Case Fatality Rate of Enteric Fever in Endemic Countries: A Systematic Review and Meta-analysis

Clinical Infectious Diseases, Aug 2018

Enteric fever is a febrile illness, occurring mostly in Asia and Africa, which can present as a severe and possibly fatal disease. Currently, a case fatality rate (CFR) of 1% is assumed when evaluating the global burden of enteric fever. Until now, no meta-analysis has been conducted to summarize mortality from enteric fever. Therefore, we conducted a systematic review and meta-analysis to aggregate all available evidence. We estimated an overall CFR of 2.49% (95% confidence interval, 1.65%–3.75%; n = 44), and a CFR in hospitalized patients of 4.45% (2.85%–6.88%; n = 21 of 44). There was considerably heterogeneity in estimates of the CFR from individual studies. Neither age nor antimicrobial resistance were significant prognostic factors, but limited data were available for these analyses. The combined estimate of the CFR for enteric fever is higher than previously estimated, and the evaluation of prognostic factors, including antimicrobial resistance, urgently requires more data.

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Case Fatality Rate of Enteric Fever in Endemic Countries: A Systematic Review and Meta-analysis

Abstract Enteric fever is a febrile illness, occurring mostly in Asia and Africa, which can present as a severe and possibly fatal disease. Currently, a case fatality rate (CFR) of 1% is assumed when evaluating the global burden of enteric fever. Until now, no meta-analysis has been conducted to summarize mortality from enteric fever. Therefore, we conducted a systematic review and meta-analysis to aggregate all available evidence. We estimated an overall CFR of 2.49% (95% confidence interval, 1.65%–3.75%; n = 44), and a CFR in hospitalized patients of 4.45% (2.85%–6.88%; n = 21 of 44). There was considerably heterogeneity in estimates of the CFR from individual studies. Neither age nor antimicrobial resistance were significant prognostic factors, but limited data were available for these analyses. The combined estimate of the CFR for enteric fever is higher than previously estimated, and the evaluation of prognostic factors, including antimicrobial resistance, urgently requires more data. typhoid fever, Salmonella enterica serovar Typhi, Salmonella enterica serovar Paratyphi, mortality, antimicrobial resistance Enteric (typhoid and paratyphoid) fever is caused by the bacteria Salmonella enterica serovars Typhi (S. Typhi) and Paratyphi A, B, and C (S. Paratyphi), which exclusively infect humans and are transmitted through the ingestion of contaminated food or water [1, 2]. Illness lasts 3–21 days on average and can be severe and possibly fatal [3, 4]. Infected individuals often present with high temperature, as well as abdominal discomfort with possible vomiting, and headache, and complications include neurologic involvement, intestinal perforation, and death [1, 4]. The burden of enteric fever mostly occurs in Africa and Asia, and globally the disease is estimated to cause about 17.8 million cases (95% confidence interval [CI], 6.9–48.4) and 129000 deaths (95% CI: 75000–208000) annually [5–8]. Morbidity and mortality rates due to enteric fever may increase further in light of rising antimicrobial resistance (AMR). Antimicrobial therapy was first introduced in 1948, with chloramphenicol-resistant isolates emerging within 2 years after its introduction [9, 10]. In the 1980s, continued and inappropriate use of ampicillin, chloramphenicol, and cotrimoxazole resulted in the emergence of multidrug-resistant strains of S. Typhi, which exhibit simultaneous resistance to all 3 antibiotics [11]. Currently, fluoroquinolones are the preferred treatment option, although decreased susceptibility to these antimicrobials has resulted in few remaining effective treatments for enteric fever [12, 13]. Sustainable infrastructural changes to tackle the root causes of enteric fever—unclean water and inadequate sanitation—remain out of reach for the majority of the population in most endemic countries. Therefore, vaccination has been championed as an effective control strategy for enteric fever [14]. However, this strategy has been hindered by the moderate efficacy of currently licensed vaccines for S. Typhi, which cannot be used in children <2 years old, and by the absence of a vaccine for the S. Paratyphi serovars. New vaccines, such as the Tybar typhoid conjugate vaccine (TCV), recently licensed in India and prequalified by the World Health Organization (WHO), are more efficacious and immunogenic in infants [15, 16]. The WHO’s Strategic Advisory Group of Experts recently recommended the introduction of TCVs to help control the burden of enteric fever, with priority given to countries with the highest burden of disease or high AMR [17]. Implementation of these novel vaccines requires a precise understanding of the burden—and, in particular, the mortality rate—associated with enteric fever. A recent analysis showed that between 86% and 98% of the disability-adjusted life-years caused by typhoid fever were attributed to death in 5 settings in India, Kenya, and Vietnam [18]. Moreover, uncertainty in the case fatality rate (CFR) was among the factors responsible for the largest proportion of uncertainty in the cost-effectiveness of TCV delivery strategies [18]. These findings underline the importance of a better understanding of enteric fever mortality. Therefore, we conducted a systematic review and meta-analysis to aggregate all available evidence on enteric fever mortality. We aimed to estimate the CFR, quantify the uncertainty, and explore the impact of potential prognostic factors, such as age and the presence of AMR. METHODS The reporting of this systematic review and meta-analysis adhere to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and an a priori specified protocol registered in PROSPERO (registration No. CRD42017057428) [19, 20]. Study Eligibility and Selection Eligible studies were identified according to predefined inclusion and exclusion criteria (Table 1). We searched MEDLINE, PubMed Central, Embase, and Web of Science for eligible articles using terms r (...truncated)


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Pieters, Zoë, Saad, Neil J, Antillón, Marina, Pitzer, Virginia E, Bilcke, Joke. Case Fatality Rate of Enteric Fever in Endemic Countries: A Systematic Review and Meta-analysis, Clinical Infectious Diseases, 2018, pp. 628-638, Volume 67, Issue 4, DOI: 10.1093/cid/ciy190