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Background Typhoid fever remains a major source of morbidity and mortality in low-income settings. Its most feared complication is intestinal perforation. However, due to the paucity of diagnostic facilities in typhoid-endemic settings, including microbiology, histopathology, and radiology, the etiology of intestinal perforation is frequently assumed but rarely confirmed. This poses a challenge for accurately estimating burden of disease. Methods We recruited a prospective cohort of patients with confirmed intestinal perforation in 2016 and performed enhanced microbiological investigations (blood and tissue culture, plus tissue polymerase chain reaction [PCR] for Salmonella Typhi). In addition, we used a Poisson generalized linear model to estimate excess perforations attributed to the typhoid epidemic, using temporal trends in S. Typhi bloodstream infection and perforated abdominal viscus at Queen Elizabeth Central Hospital from 2008–2017. Results We recruited 23 patients with intraoperative findings consistent with intestinal perforation. 50% (11/22) of patients recruited were culture or PCR positive for S. Typhi. Case fatality rate from typhoid-associated intestinal perforation was substantial at 18% (2/11). Our statistical model estimates that culture-confirmed cases of typhoid fever lead to an excess of 0.046 perforations per clinical typhoid fever case (95% CI, .03–.06). We therefore estimate that typhoid fever accounts for 43% of all bowel perforation during the period of enhanced surveillance. Conclusions The morbidity and mortality associated with typhoid abdominal perforations are high. By placing clinical outcome data from a cohort in the context of longitudinal surgical registers and bacteremia data, we describe a valuable approach to adjusting estimates of the burden of typhoid fever.

Background Sepsis is an important cause of mortality globally, although population incidence estimates from low-income settings, including sub-Saharan Africa, are absent. We aimed to estimate sepsis incidence burden using routinely available data from a large urban hospital in Malawi. Methods We linked routine-care databases at Queen Elizabeth Central Hospital, Blantyre, Malawi, to provide admission and discharge data for 217 149 adults from 2013–2016. Using a definition of sepsis based on systemic inflammatory response syndrome criteria and Blantyre census population data, we calculated population incidence estimates of sepsis and severe sepsis and used negative binomial regression to assess for trends over time. Missing data were multiply imputed with chained equations. Results We estimate that the incidence rate of emergency department–attending sepsis and severe sepsis in adults was 1772 per 100 000 person-years (95% confidence interval [CI], 1754–1789) and 303 per 100 000 person-years (95% CI, 295–310), respectively, between 2013 and 2016, with a year-on-year decrease in incidence. In-hospital mortality for patients admitted to the hospital with sepsis and severe sepsis was 23.7% (95% CI, 22.7–24.7%) and 28.1% (95% CI, 26.1 – 30.0%), respectively, with no clear change over time. Conclusions Sepsis incidence is higher in Blantyre, Malawi, than in high-income settings, from where the majority of sepsis incidence data are derived. Worldwide sepsis burden is likely to be underestimated, and data from low-income countries are needed to inform the public health response., Sepsis epidemiology in sub-Saharan Africa (sSA) is poorly described. Using large databases from a Malawian teaching hospital, we present some of the first estimates of sepsis population incidence from sSA and find it to be high compared with high-income settings.

Typhoid fever, caused by infection with the human-restricted bacterial pathogen Salmonella enterica serovar Typhi, is a major cause of illness and mortality in regions of the world with limited access to improved water and sanitation [1]. Recent estimates have placed the global burden of typhoid fever at 11.9–26.9 million cases and 129 000–270 000 deaths per year [2–5]. Although the endemic burden of typhoid fever in South and Southeast Asia has long been recognized, less is known about the burden of disease in sub-Saharan Africa. In Malawi, as in much of sub-Saharan Africa, nontyphoidal Salmonella (NTS) serovars have been a much more common cause of bloodstream infections over the past 2 decades. Sequential epidemics of Salmonella enterica serovars Typhimurium and Enteritidis have been observed [6]. Salmonella Typhi represented just 2% (105/5061) of Salmonella isolates detected by sentinel surveillance at Queen Elizabeth Central Hospital (QECH) in Blantyre, the largest hospital in Malawi, between 1998 and 2004 [6]. Since 2011, however, there has been a substantial increase in the number of confirmed cases of Salmonella Typhi at QECH. The number of typhoid cases increased from 14 per year during 1998–2010 to 843 cases in 2013. This epidemic of typhoid fever has continued for at least 3 years [7] and coincides with numerous reports of ongoing epidemics of typhoid fever in settings across Africa [7–12]. These epidemics have closely followed the recent global emergence of the H58 haplotype of Salmonella Typhi [13]. The H58 lineage is highly clonal and differentiated from other haplotypes using a simple single nucleotide polymorphism–based typing scheme [14], and is associated with high levels of multidrug resistance [13, 15]. There are a variety of hypotheses that could explain the large increase in typhoid fever cases in Blantyre, including (1) an increase in population density in Blantyre beyond a critical threshold for transmission; (2) waning heterotypic immunity to Salmonella Enteritidis that is cross-protective against Salmonella Typhi; (3) an increase in the prevalence of multidrug resistant (MDR) strains, resulting in prolonged persistence; and (4) the emergence of the MDR H58 haplotype, which has become dominant in many places around the world and may be more transmissible than other strains [13]. The latter 2 hypotheses are tightly coupled, but describe slightly different mechanisms by which the H58 haplotype, and MDR strains more broadly, may have led to the outbreak. Mathematical models provide a platform for assessing the plausibility of these hypotheses to help direct future research efforts. We therefore adapted a mathematical model for the transmission dynamics of typhoid developed previously [16] by fitting to age-specific data on microbiologically confirmed cases of typhoid fever in Blantyre, Malawi. We modified the model to explore the 4 hypotheses outlined above, and examined whether each of them could explain the recent prolonged outbreak of typhoid fever cases in this setting.