Abstract
Current diagnostic tests for typhoid fever, the disease caused by Salmonella Typhi, are poor. We aimed to identify serodiagnostic signatures of typhoid fever by assessing microarray signals to 4,445 S. Typhi antigens in sera from 41 participants challenged with oral S. Typhi. We found broad, heterogeneous antibody responses with increasing IgM/IgA signals at diagnosis. In down-selected 250-antigen arrays we validated responses in a second challenge cohort (n = 30), and selected diagnostic signatures using machine learning and multivariable modeling. In four models containing responses to antigens including flagellin, OmpA, HlyE, sipC, and LPS, multi-antigen signatures discriminated typhoid (n = 100) from other febrile bacteremia (n = 52) in Nepal. These models contained combinatorial IgM, IgA, and IgG responses to 5 antigens (ROC AUC, 0.67 and 0.71) or 3 antigens (0.87), although IgA responses to LPS also performed well (0.88). Using a novel systematic approach we have identified and validated optimal serological diagnostic signatures of typhoid fever.
Highlights
Typhoid fever is a febrile illness common in tropical regions of South and Southeast Asia, and is becoming increasingly recognized in sub-Saharan Africa (Crump et al, 2015; Wain et al, 2015)
All participants diagnosed with typhoid fever (TD) developed humoral responses; these responses were heterogeneous with few antigens represented across all samples (Figure 2)
TD participants exhibited a broader range of antibody responses for all three isotypes than participants not developing infection after challenge
Summary
Typhoid fever is a febrile illness common in tropical regions of South and Southeast Asia, and is becoming increasingly recognized in sub-Saharan Africa (Crump et al, 2015; Wain et al, 2015). While modern blood culture facilities may achieve a diagnostic sensitivity of 80% and a specificity approaching 100% (Mogasale et al, 2014; Waddington et al, 2014), sensitivity is often compromised due to a low concentration of organisms in the blood on clinical presentation and the use of antimicrobials before hospitalization (Wain et al, 1998; World Health Organisation, 2003). Typhi (Darton et al, 2014)
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