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Little is known about the molecular epidemiology of Salmonella disease in persons residing in urban Sub-Saharan Africa. We hypothesize that there are unique genotypes of Salmonella in hotspots that cause invasive and diarrheal illnesses in children, perpetuated by specific host and environmental factors. We propose a 5-year study of population-based surveillance for invasive non-typhoidal Salmonella disease (NTS IBD) typhoid fever (TF), and NTS diarrhea (NTS D), in persons under 16 years of age in Mukuru, an urban Nairobi slum with 150,000 people. Surveillance will be undertaken at the two health care facilities serving the population. Blood and stool cultures will be obtained from age-eligible patients presenting with fever and diarrhea, respectively. Each Salmonella spp clinical isolate will undergo complete genetic sequencing and antibiotic susceptibility testing, and will be geographically mapped according to the residence of the patient. Cases of invasive and diarrheal illness will be enrolled into three case-control studies (one each for TF, invasive NTS and NTS diarrhea) to evaluate personal (including HIV and malaria co- infection, presence of sickle cell trait/disease, and nutritional status), household, and environmental risk factors. <p/>For each case age and sex-matched controls who present to the same medical facility for reasons other than fever, diarrhoea, or other enteric symptoms will be selected (1 for each TF case; 4 for NTS IBD; 4 for NTS D). We expect to enroll 93 cases of NTS IBD, 422 cases of TF, 109 cases of NTS D. <p/>With these data and activities we will 1) evaluate the incidence of invasive NTS, NTS diarrhea, and TF, as well as spatial and spatio-temporal clustering of these infections and their constituent genotypes; 2) define the transmission of NTS and TF in this setting by assessment of spatial and spatio-temporal clustering and of personal, household, and environmental risk factors for these infections and their genotypes; 3) assess the incidence and prevalence of antibiotic resistance among NTS and ST, spatial and spatio-temporal clustering of antibiotic-resistant isolates, and the association of antibiotic resistance with specific genotypes and personal, household, and environmental risk factors; 4) explore candidate genomic regions in NTS to better understand invasive NTS pathogenesis and to identify antigenic targets for future vaccines; and 5) prepare the site for future use of vaccines and non-vaccine preventive interventions by determining disease incidence, identifying potentially modifiable risk factors tha could lead to the design of interventions, and delineating risk factors and spatial-temporal clustering that facilitate targeting of interventions.
PUBLIC HEALTH RELEVANCE: Although in the long term improvement of water supply and provision of sanitation in urban slums will be vital in prevention and eventual control of salmonellosis and other enteric infections, practical short-term to medium-term measures are required to save lives and to minimize the suffering of populations in the slums. We aim to use spatial and spatio-temporal modeling, building on earlier work on typhoid fever surveillance in Kathmandu, Nepal (Karkey et al., 2010) and in a separate Kenyan urban slum (Breiman et al., 2012), to study the distribution and potential transmission patterns of Salmonella serovars associated with invasive disease and with diarrhea in Mukuru slum, 15 km East of Nairobi. We expect to map hotspots of disease that Ministry of Health can utilize to plan for possible interventions, including targeted vaccination. In addition using genomic data mining, we will seek to determine areas of the genome that may be implicated in the pathogenesis of invasive salmonella disease, as well as those that may code for epitopes that may be used as targets for future vaccine Interventions.