New RNA expression-based diagnostic test highly sensitive for childhood TB

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1. An RNA expression signature for active TB in children had higher sensitivity than the PCR-based Xpert MTB/RIF assay, but lower specificity. 

Evidence Rating Level: 1 (Excellent) 

Study Rundown: Childhood tuberculosis (TB) presents a diagnostic challenge. In adults, the diagnosis is typically made by detection of acid-fast bacilli in a sputum sample. In children, the disease presents with fewer bacilli and microbiological confirmation of the organism is possible in only about 40% of cases.

In this study, the authors compared RNA transcripts between children with culture-confirmed TB, children with latent TB and children with diseases other than TB to identify RNA transcript signatures that could distinguish active TB from latent TB and other diseases. This RNA-based risk score had a sensitivity and specificity of 82.9% and 83.6% for culture-confirmed TB. The PCR-based Xpert MTB/RIF test had a sensitivity and specificity of 54.3% and 100%.

Although this RNA-based signature offers improved sensitivity, the complexity and cost of the technology behind it still limits its application to resource-poor settings. It should also be borne in mind that the gold standard for TB diagnosis in children is poor, as described above. Comparing new diagnostic tests to this weak gold standard is therefore an inherently limited approach. Outcomes data showing that these molecular tests can reduce under- and over-treatment would be even more compelling.

Click to read the study in NEJM

Relevant Reading: Tuberculosis in children

In-Depth: Three hundred and forty-six children in South Africa and Malawi formed the discovery cohort in which the RNA transcript signature for TB was determined. Fifty-one transcripts distinguished the children with TB from the children with other diseases and 42 distinguished active TB from latent TB.

A risk score based on the transcript levels was developed and validated in a cohort of 157 children in Kenya. The risk score was evaluated in children with culture-confirmed TB and in children with other diseases and a sensitivity and specificity of 82.9% and 83.6% were found.

The risk score was also tested among children with culture-negative TB, that is, children who were treated for TB based on clinical suspicion alone. In these cases the effective sensitivity was calculated based on estimated prevalence of actual tuberculosis. The RNA-based risk score had better sensitivity than the Xpert MTB/RIF assay in all cases.

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