Serologic Responses in Childhood Pulmonary Tuberculosis

Abstract

Background: Identification of the Mycobacterium tuberculosis immunoproteome and antigens associated with serologic responses in adults has renewed interest in developing a serologic test for childhood tuberculosis (TB). We investigated IgG antibody responses against M. tuberculosis antigens in children with well-characterized TB.

Methods: We studied archived sera obtained from hospitalized children with suspected pulmonary TB, and classified as having confirmed TB (culture-confirmed), unlikely TB (clinical improvement without TB treatment), or unconfirmed TB (all others). A multiplexed bead-based assay for IgG antibodies against 119 M. tuberculosis antigens was developed, validated and used to test sera. The area under the curves (AUCs) of the empiric receiver-operator characteristic curves were generated as measures of predictive ability. A cross-validated generalized linear model was used to select the most predictive combinations of antigens.

Results: For the confirmed TB versus unlikely TB comparison, the maximal single antigen AUC was 0.63, corresponding to sensitivity 0.60 and specificity 0.60. Older (age: 60+ months old) children's responses were better predictive of TB status than younger (age: 12-59 months old) children's, with a maximal single antigen AUC of -0.76. For the confirmed TB versus unlikely TB groups, the most predictive combinations of antigens assigned TB risk probabilities of 0.33 and 0.33, respectively, when all ages were considered, and 0.57 (interquartile range: 0.48-0.64) and 0.35 (interquartile range: 0.32-0.40) when only older children were considered.

Conclusion: An antigen-based IgG test is unlikely to meet the performance characteristics required of a TB detection test applicable to all age groups.

FIGURE 1

Plots of empiric AUCs for the 10 single antigens having the highest AUC for discrimination between children classified as confirmed TB versus children classified as unlikely TB for (A) all ages; (B) children 12–59 months old and (C) children 60 months old and older.

FIGURE 2

Boxplots of the log2-transformed antibody responses for the 10 single antigens having the highest AUC for discrimination between children classified as unlikely TB (designated as 0 on the x axis) versus children classified as confirmed TB (designated as 1 on the x axis) for (A) all ages; (B) children 12–59 months old and (C) children 60 months old and older. The y axis represents log2-transformed antibody responses.

FIGURE 2

Boxplots of the log2-transformed antibody responses for the 10 single antigens having the highest AUC for discrimination between children classified as unlikely TB (designated as 0 on the x axis) versus children classified as confirmed TB (designated as 1 on the x axis) for (A) all ages; (B) children 12–59 months old and (C) children 60 months old and older. The y axis represents log2-transformed antibody responses.

FIGURE 3

Correlations plot of single antibody responses with AUC >0.5 for discrimination between all children classified as confirmed TB versus all children classified as unlikely TB.

FIGURE 4

Boxplots of risk probabilities and corresponding receiver–operator characteristic curves for optimal antigen combinations selected by the cross-validated generalized linear model regularization path algorithm for discrimination between children classified as confirmed TB versus children classified as unlikely TB for (A) all ages; (B) children 12–59 months old and (C) children 60 months old and older.