Estimating typhoid incidence from community-based serosurveys: a multicohort study

Abstract

Background: The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae (Salmonella enterica serovars Typhi and Paratyphi), is largely unknown in regions without blood culture surveillance. The aim of this study was to evaluate whether new diagnostic serological markers for typhoidal Salmonella can reliably estimate population-level incidence.

Methods: We collected longitudinal blood samples from patients with blood culture-confirmed enteric fever enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana between 2016 and 2021 and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to hemolysin E and S Typhi lipopolysaccharide. We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titres and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.

Findings: The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children younger than 5 years ranged between 58·5 per 100 person-years (95% CI 42·1-81·4) in Dhaka, Bangladesh, to 6·6 per 100 person-years (4·3-9·9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.

Interpretation: The approach described here has the potential to expand the geographical scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographical regions and time.

Funding: Bill & Melinda Gates Foundation.

Translations: For the Nepali, Bengali and Urdu translations of the abstract see Supplementary Materials section.

Figure 1

Longitudinal antibody dynamics among patients with blood culture-confirmed enteric fever Longitudinal antibody dynamics were fit to ELISA-measured antibody responses using Bayesian hierarchical models. (A) The light coloured lines are the observed individual antibody concentrations; each line indicates one patient. The dark solid line indicates the median and dotted lines indicate 95% credible intervals for the model-fitted antibody decay concentrations. The white horizontal line marks the median baseline antibody response for each antigen isotype. (B) The median model-fitted antibody trajectories for each age stratum. (C) The median model-fitted antibody trajectories for patients with Salmonella Typhi to Salmonella Paratyphi A. Ages are restricted to 5–15 years old because patients with S Paratyphi A were older than patients with S Typhi. HlyE=hemolysin E. LPS=lipopolysaccharide.

Figure 2

Antibody kinetics, peak response, and decay rate among blood culture-confirmed enteric fever cases by study country All comparisons are among children aged 5 to 15 years to account for the different age-distribution of cases across countries. (A) Median longitudinal antibody decay profiles fit to ELISA-measured antibody responses in each study country. (B) Box plots of model-predicted peak antibody responses and annual antibody decay rates across study countries. HlyE=hemolysin E. LPS=lipopolysaccharide.

Figure 3

Estimated seroincidence of typhoidal Salmonella by study community and age group Age groups are denoted by point shapes for the median, with lines indicating the 95% CI. Boxes reflect the height of the median estimate for the overall population-based serosurvey.

Figure 4

Comparison of estimates for crude and adjusted clinical enteric fever incidence with typhoidal Salmonella seroincidence Crude incidence reflects the number of culture-confirmed Salmonella Typhi and Salmonella Paratyphi A cases divided by the catchment population and time. Adjusted incidence accounts for imperfect sensitivity of blood culture and the proportion of acute febrile illnesses captured by the surveillance system. The horizontal axis indicates incidence, and scale differs for type of estimate. Estimates are shown for children younger than 5 years, for the serological estimates to coincide with the period of clinical surveillance.