Serologic diagnosis of tuberculosis by combining Ig classes against selected mycobacterial targets

•We examine serodiagnosis of active tuberculosis (TB) in a TB-endemic setting.•Antibody responses to some antigens often also reflect latent infection.•Anti-lipoarabinomannan (LAM) immunoglobulin (Ig)G shows the best discrimination between TB and non-TB subjects.•Selected five-antibody combinations further improve this performance.•Best combinations include different Ig classes and protein/non-protein antigens.

SummaryIntroductionAccurate, simple and cost-effective diagnostic tests are needed for diagnosis of active tuberculosis (TB). Serodiagnosis is attractive as it can be harnessed for point-of-care tests.MethodsWe evaluated, in a blinded fashion, the sensitivity and specificity of serologic immunoglobulin (Ig)G, IgA and/or IgM responses to Apa, heat shock protein (HSP) 16.3, HSP20, PE35, probable thiol peroxidase Tpx and lipoarabinomannan (LAM) in 42 HIV-negative South African pulmonary TB patients and 67 control individuals. The status of latent Mycobacterium tuberculosis infection (LTBI) among controls was defined through the TST and IFN-γ release assays (IGRAs). We evaluated 47 definite LTBI (IGRA+/LTBI), 8 putative LTBI (IGRA–/TST+) and 12 TB-uninfected (non-LTBI) subjects.ResultsIn contrast to anti-PE35 IgA, anti-PE35 IgG and particularly anti-Apa IgA, performances of anti-LAM IgG and selected anti-protein antibodies were less affected by inclusion of LTBI participants into the analysis. Anti-LAM IgG showed with a sensitivity/specificity of 71.4%/86.6% (p < 0.001) the best discrimination between TB and non-TB subjects. Selected five-antibody-combinations (including anti-LAM IgG, anti-LAM IgA and anti-Tpx IgG) further improved this performance to an accuracy exceeding 86%.ConclusionsAntibody responses to some Mycobacterium tuberculosis antigens often also reflect latent infection explaining the poor performance of antibody-based tests for active TB in TB-endemic settings. Our results suggest that rather a combination of serological responses against selected protein and non-protein antigens and different Ig classes should be investigated for TB serodiagnostics.