Case fatality risk of diarrhoeal pathogens: a systematic review and meta-analysis

Abstract

Background: Estimates of the relative contribution of different pathogens to all-cause diarrhoea mortality are needed to inform global diarrhoea burden models and prioritize interventions. We aimed to investigate and estimate heterogeneity in the case fatality risk (CFR) of different diarrhoeal pathogens.

Methods: We conducted a systematic review and meta-analysis of studies that reported cases and deaths for 15 enteric pathogens published between 1990 and 2019. The primary outcome was the pathogen-specific CFR stratified by age group, country-specific under-5 mortality rate, setting, study year and rotavirus vaccine introduction status. We developed fixed-effects and multilevel mixed-effects logistic regression models to estimate the pooled CFR overall and for each pathogen, controlling for potential predictors of heterogeneity.

Results: A total of 416 studies met review criteria and were included in the analysis. The overall crude CFR for all pathogens was 0.65%, but there was considerable heterogeneity between and within studies. The overall CFR estimated from a random-effects model was 0.04% (95% CI: 0.026%-0.062%), whereas the pathogen-specific CFR estimates ranged from 0% to 2.7%. When pathogens were included as predictors of the CFR in the overall model, the highest and lowest odds ratios were found for enteropathogenic Escherichia coli (EPEC) [odds ratio (OR) = 3.0, 95% CI: 1.28-7.07] and rotavirus (OR = 0.23, 95% CI: 0.13-0.39), respectively.

Conclusion: We provide comprehensive estimates of the CFR across different diarrhoeal pathogens and highlight pathogens for which more studies are needed. The results motivate the need for diarrhoeal interventions and could help prioritize pathogens for vaccine development.

Keywords: Case fatality ratio; death; diarrhoea; heterogeneity; mortality.

Figure 1

Flowchart of the study selection process. In total, there were 901 individual observations for the 416 studies; some studies had multiple observations for different pathogens and/or age categories. There was substantial variation in the number of studies for each predictor category (Supplementary Figure S3, available as Supplementary data at IJE online).

Figure 2

Summary of crude case fatality risk estimate and associated binomial confidence intervals for each pathogen and overall. The total number of studies, cases and deaths for each pathogen is indicated, along with the pathogen-specific and overall I² measure of heterogeneity. The ‘other pathogens’ include Shiga toxin-producing Escherichia coli, enteroaggregative E. coli and E. coli (type not specified).

Figure 3

Fixed-effect model estimates of case fatality risk stratified by the predictors of interest overall and for seven select pathogens. The predictors include (a) age group, (b) country-specific under-5 mortality rate (U5MR), (c) study setting and (d) country rotavirus vaccine introduction status. The different line types represent the strata within each predictor. Estimates are plotted on the log10 scale for visualization purposes. Random-effect estimates are provided in Supplementary Figure S4 (available as Supplementary data at IJE online).

Figure 4

Odds ratios for overall multilevel mixed-effects logistic regression model. The reference explanatory categorical variable was Salmonella (pathogen), under-5 (age group); very low (U5MR strata), hospital (setting) and pre-vaccination (rotavirus vaccine introduction status). U5MR refers to country-specific under-5 mortality rate.

Figure 5

Summary of the risk of bias assessment for all included studies. Unfilled: high risk, lightly shaded: low risk and heavily shaded: unclear. Standardized lab test refers to whether studies employed standard laboratory tests.