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Blood Assay Can Predict Latent TB That May Become Active in Children, Study Finds

NEW YORK (360Dx) – A quantitative interferon-gamma release assay can identify young children with latent tuberculosis who are at risk of developing active cases of the disease, according to a new study.

The researchers added that their findings could lead to changes in international guidelines, which currently do not recommend the use of such tests in children.

Tuberculosis caused 1.8 million deaths worldwide in 2015, and young children are particularly vulnerable to the disease, as about 20 percent of children infected with the disease-causing bacterium develop full-blown tuberculosis. However, the common sputum test that is used to screen for tuberculosis among adults does not work in children, as they typically swallow their sputum after coughing.

Researchers from the US, UK, and South Africa, though, found Qiagen's QuantiFERON-TB Gold (QTF) assay could uncover young children who have a higher risk of developing tuberculosis, as they reported yesterday in Lancet Respiratory Medicine.

The blood-based assay measures the level of interferon-gamma produced in response to Mycobacterium tuberculosis-specific antigens. In this study, nearly 30 percent of children with high interferon-gamma levels went on to develop disease, while only 2.5 percent of children with low interferon-gamma levels did.

"Given the high rates of TB and the difficulty of diagnosing it in kids, this can be something that could be done routinely in kids to identify the high-risk ones," Stanford University's Jason Andrews, an author of the Lancet study, said in a statement. "You could imagine in a high-burden country that at a child's 12-month visit, they could also get a QuantiFERON test, and if it's high, they'd get aggressively investigated for TB."

To gauge whether QTF testing could predict later disease, Andrews and his colleagues analyzed data collected by a failed TB vaccine efficacy trial conducted in South Africa, outside Cape Town. In it, healthy infants without HIV were tested via QTF shortly after birth, at about one year of age, and six months to 24 months after that. They were evaluated every three months for signs of TB.

By age one, 172 of the 2,512 children enrolled in the trial converted to positive QTF tests, a 6.8 percent infection rate, which the researchers noted was quite high. Of these, 30 had already been diagnosed and begun treatment for TB, while the others were watched.

Children who had high levels of interferon-gamma at conversion — more than 4.0 IU/mL — had a 40 fold higher incidence of later TB than children with lower levels, the researchers reported. Twenty-eight percent of the children in that range went on to develop disease. Meanwhile, only 2.5 percent of children with lower interferon-gamma levels developed TB, and 0.7 percent of children with a negative test did.

"We found that as your value goes up, your risk goes up, and the risk really begins to accelerate after a value of 4," Andrews said.

He and his colleagues suggested that these high values might reflect incipient or subclinical disease in the children. Screening for disease could identify children who should receive preventive therapy to halt disease progression, they added.

The researchers noted, though, that the World Health Organization, US Centers for Disease Control and Prevention, and other bodies do not recommend the use of interferon-gamma release assays on children. Instead, they call for the use of tuberculin skin testing of young children in high-burden regions like South Africa. Andrews and his colleagues noted that these guidelines stem in part from a lack of evidence on interferon-gamma release testing in children and argued that their findings, if validated, could lead to policy revisions.

"What we are hoping is that this will show the international community … that QuantiFERON testing can be reliable in kids, and that the quantitative values may be important so we may need to look a different thresholds than we use in adolescents or adults," Andrews added.

He said, though, that testing is moderately expensive and requires an equipped lab and trained technicians, and while that may be feasible in South Africa, it might not be in poorer countries.