Abstract
SummaryBackgroundImproved diagnostics for typhoid are needed; a typhoid controlled human infection model may accelerate their development and translation. Here, we evaluated a blood culture-PCR assay for detecting infection after controlled human infection with S. Typhi and compared test performance with optimally performed blood cultures.Methodology/Principal findingsCulture-PCR amplification of blood samples was performed alongside daily blood culture in 41 participants undergoing typhoid challenge. Study endpoints for typhoid diagnosis (TD) were fever and/or bacteraemia. Overall, 24/41 (59%) participants reached TD, of whom 21/24 (86%) had ≥1 positive blood culture (53/674, 7.9% of all cultures) or 18/24 (75%) had ≥1 positive culture-PCR assay result (57/684, 8.3%). A further five non-bacteraemic participants produced culture-PCR amplicons indicating infection; overall sensitivity/specificity of the assay compared to the study endpoints were 70%/65%. We found no significant difference between blood culture and culture-PCR methods in ability to identify cases (12 mismatching pairs, p = 0.77, binomial test). Clinical and stool culture metadata demonstrated that additional culture-PCR amplification positive individuals likely represented true cases missed by blood culture, suggesting the overall attack rate may be 30/41 (73%) rather than 24/41 (59%). Several participants had positive culture-PCR results soon after ingesting challenge providing new evidence for occurrence of an early primary bacteraemia.Conclusions/SignificanceOverall the culture-PCR assay performed well, identifying extra typhoid cases compared with routine blood culture alone. Despite limitations to widespread field-use, the benefits of increased diagnostic yield, reduced blood volume and faster turn-around-time, suggest that this assay could enhance laboratory typhoid diagnostics in research applications and high-incidence settings.
Highlights
A non-specific febrile illness caused by infection with Salmonella enterica serovar Typhi
A key limitation to improving the control of typhoid fever is the lack of reliable diagnostic tests.[2,3]
684 serial samples were collected for culturePCR from 41 challenge participants, 24 of whom were diagnosed with typhoid fever (TD)
Summary
A non-specific febrile illness caused by infection with Salmonella enterica serovar Typhi Typhi), is common in tropical regions.[1] A key limitation to improving the control of typhoid fever is the lack of reliable diagnostic tests.[2,3] In addition to confirming infection in individuals, accurate laboratory diagnostics are needed to ascertain true disease burden, to improve understanding of the natural history of infection in humans, and to evaluate vaccine efficacy.[1,2,4]. Diagnostic approaches for typhoid infection are broadly aimed either at directly detecting bacteria or bacterial products or measuring the host response in clinical samples.[2,4,5] Blood culture remains the diagnostic technique of choice, but only identifies 45e70% of confirmed cases, even with the availability of newer continuous automated culture systems.5e7 Serological tests including the Widal test are widely available in endemic settings, in the absence of paired clinical samples or background population serosurveillance data these tests perform poorly with low sensitivity and specificity.[5,8]
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