Challenges in the Estimation of the Annual Risk of Mycobacterium tuberculosis Infection in Children Aged Less Than 5 Years.

P Y Khan,Judith R Glynn,Katharina Kranzer,D Mulawa,Katherine L Fielding,Amelia C Crampin,R Chiumya,T Mzembe

doi:10.1093/aje/kwx153

Abstract

Accurate estimates of Mycobacterium tuberculosis infection in young children provide a critical indicator of ongoing community transmission of M. tuberculosis. Cross-reactions due to infection with environmental mycobacteria and/or bacille Calmette-Guérin (BCG) vaccination compromise the estimates derived from population-level tuberculin skin-test surveys using traditional cutoff methods. Newer statistical approaches are prone to failure of model convergence, especially in settings where the prevalence of M. tuberculosis infection is low and environmental sensitization is high. We conducted a tuberculin skin-test survey in 5,119 preschool children in the general population and among household contacts of tuberculosis cases in 2012–2014 in a district in northern Malawi where sensitization to environmental mycobacteria is common and almost all children are BCG-vaccinated. We compared different proposed methods of estimating M. tuberculosis prevalence, including a method described by Rust and Thomas more than 40 years ago. With the different methods, estimated prevalence in the general population was 0.7%–11.5% at ages <2 years and 0.8%–3.3% at ages 2–4 years. The Rust and Thomas method was the only method to give a lower estimate in the younger age group (0.7% vs 0.8%), suggesting that it was the only method that adjusted appropriately for the marked effect of BCG-attributable induration in the very young.

Highlights

Childhood tuberculosis has not been considered a priority in high-burden settings until recent years [1]
Our findings highlight the challenges of using tuberculin surveys to estimate the risk of M. tuberculosis infection in young bacille CalmetteGuérin (BCG)-vaccinated children
The Rust and Thomas method generated a consistent estimate of infection prevalence and ARTI, irrespective of age, in a setting where sensitization to environmental mycobacteria is known to be high [22] and over 90% of children are BCGvaccinated within 3 months of birth

Summary

Introduction

Childhood tuberculosis has not been considered a priority in high-burden settings until recent years [1]. Despite the lack of specificity of the TST [14], and because of the cost and logistical issues (need for venipuncture, skilled personnel, and laboratory equipment) [15] and the lack of clarity around the conversion and reversion phenomena associated with serial testing of the more specific interferon-gamma release assays (IGRAs) [16], serial population-wide tuberculin surveys undertaken in young children in high-burden countries remain among the few ways to assess the impact of tuberculosis-control strategies over time This assessment relies on the need for a consistent estimate of the prevalence of M. tuberculosis infection, which is not always possible with the traditional cutoff methods, especially in settings where cross-reactivity with environmental mycobacteria and BCG-attributable reactions are common [11, 17]. We compared these estimates with those derived using the classical TST cutoff methods (indurations of ≥10 mm or ≥15 mm), fixed-mirror method [6, 20], and mixture analysis [21,22,23,24]

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