Typhoid Diagnostics: Looking Beneath the Surface

Typhoid fever is a systemic life-threatening infection caused by S. typhi, which specifically infects humans. It is a major public health concern in the developing world. The clinical symptoms of typhoid often overlap with other febrile infections, affecting timely and accurate diagnosis. The current gold standard, blood or bone marrow culture is used for definite diagnosis, however its utility is limited due to the requirement of dedicated culture facilities, technical expertise and prior antibiotic use. The existing serological tests demonstrate variable and suboptimal sensitivity and specificity, because of cross-reactivity exhibited by the conserved, somatic antigens of Lipopolysaccharides (LPS) and terminal regions of flagellin. The lack of accurate detection further leads to imprudent antibiotic use, causing complications and morbidity, and even contributes to drug resistance. This emphasises the need for superior tests for efficient typhoid diagnosis. The need has propelled the pursuit of infection-specific markers using high-yield approaches like proteomics, metabolomics, transcriptomics and potential markers have been enumerated. Bio-marker discovery serves as a start point in diagnostic development and the subsequent assessment of the diagnostic tests must be governed by pre-defined metrics to determine their accuracy and field-feasibility. The evaluation of sensitivity and specificity in endemic regions is particularly important. In the present review, we discuss the existing diagnostic modalities; their challenges and the novel approaches being utilised for the discovery of specific biomarkers. We also review the new diagnostic tests under development while also discussing the important metrics to be considered during development of improved tests.