Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study

Abstract

Background: The value of quantitative interferon-γ release assay results for predicting progression from Mycobacterium tuberculosis infection to active disease is unknown. Methods: We analysed data from a reported vaccine efficacy trial of MVA85A in South Africa. QuantiFERON-TB Gold In-Tube (QFT) negative, HIV uninfected infants aged 18–24 weeks were enrolled. We stratified participants by quantitative QFT result (IFN-γ <0.35, 0·35–4·00, >4·00 IU/ml) at the intermediate study visit (Day 336) and determined risk of progression to active tuberculosis disease over the subsequent 6–24 months. No QFT differences were observed between placebo and MVA85A groups; therefore, both groups were included in analyses. Study clinicians were not blinded to QFT values, but strict case definitions were used and excluded QFT results. Findings: Among 2,512 infants with QFT tests performed at Day 336, 172 (6·8%) were positive. Compared with QFT non-converters (disease incidence 0·7 per 100 person-years; 95% CI: 0·4–1·1), children with QFT conversion at IFN-γ values between 0·35–4·00 IU/ml did not have significantly increased risk of disease (2·5 per 100 person-years; 95% CI: 0·4–9·4; IRR 3·7; p=0·23). However, QFT conversion at IFN-γ values >4·00 IU/ml was associated with markedly increased disease incidence (28·0 per 100 person-years; 95% CI: 14·9–45·7) compared to nonconverters (IRR 42·5; p<0·0001); and compared to children with IFN-γ values between 0·35–4·00 IU/ml (IRR: 11·4; p=0·00047). Among 91 QFT converters with a repeat test, 53 (58·2%) reverted from positive to negative. QFT reversion risk was inversely associated with IFN-γ value at QFT conversion and was highest (47/61; 77·0%) with IFN-γ values <4·00 IU/ml. Interpretation: In young children, tuberculosis disease risk was not significantly elevated, and QFT reversion was common, following QFT conversion at IFN-γ values up to 10 times the recommended test threshold. By contrast, QFT conversion at very high IFN-γ values (>4·00 IU/ml) warrants intensified diagnostic and preventive intervention for extremely high risk of tuberculosis disease.

MVA85A vaccine to enhance BCG for preventing tuberculosis

“…Andrews 2017 and Bunyasi 2017 presented data based on the Tameris 2013 clinical trial. The six included studies are described in the Characteristics of included studies table.…”

“…Aeras sponsored five trials (Andrews 2017; Bunyasi 2017; Ndiaye 2015; Nemes 2018; Tameris 2013). The University of Oxford sponsored one trial (Scriba 2011).…”

“…Other funders were Oxford Emergent Tuberculosis Consortium (OETC) for Ndiaye 2015 and Tameris 2013, the European and Developing Countries Clinical Trials Partnership and the Bill and Melinda Gates Foundation for Ndiaye 2015, the UK Medical Research Council for Nemes 2018, and the EuropeAID European Commission for Scriba 2011. Andrews 2017 and Bunyasi 2017 conducted further follow‐up based on the participants enrolled in Tameris 2013, and mentioned that there was no specific additional funding for the analysis performed.…”

“…Five trials included infants (Andrews 2017; Bunyasi 2017; Nemes 2018; Scriba 2011; Tameris 2013). One trial assessed the efficacy and safety of the vaccine in adults with HIV (Ndiaye 2015).…”

“…Five trials gave Candida skin test antigen (Candin®) as a placebo, using the same route (intradermal) and schedule (one or two doses) as for the intervention group in each of the trial (Andrews 2017; Bunyasi 2017; Ndiaye 2015; Nemes 2018; Tameris 2013). Scriba 2011 gave the infants in the comparator group one dose of pneumococcal 7‐valent conjugate vaccine by the intramuscular route.…”