Abstract
An accurate urine test for diverse populations with active tuberculosis could be transformative for preventing TB deaths. Urinary liporabinomannan (LAM) testing has been previously restricted to HIV co-infected TB patients. In this study we evaluate urinary LAM in HIV negative, pediatric and adult, pulmonary and extrapulmonary tuberculosis patients. We measured 430 microbiologically confirmed pretreatment tuberculosis patients and controls from Peru, Guinea Bissau, Venezuela, Uganda and the United States using three monoclonal antibodies, MoAb1, CS35, and A194, which recognize distinct LAM epitopes, a one-sided immunoassay, and blinded cohorts. We evaluated sources of assay variability and comorbidities (HIV and diabetes). All antibodies successfully discriminated TB positive from TB negative patients. ROAUC from the average of three antibodies’ responses was 0.90; 95% CI 0.87–0.93, 90% sensitivity, 73.5% specificity (80 pg/mL). MoAb1, recognizing the 5-methylthio-d-xylofuranose(MTX)-mannose(Man) cap epitope, performed the best, was less influenced by glycosuria and identified culture positive pediatric (N = 19) and extrapulmonary (N = 24) patients with high accuracy (ROAUC 0.87, 95% CI 0.77–0.98, 0.90 sensitivity 0.80 specificity at 80 pg/mL; ROAUC = 0.96, 95% CI 0.92–0.99, 96% sensitivity, 80% specificity at 82 pg/mL, respectively). The MoAb1 antibody, recognizing the MTX-Man cap epitope, is a novel analyte for active TB detection in pediatric and extrapulmonary disease.
Highlights
IntroductionLAM is a complex molecule and differences in its antigenic properties in the body fluids of infected patients, and animal models, compared to LAM produced by mycobacteria grown in vitro have been observed[7]
Measurement of the urinary TB carbohydrate antigen lipoarabinomannan has proved valuable for HIV positive patients with active pulmonary TB who have low CD4 counts[5]
Three anti-LAM antibodies MoAb1 IgG, CS35 IgG, A194 IgG were selected from a panel of 12 (Supplementary Table S1, Supplementary Methods) based on sensitivity, specificity and diversity of antigenic LAM epitopes using a previously published quantitative immunoassay described in Paris et al.[6] (Fig. 1, Supplementary Fig. S1)
Summary
LAM is a complex molecule and differences in its antigenic properties in the body fluids of infected patients, and animal models, compared to LAM produced by mycobacteria grown in vitro have been observed[7] It is not clear which of its epitopes would be suitable for a highly sensitive assay for both HIV positive and HIV negative patients across geographic regions that differ in the prevalence of genetic strains of mycobacterium. A second unresolved challenge is determining the absolute concentration range of LAM in urine for HIV negative and HIV positive active TB This is mandatory to establish the required sensitivity and quantitative range for ongoing and future development of point of care testing methods[5,8].
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