Estimating typhoid incidence from community-based serosurveys: A multicohort study in Bangladesh, Nepal, Pakistan and Ghana

Abstract

The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae, is largely unknown in regions lacking blood culture surveillance. New serologic markers have proven accurate in diagnosing enteric fever, but whether they could be used to reliably estimate population-level incidence is unknown. We collected longitudinal blood samples from blood culture-confirmed enteric fever cases enrolled from surveillance studies in Bangladesh, Nepal, Pakistan and Ghana and conducted cross-sectional sero-surveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to Hemolysin E (HlyE) and S. Typhi lipopolysaccharide (LPS). We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal sero-responses among enteric fever cases and used the joint distributions of the peak antibody titers and decay rate to estimate population-level incidence rates from cross-sectional serosurveys. The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The incidence of typhoidal Salmonella infection ranged between 41.2 per 100 person years (95% CI: 34.0-50.1) in Dhaka, Bangladesh to 5.8 (95% CI: 4.8-7.1) in Kavrepalanchok, Nepal and followed the same rank order as clinical incidence estimates. The approach described here has the potential to expand the geographic scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographic regions and time.

Seroincidence of Enteric Fever in Juba, South Sudan

“…Median HlyE IgG (10.4, IQR 6.1 – 12.7) and IgA (3.5, IQR 2.3 – 5.2) responses were elevated well above a North American pediatric control population (IgG: 0.16, IQR 0.07 – 0.35; IgA: 0.3, IQR 0.001 – 0.92) and were comparable to responses observed among blood-culture confirmed enteric fever cases 8-12 months after symptom onset (IgG: 12, IQR 5.9– 24; IgA: 4.4, IQR 2.2 – 9.4) (10) (Figure 1).…”

“…Each point is an individual sample. (B) Density of antibody responses among 1410 blood-culture confirmed enteric fever cases in Bangladesh, Nepal, Pakistan and Ghana between 8 and 12 months after symptom onset as reported in (10) and anegative control population of 1) 48 children aged 1-5 years who had first degree relatives with celiac disease, enrolled nationally and 2) 31 healthy controls, children and young adults aged 2-18 years, enrolled at Massachusetts General Hospital (17). The dashed blue line across all three panels represents the mean plus three standard deviations of HlyE IgA and IgG values observed in the pediatric control population.…”

“…We generated joint incidence estimates by combining the likelihood for HlyE IgA and IgG for each age stratum (0-4yr, 5 - 15yr, ≥16yr) using age-specific antibody dynamics. This method incorporates heterogeneity in antibody responses and explicitly accounts for measurement error and biologic noise as detailed in (10). We used the same method to generate individual-level incidence estimates based on quantitative HlyE IgA and IgG responses and used the exponential probability distribution to calculate the two-year and four-year cumulative incidence.…”

“…The eluate was stored frozen at -20 C until testing. We used the antibody dynamics modeled from a longitudinal cohort of 1410 blood cultureconfirmed enteric fever cases (10) to estimate enteric fever incidence as described in (12)(13)(14). In brief, we created a likelihood function for the observed cross-sectional population data based on antibody dynamics following blood-culture confirmed infection.…”

“…Hemolysin E (HlyE), a pore-forming toxin, has proven to be an accurate serologic marker for diagnosing typhoidal salmonella (4)(5)(6)(7)(8)(9). New serologic tools have recently been developed to measure population-level enteric fever incidence from cross-sectional serosurveys using anti-IgG and IgA responses HlyE (10). Here, we apply these tools to generate population-level enteric fever incidence estimates in Juba, South Sudan, using banked dried blood spots collected for a SARS-CoV-2 serosurvey (11).…”