Investigating the burden of acute and chronic typhoid fever and the relative contribution to ongoing transmission of salmonella typhi in three urban sites in Africa and Asia
Keywords: salmonella
Asia
vaccines
epidemiology
Africa
antimicrobial resistance
typhoid fever

Enteric fever is a serious public health concern in many low- and middle-income countries. However, numerous data gaps exist concerning the epidemiology and transmission of Salmonella Typhi and Paratyphi A, the causative agents of enteric fever, in different global contexts. Facility-based passive surveillance for enteric fever underestimates true incidence of disease as not all cases of infection can be captured. In typhoid endemic sites, where febrile illness is a common clinical syndrome, there are many healthcare facilities that individuals utilise when they develop fever. In addition, blood-culture, the current gold-standard for typhoid diagnosis, is not collected on all individuals who seek healthcare within a healthcare facility. Blood-culture also has a low sensitivity for diagnosis and is affected by prior antimicrobial usage and the volume of blood collected. A proportion of acutely infected individuals develop chronic carriage of Salmonella Typhi with the pathogen resident in the gall bladder. These individuals continue to shed the bacteria in their stool contributing to ongoing transmission within their community. It is not known what the prevalence of these chronic carriers are in endemic sites and the relative contribution of transmission from carriers compared with acutely infected individuals.
This thesis provides data from a comprehensive surveillance study designed to answer some of these data gaps. A demographic census was used to enumerate an open cohort of approximately 100,000 individuals in each of three urban sites in Africa (Malawi) and Asia (Nepal and Bangladesh). Facility-based passive surveillance was conducted for two years with blood culture collection for febrile illness. Healthcare utilisation surveys carried out in a sample of households enabled adjustment of incidence estimates for healthcare-seeking behaviour. A community-based serological survey was performed enrolling over 15,000 randomly selected individuals, stratified by age, with paired blood samples collected three months apart throughout a 12-month period to provide data on serologically defined infections and to identify the prevalence of chronic carriers.
Between November 2016 and December 2018, 423, 618 participants were enrolled in the demographic census across the three sites. From this population, 625 S. Typhi and 107 S. Paratyphi A isolates were cultured from the blood of 11,529 febrile patients. Multi-drug resistance was observed in 44% and fluoroquinolone resistance in 61% of S. Typhi isolates. The overall crude incidence of blood culture confirmed S. Typhi per 100,000 person-years of observation was 58 (95% confidence interval (CI): 48-70) in Malawi, 74 (95% CI: 62-87) in Nepal, and 161 (95% CI: 145-179) in Bangladesh. Adjusted incidence (with adjustment made for healthcare-seeking behaviour, blood culture collection of eligible individuals and blood culture sensitivity) was highest in the 5-9-year age group in all three sites, with overall adjusted incidence per 100,000 person-years of observation of 482 (95% CI: 398-578) in Malawi, 947 (95% CI: 801-1,111) in Nepal and 1,054 (95% CI: 948-1,169) in Bangladesh. Incidence rates per 100,000 person-years estimated from seroconversion episodes in serological surveillance were 3382 (95% CI: 2845-3991) in Malawi, 4326 (95% CI: 3753-4962) in Nepal and 3157 (95% CI: 2786-3565) in Bangladesh, suggesting higher rates of infection than captured through passive surveillance. Only one individual in Bangladesh was defined as a chronic carrier, with the highest rate of stool shedding identified in acutely infected individuals at the time of bacteraemia.
The design of this study applying multiple surveillance methodologies, and adjustment for known factors that lead to underestimation, has enabled a comprehensive estimation of incidence demonstrating S. Typhi to be a major cause of febrile illness particularly among the youngest children in the populations studied, with S. Paratyphi A contributing to disease incidence in the Asian sites. High rates of disease in combination with the observed high rates of antimicrobial resistance, necessitate multiple intervention strategies to achieve global control of these pathogens through development in water and sanitation infrastructure, the introduction of efficacious typhoid conjugate vaccines and the development of vaccines for S. Paratyphi A.