Estimating the proportion of hemolytic uremic syndrome cases in Shiga toxin-producing Escherichia coli cases – A systematic review and proportional meta-analysis

Abstract

Background: Shiga-toxin producing Escherichia coli (STEC) infection is a foodborne zoonotic infection causing a range of diseases, permanent injury and even death. STEC has been linked to large epidemics globally. While STEC can affect different organs of the human host, the kidneys are the primary site of pathological injury during infection. Hemolytic uremic syndrome (HUS) is a common sequela affecting the kidneys and can affect certain subpopulations disproportionately. This thesis aimed to estimate the cumulative incidence of HUS among symptomatic STEC cases, based on available data. Methods: I conducted a systematic review and meta-analysis to determine the overall and stratified cumulative incidence of HUS. I searched PubMed, Web of Science, Ovid® Embase and Scopus for published literature, followed by five grey literature databases, which were Google Scholar, INASP Journals Online project, OAIster, GreyGuide, and WHO IRIS. The inclusion criteria were human populations of all sociodemographic factors, as either confirmed or probable cases of symptomatic STEC infection. HUS was the condition of interest. Eligible records published in English, between 1 January 1990 and 14 January 2024 from all geographical regions were included. A second screener and I independently identified and included eligible studies in the systematic review. I extracted summary-level data on study information, STEC cases and HUS cases from included studies. A second reviewer and I assessed study quality of included records using tools by the Joanna Briggs Institute. To estimate the pooled cumulative incidence of HUS, I performed a random-effects meta-analysis for single proportions. To estimate the stratified cumulative incidence, I used subgroup analyses and meta-regression models for age, sex, STEC characteristics and study characteristics. Results: I identified 4,906 records from the literature searches, of which 269 studies (comprising 189,350 STEC cases aged 0 – 98 years) from 28 countries were included. The pooled cumulative incidence of HUS was 8.22% (95% CI, 7.82 – 8.61). In subgroup analyses, the cumulative incidence of HUS was highest among children aged between 0 and 4 years at 17.82% (95% CI, 14.57 – 21.07) and among female STEC cases at 13.03% (95% CI, 11.04 – 15.02). STEC O157 and co-infections with multiple serotypes were the most common serogroups among included studies. By study year, the highest cumulative incidence of HUS occurred between 2010 to 2014 at 14.79% (95% CI, 12.74 – 16.84). By study regions, the highest cumulative incidence of HUS was from the WHO European Region at 12.66% (95% CI, 11.47 – 13.85). The included studies were mostly high- quality studies. Age, sex, STEC serogroup, STEC genes, study year range and WHO Regions were significant predictors of cumulative incidence of HUS. Conclusion: The proportion of STEC cases that progress to HUS is relatively low. However, STEC cases are underestimated, and these proportions may overrepresent the true cumulative incidence estimates of the population. Some subpopulations had higher HUS incidence estimates, with age, sex, infecting STEC serogroup, STEC genes, study year range and region being significant predictors of STEC-HUS development. Thereby, these findings support current knowledge of STEC-HUS, provide important insights into STEC-HUS epidemiology, and can be used by clinical specialists and other stakeholders in research, policymaking and clinical guidance.