Updated Estimates of the Global, Regional and National Burden, and Etiology of Diarrheal Diseases Transmissible via Food: A Systematic Review and Meta-Analytical Modelling Study for the World Health Organization

Diarrheal disease is caused by diverse species of viruses, bacteria and protozo that are transmitted from different sources, including from contaminated food. Sustaining progress in reducing diarrheal illnesses and deaths, including vaccines and food safety measures, may require interventions targeting specific pathogens. In 2015, the WHO's published etiology-specific estimates by their Foodborne Disease Burden Epidemiology Reference Group (FERG) of the incidence and mortality of diarrheal diseases caused by 11 pathogens at global and regional scales in 2010. Since then, much new evidence has been published about the epidemiology of enteropathogens. This study aims to update estimates to the year 2021 with the addition of three pathogens (Rotavirus, <i>Cyclospora cayetanensis</i>, Enteroaggregative <i>E. coli</i> (EAEC)). For low- and middle-income countries (LMICs), we conducted a systematic review of publications that reported the prevalence of pathogens diagnosed in stool samples from asymptomatic subjects, community-detected and outpatient diarrhea cases, and those treated as inpatients. Hierarchical, mixed effects models were fitted to pathogen-specific prevalence data extracted from studies that met prespecified inclusion criteria, and population attributable fractions (PAF) were calculated from the model parameter estimates, adjusting for background asymptomatic transmission where appropriate. The PAFs were applied to previously estimated diarrhea incidence and mortality envelopes. A separate, parallel systematic review identified studies that estimated diarrhea incidence and mortality due to specific etiologies for high income countries (HICs) from surveillance data. Meta-analytical models were fitted to data extracted from these. Data from 324 studies published between 1990 and 2023 representing results from up to 540,000 samples were used in the meta-analysis. Globally the 14 pathogens were responsible for 2.2 billion diarrheal disease cases and 880,000 deaths in 2021, with the largest number of cases occurring in South-East Asia, the largest number of deaths in Sub-Saharan Africa, and Europe being the region with the lowest burden by both measures. We found the leading causes of diarrhea morbidity to be bacteria - <i>Shigella</i> (426.4 million cases in 2021), <i>Campylobacter</i> (291.4 million) and ETEC (259.7 million)) - as well as the protozoon <i>Giardia</i> (321.2 million), in contrast to previous studies that have ranked rotavirus and norovirus highest. Our estimates support a much higher morbidity burden for <i>Shigella</i> than previously estimated with an incidence rate for 2021 (5,400 per 100,000). This is due to its high PAF in outpatients aged ≥5 years. As causes of diarrhea mortality, our estimates rank rotavirus first (214,700 deaths in 2021), <i>Shigella</i> second (152,500), and <i>V. cholerae</i> (94,100) third, due to the latter's large PAF in inpatients aged ≥5 years and high case fatality rate. Caution is urged when interpreting PAFs for pathogens that elicit prolonged residual shedding following resolution of symptoms (e.g., norovirus, <i>Campylobacter</i>, <i>Giardia</i>). These findings, derived from rigorous systematic review and statistical methodologies and the largest database yet compiled of pathogen detection rates, will serve as inputs for the WHO's broader estimates of hazard-specific incidence and mortality from foodborne diseases and are made available to the research and policy-making communities to inform targeted strategies for global diarrheal disease control.