Abstract
Accurate and affordable point-of-care diagnostics for tuberculosis (TB) are needed. Host serum protein signatures have been derived for use in primary care settings, however validation of these in secondary care settings is lacking. We evaluated serum protein biomarkers discovered in primary care cohorts from Africa reapplied to patients from secondary care. In this nested case-control study, concentrations of 22 proteins were quantified in sera from 292 patients from Malawi and South Africa who presented predominantly to secondary care. Recruitment was based upon intention of local clinicians to test for TB. The case definition for TB was culture positivity for Mycobacterium tuberculosis; and for other diseases (OD) a confirmed alternative diagnosis. Equal numbers of TB and OD patients were selected. Within each group, there were equal numbers with and without HIV and from each site. Patients were split into training and test sets for biosignature discovery. A nine-protein signature to distinguish TB from OD was discovered comprising fibrinogen, alpha-2-macroglobulin, CRP, MMP-9, transthyretin, complement factor H, IFN-gamma, IP-10, and TNF-alpha. This signature had an area under the receiver operating characteristic curve in the training set of 90% (95% CI 86–95%), and, after adjusting the cut-off for increased sensitivity, a sensitivity and specificity in the test set of 92% (95% CI 80–98%) and 71% (95% CI 56–84%), respectively. The best single biomarker was complement factor H [area under the receiver operating characteristic curve 70% (95% CI 64–76%)]. Biosignatures consisting of host serum proteins may function as point-of-care screening tests for TB in African hospitals. Complement factor H is identified as a new biomarker for such signatures.
Highlights
Tuberculosis (TB) remains a leading cause of death from any infection worldwide
In 2016, a cohort study was published by the African European TB Consortium (AE-TBC) in which a seven-protein signature was reported that distinguished pulmonary TB from other respiratory diseases with an area under the receiver operating characteristic (ROC) curve of 91% [7]
We retested the signature and all 22 biomarkers from the AE-TBC study in cohorts from a casecontrol study that recruited adults presenting with features of TB to hospitals in Cape Town, South Africa, and Karonga, Malawi, and a TB clinic in Cape Town [8]
Summary
Tuberculosis (TB) remains a leading cause of death from any infection worldwide. The number of people accessing treatment is increasing each year, but in 2019 there were still an estimated 10 million cases and 1.4 million deaths [1]. In 2016, a cohort study was published by the African European TB Consortium (AE-TBC) in which a seven-protein signature was reported that distinguished pulmonary TB from other respiratory diseases with an area under the receiver operating characteristic (ROC) curve of 91% [7]. We retested the signature and all 22 biomarkers from the AE-TBC study in cohorts from a casecontrol study that recruited adults presenting with features of TB to hospitals in Cape Town, South Africa, and Karonga, Malawi, and a TB clinic in Cape Town (the “ILULU-TB study”) [8]. Equal numbers of patients were recruited with and without HIV to both TB and other diseases (OD) groups [8]. All OD patients were recruited from hospitals We considered this cohort to be reflective of patients presenting to secondary care. We hypothesised that the seven-protein signature from the AE-TBC study, or a new signature derived from the same 22 proteins, would distinguish TB from OD in patients from the ILULU-TB study, regardless of HIV status, with a similar degree of accuracy as in the AE-TBC study
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