The Severe Typhoid Fever in Africa Program: Study Design and Methodology to Assess Disease Severity, Host Immunity, and Carriage Associated With Invasive Salmonellosis

Abstract

Background Invasive salmonellosis is a common community-acquired bacteremia in persons residing in sub-Saharan Africa. However, there is a paucity of data on severe typhoid fever and its associated acute and chronic host immune response and carriage. The Severe Typhoid Fever in Africa (SETA) program, a multicountry surveillance study, aimed to address these research gaps and contribute to the control and prevention of invasive salmonellosis. Methods A prospective healthcare facility–based surveillance with active screening of enteric fever and clinically suspected severe typhoid fever with complications was performed using a standardized protocol across the study sites in Burkina Faso, the Democratic Republic of Congo (DRC), Ethiopia, Ghana, Madagascar, and Nigeria. Defined inclusion criteria were used for screening of eligible patients for enrollment into the study. Enrolled patients with confirmed invasive salmonellosis by blood culture or patients with clinically suspected severe typhoid fever with perforation were eligible for clinical follow-up. Asymptomatic neighborhood controls and immediate household contacts of each case were enrolled as a comparison group to assess the level of Salmonella-specific antibodies and shedding patterns. Healthcare utilization surveys were performed to permit adjustment of incidence estimations. Postmortem questionnaires were conducted in medically underserved areas to assess death attributed to invasive Salmonella infections in selected sites. Results Research data generated through SETA aimed to address scientific knowledge gaps concerning the severe typhoid fever and mortality, long-term host immune responses, and bacterial shedding and carriage associated with natural infection by invasive salmonellae. Conclusions SETA supports public health policy on typhoid immunization strategy in Africa.

The Surveillance for Enteric Fever in Asia Project (SEAP), Severe Typhoid Fever Surveillance in Africa (SETA), Surveillance of Enteric Fever in India (SEFI), and Strategic Typhoid Alliance Across Africa and Asia (STRATAA) Population-based Enteric Fever Studies: A Review of Methodological Similarities and Differences

“…Within each of the SETA study areas, patients were recruited at healthcare facilities across multiple tiers. Each site included a referral hospital, which, to be included in SETA, had to be equipped with imaging and surgical capacity to identify and treat intestinal perforations, as well as primary or secondary healthcare centers, which enrolled less severe febrile subjects using broader enrollment criteria [ 11 ]. Each recruitment center was assigned a geographic catchment area from which a defined population was identified.…”

“…Patients with blood culture–confirmed Salmonella Typhi, Salmonella Paratyphi, and non-Typhi Salmonella serotype infections were recruited into the long-term follow-up component of the study. Two healthy household members and 4 healthy neighborhood controls were enrolled for each case, and the entire cohort was followed for 1 year with contact points at predefined intervals to collect clinical information, blood and stool samples, and cost-of-illness and quality-of-life assessments [ 11 ].…”

Methodological Considerations for Cost of Illness Studies of Enteric Fever

“…Each clinical case was matched to a blood culture–confirmed S. Typhi case by duration of fever, neighborhood, age proximity (± 5 years), and sex—factors that could be potential cost drivers—to better isolate variation in COI attributable to the difference between blood culture–confirmed vs clinically suspected but blood culture–negative cases. As SETA focused on severe typhoid fever, special cases suffering from nontraumatic terminal ileal gastrointestinal perforations (ie, clinically diagnosed typhoid fever gastrointestinal perforation), even in the absence of laboratory confirmation, were included as they are likely to have long recovery time and associated costs [ 10 ]. Depending upon self-reported recovery, follow-up was performed up to 7 times starting from 3 to 7 days after enrollment upon earliest availability of blood culture results and continued at 12–14, 28–30, 90 ± 7, 180 ± 7, 270 ± 7, and 360 ± 7 days.…”

A Multicenter Cost-of-Illness and Long-term Socioeconomic Follow-up Study in the Severe Typhoid Fever in Africa Program: Study Protocol

“…Consequently, TSAP was succeeded by the Severe Typhoid Fever in Africa (SETA) program. SETA implemented a surveillance program that will allow the collection of the information related to typhoid fever incidence as well as complications in several sites across sub-Saharan Africa by following up cases up to 360 days [18]. The program will establish surveillance for febrile illness at tertiary, secondary, and primary healthcare facilities where clinical and microbiological data will be collected from participants with suspected typhoid fever and febrile participants with invasive nontyphoidal Salmonella (iNTS).…”

“…The program will establish surveillance for febrile illness at tertiary, secondary, and primary healthcare facilities where clinical and microbiological data will be collected from participants with suspected typhoid fever and febrile participants with invasive nontyphoidal Salmonella (iNTS). The SETA research program, described elsewhere [18], will provide an opportunity to conduct COI and long-term socioeconomic studies (LT-SES) in Africa by sharing a common platform and resources used for typhoid fever surveillance. Typhoid fever cases identified through surveillance will serve as cohort participants for these 2 studies.…”