Evaluation of Host Serum Protein Biomarkers of Tuberculosis in sub-Saharan Africa

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.

Activation Phenotype of Mycobacterium tuberculosis-Specific CD4+ T Cells Promoting the Discrimination Between Active Tuberculosis and Latent Tuberculosis Infection

“…Meanwhile, immunodiagnostics has received considerable attention as an alternative for discrimination of MTB infection status in recent years (63)(64)(65)(66)(67)(68)(69)(70). Nevertheless, the identified biomarkers including proteins and cytokines in serum or plasma for diagnostic aim may not be specific for TB due to the influence brought by other immune related diseases such as infection and autoimmune diseases (71)(72)(73)(74)(75)(76)(77). Thus, an intensified search for suitable host-specific biomarkers targeting TB diagnostic purpose was urgently needed (78).…”

Serum Biomarker Profile Including CCL1, CXCL10, VEGF, and Adenosine Deaminase Activity Distinguishes Active From Remotely Acquired Latent Tuberculosis

“…Activity measurement of the enzyme adenosine deaminase (ADA) and its two isoforms (ADA1 and ADA2) in a variety of biological fluids has been suggested to aid in the diagnosis of ATB; however, ADA activity in serum has never been used to distinguish ATB from LTBI (19)(20)(21)(22)(23). Several studies exploring the use of inflammatory serum cytokines involved in Mtb infection have been performed (24)(25)(26)(27)(28)(29), with inconsistent conclusions for cytokine production in Mtb-specific stimulated CD4 + and CD8 + T cells (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). Most of these studies showed that the discriminative value of a single marker is limited.…”

Past and Present Approaches to Diagnosis of Active Pulmonary Tuberculosis

“…Active TB predictive biosignatures included; “IL-6, MIP-1β, VEGF and saliva G-CSF and MIP-1α” ( 60 ) in a Ugandan population. In a South African study, the predictive biosignature among the HIV co-infected patients included IFN-gamma, fibrinogen, IFN- alpha-2, MMP-2 ( 61 ), and IL-1RA; ApoA-1, CFH, CRP, IFN-g, IP-10, SAA, and transthyretin ( 62 ).…”