The Current Status of Enteric Fever Diagnostics and Implications for Disease Control

Enteric (typhoid) fever remains a problem in low- and middle-income countries that lack the infrastructure to maintain sanitation and where inadequate diagnostic methods have restricted our ability to identify and control the disease more effectively. As we move into a period of potential disease elimination through the introduction of typhoid conjugate vaccine (TCV), we again need to reconsider the role of typhoid diagnostics in how they can aid in facilitating disease control. Recent technological advances, including serology, transcriptomics, and metabolomics, have provided new insights into how we can detect signatures of invasive Salmonella organisms interacting with the host during infection. Many of these new techniques exhibit potential that could be further explored with the aim of creating a new enteric fever diagnostic to work in conjunction with TCV. We need a sustained effort within the enteric fever field to accelerate, validate, and ultimately introduce 1 (or more) of these methods to facilitate the disease control initiative. The window of opportunity is still open, but we need to recognize the need for communication with other research areas and commercial organizations to assist in the progression of these diagnostic approaches. The elimination of enteric fever is now becoming a real possibility, but new diagnostics need to be part of the equation and factored into future calculations for disease control.

Assessing the Feasibility of Typhoid Elimination

In 1993, the International Task Force on Disease Eradication classified the political will for typhoid eradication as “none.” Here we revisit the Task Force’s assessment in light of developments in typhoid vaccines and increasing antimicrobial resistance in Salmonella Typhi that have served to increase interest in typhoid elimination. Considering the requisite biological and technical factors for elimination, effective interventions exist for typhoid, and humans are the organism’s only known reservoir. Improvements in water supply, sanitation, hygiene, and food safety are critical for robust long-term typhoid control, and the recent Strategic Advisory Group of Experts on Immunization recommendation and World Health Organization prequalification should make typhoid conjugate vaccine more accessible and affordable in low-income countries, which will allow the vaccine to offer a critical bridge to quickly reduce burden. While these developments are encouraging, all current typhoid diagnostics are inadequate, having either poor performance characteristics, limited scalability, or both. No clear solution exists, and this should be viewed as a critical challenge to any elimination effort. Moreover, asymptomatic carriers and limited data and surveillance remain major challenges, and countries considering elimination campaigns will need to develop strategies to identify high-risk populations and to monitor progress over time. Finally, policymakers must be realistic in planning, learn from the planning failures of previous elimination and eradication efforts, and expect unforeseeable shocks and setbacks. In the end, if we assume neither unanticipated breakthroughs in typhoid control nor any chaotic shocks, history suggests that we should expect typhoid elimination to take decades.

Reproducible diagnostic metabolites in plasma from typhoid fever patients in Asia and Africa

Salmonella Typhi is the causative agent of typhoid. Typhoid is diagnosed by blood culture, a method that lacks sensitivity, portability and speed. We have previously shown that specific metabolomic profiles can be detected in the blood of typhoid patients from Nepal (Näsström et al., 2014). Here, we performed mass spectrometry on plasma from Bangladeshi and Senegalese patients with culture confirmed typhoid fever, clinically suspected typhoid, and other febrile diseases including malaria. After applying supervised pattern recognition modelling, we could significantly distinguish metabolite profiles in plasma from the culture confirmed typhoid patients. After comparing the direction of change and degree of multivariate significance, we identified 24 metabolites that were consistently up- or down regulated in a further Bangladeshi/Senegalese validation cohort, and the Nepali cohort from our previous work. We have identified and validated a metabolite panel that can distinguish typhoid from other febrile diseases, providing a new approach for typhoid diagnostics.