Researchers have identified four genes that could help identify people who are at high risk of developing active tuberculosis (TB) up to 2 years before they develop clinical symptoms. Results were published online April 6 in the American Journal of Respiratory and Critical Care Medicine.
The four-gene test could be developed into a point-of-care blood test for use in TB-endemic areas with limited healthcare resources and could help identify individuals who could benefit most from preventive treatment.
“Overall, our study identifies and validates a simple [polymerase chain reaction (PCR)]-based test from accessible blood samples that predicts TB in heterogeneous African populations with intermediate to high TB burdens,” write Sara Suliman, PhD, MPH, from the University of Cape Town, South Africa, and colleagues. “Such a test can potentially be developed into a screening test for risk of progression during TB contact investigation, implemented by national public health structures.”
To develop a blood test that might better predict who will progress to active TB, researchers conducted a case–control study in South Africa, The Gambia, Ethiopia, and Uganda. The study included 79 people who progressed to clinical disease 3 to 24 months after exposure to active TB in household contacts. These progressors were matched to 328 individuals exposed to active TB who did not progress to clinical disease (nonprogressors). All participants were HIV-negative and came from a larger study of household contacts called the Grand Challenges 6-74 study.
First, researchers used pooled PCR results from South Africa and The Gambia to identify four genes predictive of TB progression. They called this result the genetic risk signature, or RISK4. Next, they tested RISK4 in South Africa, The Gambia, and Ethiopia (too few samples were available from Uganda to include in the analysis). Finally, they compared RISK4 with other published diagnostic TB signatures, including three-gene, four-gene, and 16-gene signatures.
RISK4 significantly predicted TB progression up to 2 years before clinical symptoms appeared in the combined population (P = 2.6 × 10−4). RISK4 also had similar accuracy in separate analyses for South Africa, The Gambia, and Ethiopia (P < .03 for all).
The researchers confirmed results in an independent sample of South African adolescents with latent TB whose time of TB exposure was unknown (P = 3.4 × 10−7).
Analysis of other published diagnostic TB signatures failed to confirm their predictive value at some sites, suggesting RISK4 may yield more consistent results across different populations.
Limitations include small sample size and geographical restriction to just three regions in Africa. Further large, multicenter studies are needed in Africa and other TB-endemic regions to confirm the findings. More work is also needed to develop point-of-care PCR technologies that can be used in resource-poor settings.
Only about 5% to 10% of people who are infected with TB go on to develop clinical disease. However, about 1.7 billion people worldwide are thought to be infected with the TB organism, so the number of asymptomatic individuals is very large.
Identifying asymptomatic people who are more likely to develop symptoms would be an important stride forward in improving TB control. Although current tests such as the tuberculin skin tests and interferon gamma release assays can detect asymptomatic (or latent) TB, they have limited value in predicting progression to active TB.
“We envision platforms where blood from a finger prick can be translated through field-friendly, handheld PCR instruments to interpretable scores. Field staff would then triage near-patient contacts into low-risk and higher-risk groups for further assessment and potential treatment for subclinical or active TB disease,” the authors conclude.
The study was supported by Bill & Melinda Foundation grants, the National Institutes of Health, and the South African Medical Research Council. Suliman one coauthor report support from the Carnegie Corporation of New York. Suliman was also supported by the South African National Research Foundation. The coauthor was also supported by the Claude Leon Foundation and the Columbia University-Southern African Fogarty AIDS International Training and Research Program. Two other coauthors report receiving funding from the European Commission.
Am J Respir Crit Care Med. Published online April 6, 2018. Abstract
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