Tuberculosis (TB) is one of the top 10 causes of death worldwide. In 2018, 10 million people fell ill with TB, and 1.5 million died from the disease (including 251 000 among people with HIV).
TB is curable, but highly contagious and difficult to diagnose. A person who develops active TB disease may experience only mild symptoms for many months, which often leads to delays in seeking care and further spread of the disease. People with active disease can infect 10–15 other people through close contact over the course of a year.
But even among people with TB who seek care, approximately 30% are not started on treatment right away due to diagnostic tests not being performed, loss of follow-up before test results are available, or because health care systems simply fail to respond to test results. Despite the introduction of a highly sensitive and specific test (GeneXpert MTB/RIF) that has a potential turn-around time of two hours, logistical constraints prevent access to testing in high TB prevalence areas. A more traditional way of diagnosing the disease, liquid culture, is even less accessible, prone to contamination, and takes weeks to deliver a result.
The high burden of undiagnosed TB fuels on-going transmission and poor treatment outcomes.
A triage test, or rule-out test, with low complexity that can be performed at the point-of-care (POC) in a laboratory-free manner by minimally trained health care workers, would identify those patients with the highest risk for active TB.
The test would quickly rule out the majority patients who do not suffer from TB but have other respiratory illnesses such as acute upper or lower respiratory tract infections or exacerbation of chronic obstructive pulmonary disease. A positive test result would indicate a high likelihood for active TB and i) focus health worker attention on this smaller number of patients and ii) might increase adherence of patients as well as primary health care workers to the diagnostic workup process, which includes return visits for GeneXpert or culture results, allowing a definitive diagnosis and quick initiation of treatment.
The performance of a 3-marker host signature for active TB is shown with sensitivity of 90.7% and specificity of 73%.
A perfect test would perform as shown in the dotted blue line and a test without any value in the red dotted line.
TriageTB was an international collaborative project that aimed to refine and prospectively evaluate the performance of a POC multi-biomarker test (MBT) as triage test on fingerstick blood utilizing upconverting phosphor technology at three African sites (i.e., in Uganda, The Gambia and South Africa) in a laboratory-free manner. As explained above, such a POC triage test for active TB could significantly speed up and streamline diagnostic approaches in resource-limited settings.
Our project built on extensive experience gained during previous EDCTP-funded projects, was based on strong biomarker data, an advanced user-friendly, rapid, multiplex test device and implementation expertise supported through EDCTP2.
In the projects leading up to TriageTB, we had evaluated a 6-marker triage biosignature on serum, developed an MBT strip assay with good performance on serum and adapted the assay for fingerstick capillary blood. All of these studies were implemented in Africa.
In TriageTB we validated the applied biosignature on samples from other areas, to ensure that our test can be applied globally. To assess wider geographical performance of the diagnostic signature on samples from TB patients and other respiratory diseases (ORD), we evaluated host signature performance using stored serum samples from Asia, South America and Eastern Europe. Results from that evaluation were used to inform biosignature refinement to make it globally applicable.
As the number of biomarkers on the strip are directly related to the ease of production and cost, we targeted the lowest possible number of biomarkers for the MBT strip in line with the targeted sensitivity and specificity. A 3-marker basic MBT strip which was already available at the beginning of the project and its performance were examined in parallel with other activities in this project. However, for global applications and to reach the required 90%/70% Sensitivity/Specificity according to WHO’s target product profile (TPP), an enhanced MBT strip using more than three markers was likely to be required.
The performance of the MBT test was compared to the results of the composite, gold standard diagnostic consisting of clinical features, sputum microbiology (smear, culture and GeneXpert), chest radiography and treatment response. This allowed a secondary aim to estimate the efficiency of different diagnostic work-up algorithms that include the POC screening test to make a definitive TB diagnosis. Participants were people with symptoms suggestive of active TB, who visit peripheral health care centers in high TB prevalence areas of Africa. The consortium carefully considered all necessary steps needed to meet the long-term goal of WHO endorsement and delivery in low- and middle-income countries.
Project strategy:
