshmi Murali, Sanjay Gaikwad, Luke Elizabeth Hanna, Vandana Kulkarni, Sathyamoorthy Pattabiraman, Nishi Suryavanshi, Beena Thomas, Rewa Kohli, Gomathi Narayan Sivaramakrishnan, Neeta Pradhan, Brindha Bhanu, Anju Kagal, Jonathan Golub, Neel Gandhi, Akshay Gupte, Nikhil Gupte, Soumya Swaminathan, Amita Gupta, Olivier Neyrolles.
Despite substantial exposure to infectious pulmonary tuberculosis (TB) cases, some household contacts (HHC) never acquire latent TB infection (LTBI). Characterizing these “resisters” can inform who to study immunologically for the development of TB vaccines. We enrolled HHCs of culture-confirmed adult pulmonary TB in India who underwent LTBI testing using tuberculin skin test (TST) and QuantiFERON TB Gold Test-in-tube (QFT-GIT) at baseline and, if negative by both (<5mm TST and <0.35IU/mL QFT-GIT), underwent follow-up testing at 4–6 and/or 12 months. We defined persons with persistently negative LTBI tests at both baseline and followup as pLTBI- and resisters as those who had a high exposure to TB using a published score and remained pLTBI-. We calculated the proportion of resisters overall and resisters with complete absence of response to LTBI tests (0mm TST and/or QFT-GIT <0.01 IU/ml). Using random effects Poisson regression, we assessed factors associated with pLTBI-. Of 799 HHCs in 355 households, 67 (8%) were pLTBI- at 12 months; 52 (6.5%) pLTBI- in 39 households were resisters. Complete absence of response to LTBI tests was found in 27 (53%) resisters. No epidemiological characteristics were associated with the pLTBI- phenotype. LTBI free resisters among HHC exist but are uncommon and are without distinguishing epidemiologic characteristics. Assessing the genetic and immunologic features of such resister individuals is likely to elucidate mechanisms of protective immunity to TB.
Tuberculosis (TB) continues to have a sustained impact on medical and public health systems in low- and middle-income countries (LMIC) and is the leading cause of mortality by an infectious disease pathogen. In 2017, an estimated 10.4 million new TB cases were diagnosed worldwide, and of these, 1.7 million died. Furthermore, 24% of the world’s population (1.7 billion) is estimated to be infected with Mycobacterium tuberculosis (Mtb), representing a large reservoir at risk for progressing to TB disease. To achieve the World Health Organization End TB Strategy targets of 2025, TB incidence should decline by 4–5% per year rather than the current rate of 1.5% per year. Improved socio-economic conditions, nutritional status and living standards can contribute to the reduction of TB, as demonstrated in Western Europe in the past several decades. However, an effective TB vaccine is needed to interrupt TB transmission in LMIC[3,4]. A key rate limiting step for the development of TB vaccines is the limited evidence on immune correlates of protection against acquiring latent Mtb infection (LTBI) or developing TB disease.
Our large prospective cohort study assessed epidemiological characteristics of pLTBI- and resisters among HHCs of TB index cases in a high TB burden setting. We found that pLTBI- HHCs are relatively rare and those meeting an epidemiological definition of resister are especially rare. Our analysis did not identify any epidemiological characteristics that could be clearly associated with the pLTBI- or resister phenotype, and none of the resisters had complete absence of response to both TST and IGRA. We did, however, observe clusters of resisters within families living in the same household, Overall, our study adds to the body of evidence supporting the existence of a resister phenotype, at least based on quantified TB exposure and LTBI testing, and our large, well-characterized cohort provides data on a subset of persons who may be resistant to LTBI and will facilitate future research on genomic and immunologic characteristics.
In conclusion, LTBI resisters are relatively uncommon and identification requires large, carefully cultivated cohorts of HHCs with well-characterized exposure measurement, LTBI testing, and longitudinal follow-up. Focusing future research on households that are outliers (i.e. those that lack LTBI despite high exposure) is likely to be the most fruitful approach. In particular, family members in such households should be included in further studies of genetic and immunologic mechanisms of protection against Mtb infection acquisition. Specifically for India, which bears the world’s largest TB burden, our well-characterized cohort linked to a specimen repository could facilitate important basic and translational research to accelerate development of novel TB vaccines and further progress towards TB elimination.