Abstract
BackgroundIdentifying and treating individuals with high risk of progression from latent tuberculosis infection to active tuberculosis (TB) disease is critical for eliminating the disease. We aimed to conduct a systematic review and meta-regression analysis to quantify the dose-response relationship between interferon-gamma release assay (IGRA) levels and the risk of progression to active TB.MethodsWe searched PubMed and Embase from 1 January 2001 to 10 May 2020 for longitudinal studies that reported the risk of progression from latent to active TB as a function of baseline IGRA values. We used a novel Bayesian meta-regression method to pool effect sizes from included studies and generate a continuous dose-response risk curve. Our modeling framework enabled us to incorporate random effects across studies, and include data with different IGRA ranges across studies. The quality of included studies were assessed using the Newcastle-Ottawa scale (NOS).ResultsWe included 34 studies representing 581,956 person-years of follow-up with a total of 788 incident cases of TB in the meta-regression analysis. Higher levels of interferon-gamma were associated with increased risk of progression to active tuberculosis. In the dose-response curve, the risk increased sharply between interferon-gamma levels 0 and 5 IU/ml, after which the risk continued to increase moderately but at a slower pace until reaching about 15 IU/ml where the risk levels off. Compared to 0 IU/ml, the relative risk of progression to active TB among those with interferon-gamma levels of 0.35, 1, 5, 10, 15, and 20 IU/ml were: 1.64 (1.28–2.08), 2.90 (2.02–3.88), 11.38 (6.64–16.38), 19.00 (13.08–26.90), 21.82 (14.65–32.57), and 22.31 (15.43–33.00), respectively. The dose-response relationship remains consistent when limiting the analysis to studies that scored highest in the NOS.ConclusionThe current practice of dichotomizing IGRA test results simplifies the TB infection disease continuum. Evaluating IGRA test results over a continuous scale could enable the identification of individuals at greatest risk of progression to active TB.
Highlights
Identifying and treating individuals with high risk of progression from latent tuberculosis infection to active tuberculosis (TB) disease is critical for eliminating the disease
Mycobacterium tuberculosis (Mtb) is the causative agent of TB, though a person with Mtb infection can remain asymptomatic in a state known as latent TB infection (LTBI)
We excluded studies that contained a sample with a confounding disease, that did not test all individuals with QuantiFERON-TB, or did not follow-up all individuals for progression to active TB disease
Summary
Identifying and treating individuals with high risk of progression from latent tuberculosis infection to active tuberculosis (TB) disease is critical for eliminating the disease. Mycobacterium tuberculosis (Mtb) is the causative agent of TB, though a person with Mtb infection can remain asymptomatic in a state known as latent TB infection (LTBI). Identifying individuals with LTBI and placing those at risk of developing active TB on preventive treatment is critical for eliminating the disease [5]. Despite the higher cost of the test and some challenges with reproducibility, the use of IGRAs is expected to further expand in high TB burden countries, as the World Health Organization (WHO) has recently endorsed the use of QFT-GIT and TSPOT.TB for the End TB strategy [8]
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