Andrews JR, Khanam F, Rahman N, Hossain M, Bogoch II, Vaidya K, Kelly M, Calderwood SB, Bhuiyan TR, Ryan ET, Qadri F, Charles RC.
There is a need for a reliable, simple diagnostic assay for typhoid fever. Available commercial serologic assays for typhoid fever have limited sensitivity and specificity. Using high-throughput immuno-screening technologies, we previously identified several immuno-reactive Salmonella Typhi antigens that appear promising for possible inclusion in a new diagnostic assay: hemolysin E (HlyE); cytolethal distending toxin (CdtB), S. Typhi LPS, and S. Typhi membrane preparation (MP).
We assessed plasma antibody responses (IgM, IgA, and IgG) to these antigens via ELISA in patients with suspected enteric fever, controls with other febrile illnesses, and healthy controls in Dhaka, Bangladesh and performed Tubex, Typhidot, Widal and the Typhoid/Paratyphoid test (TPTest) on each patient. Using machine learning methods, we identified a parsimonious serology signature to distinguish acute typhoid cases from controls and then validated our findings in an independent test cohort from Nepal of culture-confirmed S. Typhi patients and controls with other bacteremic illnesses.
We identified anti-MP IgG and IgA plasma responses to HlyE, LPS, and MP as important predictors of acute typhoid in the Bangladesh cohort. Using our Nepalese validation cohort, we demonstrated that the use of two antigens (HlyE and LPS) with one antibody isotype (IgA) could distinguish typhoid from other invasive bacterial infections (AUC 0.95; sensitivity 90%, specificity 92%). Use of a single antigen (HlyE) and isotype (IgA) had an AUC of 0.93.
Our results suggest that development of a diagnostic assay for acute typhoid fever focused on detecting IgA responses against HlyE, with or without LPS, is warranted.
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