Predictive value of interferon-γ release assays for incident active tuberculosis: a systematic review and meta-analysis

Abstract

Background: We aimed to assess whether interferon-γ release assays (IGRAs) can predict the development of active tuberculosis and whether the predictive ability of these tests is better than that of the tuberculin skin test (TST).

Methods: Longitudinal studies of the predictive value for active tuberculosis of in-house or commercial IGRAs were identified through searches of PubMed, Embase, Biosis, and Web of Science and complementary manual searches up to June 30, 2011. Eligible studies included adults or children, with or without HIV, who were free of active tuberculosis at study baseline. We summarised incidence rates in forest plots and pooled data with random-effects models when appropriate. We calculated incidence rate ratios (IRR) for rates of disease progression in IGRA-positive versus IGRA-negative individuals.

Findings: 15 studies had a combined sample size of 26 680 participants. Incidence of tuberculosis during a median follow-up of 4 years (IQR 2-6), even in IGRA-positive individuals, was 4-48 cases per 1000 person-years. Seven studies with no possibility of incorporation bias and reporting baseline stratification on the basis of IGRA results showed a moderate association between positive results and subsequent tuberculosis (pooled unadjusted IRR 2·10, 95% CI 1·42-3·08). Compared with test-negative results, IGRA-positive and TST-positive results were much the same with regard to the risk of tuberculosis (pooled IRR in the five studies that used both was 2·11 [95% CI 1·29-3·46] for IGRA vs 1·60 [0·94-2·72] for TST at the 10 mm cutoff). However, the proportion of IGRA-positive individuals in seven of 11 studies that assessed both IGRAs and TST was generally lower than TST-positive individuals.

Interpretation: Neither IGRAs nor the TST have high accuracy for the prediction of active tuberculosis, although use of IGRAs in some populations might reduce the number of people considered for preventive treatment. Until more predictive biomarkers are identified, existing tests for latent tuberculosis infection should be chosen on the basis of relative specificity in different populations, logistics, cost, and patients' preferences rather than on predictive ability alone.

Funding: Special Programme for Research and Training in Tropical Diseases (WHO), Wellcome Trust, Canadian Institutes of Health Research, UK Medical Research Council, and the European and Developing Countries Clinical Trials Partnership.

Figure 1. Study selection

*See webappendix p 4 for further exclusion details.

Figure 2. Unadjusted incidence rates for all tuberculosis diagnoses stratified by interferon-γ release assay (IGRA) status

Incidence rate estimates are per 1000 person-years from individual studies that provided person-time data stratified by IGRA status at baseline.

Figure 3. Unadjusted cumulative incidence risk ratios for positive versus negative interferon-γ release assay (IGRA) results, by possibility of incorporation bias

One study did not report whether tuberculosis diagnoses methods included IGRA and was therefore included along with the six studies^,,,– in which IGRA formed part of tuberculosis diagnoses methods and, therefore, incorporation bias could not be ruled out. Data from Kenya has been stratified into HIV-exposed infants and their mothers who had HIV. Pooled risk ratio (RR) estimate with Netherlands T-Spot.TB results (rather than QuantiFERON Gold in tube): RR=3·61 (95% CI 2·29–5·69), I²=67·4%, p=0·005.

Figure 4

Unadjusted incidence rate ratios for positive versus negative interferon-γ release assay results, by type of assay

Figure 5. Unadjusted incidence rate ratios for positive versus negative test result, by test type

Tuberculin skin test (TST) is stratified by cutoff for studies that provided values in the original paper or on request. TST (10)=TST more than 10 mm. TST (5)=TST more than 5 mm.