New Blood Test Accurately Identifies Typhoid Fever Across Three Countries

Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A, infects millions annually in low-resource settings where sanitation is poor. Despite its burden, accurate diagnosis remains elusive. Blood culture — the gold standard — is slow, expensive, and largely inaccessible in endemic regions. The widely-used Widal test performs poorly, and commercial rapid diagnostics have failed to consistently exceed 90% sensitivity and specificity. Better diagnostic tools are urgently needed.

This study, embedded within the multisite SeroEpidemiology and Environmental Surveillance (SEES) Study, evaluated the diagnostic performance of IgA antibodies against two Salmonella Typhi antigens: pore-forming cytotoxin hemolysin E (HlyE) and lipopolysaccharide (LPS). Researchers measured plasma IgA concentrations via kinetic ELISA in 650 blood culture–confirmed enteric fever cases (568 Typhi, 82 Paratyphi A) and 263 febrile controls with laboratory-confirmed alternative etiologies, recruited from six hospitals across Bangladesh, Nepal, and Pakistan between 2016 and 2022.

The combined HlyE and LPS IgA biomarker panel achieved an area under the ROC curve (AUC) of 0.93 overall, with 86% specificity at a fixed 90% sensitivity threshold. LPS IgA alone performed nearly identically (AUC 0.92), while HlyE IgA alone was modestly lower. Importantly, in children under five years of age — a high-risk and diagnostically challenging group — the combined biomarkers outperformed either antigen individually, achieving an AUC of 0.96 versus 0.94 for HlyE and 0.93 for LPS alone. Performance was consistent across all three countries and across both Typhi and Paratyphi A serovars.

The study also modeled longitudinal antibody dynamics post-infection using hierarchical two-phase within-host models in a Bayesian framework. This analysis estimated how long after infection a patient would test positive, informing the risk of false positives from prior infection in high-incidence endemic settings — a critical real-world consideration.

These findings meaningfully extend prior single-site work and validate HlyE and LPS IgA as robust, geographically generalizable biomarkers for enteric fever. They support translation into point-of-care lateral flow formats already piloted in Pakistan and Bangladesh, which could dramatically improve diagnosis in resource-limited endemic settings. Caveats include the hospital-based design, age differences between cases and controls, and the absence of blood cultures in all controls.