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Rapid Triage Test Identifies Active Tuberculosis

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News

Rapid Triage Test Identifies Active Tuberculosis

In the Department of Parasitology and Entomology at Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania, first author Rushdy Ahmad trains local staff in processing blood samples. Credit: Rushdy Ahmad
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Researchers report in Science Translational Medicine the development of a novel triage test that can rapidly and cheaply identify patients likely to have active tuberculosis (ATB). Use of the test could help detect those needing further diagnostics and treatment, as well as contribute to the improved prevention and control of the disease.

Reaching the missing 3 million

Caused by the bacterium Mycobacterium tuberculosis, tuberculosis (TB) is one of the top ten causes of death worldwide, accounting for 1.6 million deaths in 2017. Early diagnosis and appropriate treatment with anti-TB drugs could prevent the majority of these deaths, but estimates suggest that of the 10 million people who developed TB in 2017, 3 million did not get the care they needed. Around 95% of TB patients live in low-resource countries, where access to healthcare and associated technologies can be limited.

Historical methods of detecting TB can be cumbersome and lack sensitivity, whereas newer tests depend on expensive lab equipment that is not always readily available in the areas it is required. Difficulties associated with the use of sputum also present additional challenges in the diagnosis of TB in adults with HIV infection and young children. In order to reach the WHO End TB Strategy target of a 90% reduction in the TB incidence and a 95% reduction in TB deaths by 2035, urgent improvements are needed in the way patients are diagnosed.

Improving community-based triage

Currently, patients presenting with a history of two or more weeks of cough in countries with high TB rates are triaged for further diagnostic tests, but the proportion of patients with ATB in this group is low, highlighting the need for a more effective community-based triage test. A WHO consensus panel in 2014 defined that such a test should have a minimum sensitivity of 90% and specificity of 70%, whilst being less expensive and easier to use than the confirmatory test.

To address this challenge, a team of researchers from the Wyss Institute, along with several collaborators, set out to develop an inexpensive and rapid blood-based triage test that would effectively identify patients likely to have ATB. They reasoned that a blood protein-based host response signature of biomarkers for ATB would be a suitable basis for a of a point-of-care test.

An ATB signature

To develop the test, the researchers first measured the levels of 47 proteins in plasma samples from 387 patients from Tanzania and the Philippines who had been diagnosed with ATB or other TB-like diseases. They then used machine learning algorithms to identify four host blood proteins (IL-6, IL-8, IL-18 and VEGF) that were elevated in the ATB patients. The algorithm was able to detect the presence of ATB with 86% sensitivity and 65% specificity. Importantly, the test was also able to identify 100% of ATB samples from HIV positive patients, and the absence of ATB in 84% of “cured controls” (patients who had completed 6 months of TB treatment and were assumed to be successfully treated).

"Elevated levels of all four of the blood proteins we analyzed have been identified in a range of different diseases, but only when combined into a predictive algorithm do they have the power to distinguish ATB from other conditions," said co-corresponding author David Walt, Ph.D., a Core Faculty member of the Wyss Institute in a press release.

Validation and enhancement of the algorithm

To improve the algorithm, the researchers developed an ultrasensitive POC-amenable single-molecule array (Simoa) panel, which resulted in a sensitivity of 87% and specificity of 66% and could potentially enable testing from just a finger prick of blood.

The next step was validation of the assay using 317 samples from the TB specimen repository, representing patients from Vietnam, South Africa, and Peru. A sensitivity of 80% and specificity of 65% was observed, and performance was unaffected by HIV status.

The addition of a fifth marker to the assay, host antibodies against TB antigen Ag85B, resulted in sensitivity of 86% and specificity of 69%. Further improvements could be seen by the addition of other markers, with the team aiming to increase the marker panel up to a six- to ten-plex assay in the future.

A paradigm shift

"The approach taken to create this triage test - first identifying multiplexed biomarkers that provide a highly specific signature for a disease and then designing an assay to achieve endpoints that have been established by clinical need - represents a paradigm shift in the way that diagnostic tests are developed, …," said Wyss Founding Director Donald Ingber, M.D., Ph.D. in a recent press release.

Further work will be needed to refine the assay, but these results are promising and demonstrate the feasibility of the test meeting the WHO guidelines in the future. 


Meet The Author
Anna MacDonald
Anna MacDonald
Science Writer
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