Estimating the disease burden ascribed to specific enteropathogens
Authors: Halvor Sommerfelt
Journal: The Lancet Global Health (2021)

Julia Baker and colleagues1Baker JM Hasso-Agopsowicz M Pitzer VE et al.Association of enteropathogen detection with diarrhoea by age and high versus low child mortality settings: a systematic review and meta-analysis.Lancet Glob Health. 2021; 9: e1402-e1410Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar report a systematic review and meta-analysis (SRMA) in The Lancet Global Health, which informs the estimation of disease burden ascribed to individual diarrhoeal pathogens. When accurate, such estimates provide evidence to prioritise the development and deployment of rapid diagnostic tests, targeted treatment, and vaccines. Their review yields summary odds ratios (ORs), which compare the occurrence of pathogens in stool of individuals with and without diarrhoea. The attributable fraction among the exposed (ie, infected patients), adequately approximated as 1 – 1/OR, can, by multiplication with the proportion of patients with diarrhoea who shed the microorganism in question, give us its population attributable proportion (PAF). PAF reflects the proportion of illness that can be removed from a population if it had full access to 100% effective treatment or rendered completely immune by vaccination. While PAF and attributable incidence2Kotloff KL Nataro JP Blackwelder WC et al.Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study.Lancet. 2013; 382: 209-222Summary Full Text Full Text PDF PubMed Scopus (2116) Google Scholar, 3Platts-Mills JA Babji S Bodhidatta L et al.Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED).Lancet Glob Health. 2015; 3: e564-e575Summary Full Text Full Text PDF PubMed Scopus (520) Google Scholar might provide the best basis for prioritising interventions in the studied populations, this SRMA focuses on the OR.1Baker JM Hasso-Agopsowicz M Pitzer VE et al.Association of enteropathogen detection with diarrhoea by age and high versus low child mortality settings: a systematic review and meta-analysis.Lancet Glob Health. 2021; 9: e1402-e1410Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar The OR, in principle, is independent of the prevalence of the infection; thus, it is more generalisable than PAF and attributable incidence. Studies of cause-specific disease burden should, in addition to these estimates,2Kotloff KL Nataro JP Blackwelder WC et al.Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study.Lancet. 2013; 382: 209-222Summary Full Text Full Text PDF PubMed Scopus (2116) Google Scholar follow suit, and present ORs, as does the Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED), albeit only in its appendix.3Platts-Mills JA Babji S Bodhidatta L et al.Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED).Lancet Glob Health. 2015; 3: e564-e575Summary Full Text Full Text PDF PubMed Scopus (520) Google Scholar The OR not only depends on the microbe's inherent traits, but also on the population studied. Age-dependent biological features, such as receptor maturity and density, might play a role, but the most important modifiable factor that influences microbes’ ability to cause disease is immunity—whether passively transferred from mother to baby or induced actively by natural infection or vaccination. It might prevent illness by reducing the risk of becoming infected, which does not affect the OR, but for many pathogens, immunity primarily reduces the risk of falling ill if infected; the OR is then correspondingly reduced. Thus, the OR, a measure of epidemiological pathogenicity, is not only a characteristic of the microbe itself; it also captures the degree to which individuals are susceptible to illness once infected. This understanding is important when synthesising evidence from different study populations and supports the SRMA's stratification on age and setting.1Baker JM Hasso-Agopsowicz M Pitzer VE et al.Association of enteropathogen detection with diarrhoea by age and high versus low child mortality settings: a systematic review and meta-analysis.Lancet Glob Health. 2021; 9: e1402-e1410Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar As the understanding of microbes and the epidemiology of the infections they cause expand, important information regarding new subtypes, many of which have different pathogenic potentials, emerge. Enterotoxigenic Escherichia coli (ETEC) illustrate how subtype and population characteristics can influence microbes’ epidemiological pathogenicity. ETEC produce one or more of three distinct enterotoxins, STh, STp and LT. Although either subtype seems to be pathogenic for immunologically naive travellers to endemic countries4Behrens RH Cramer JP Jelinek T et al.Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala.Lancet Infect Dis. 2014; 14: 197-204Summary Full Text Full Text PDF PubMed Scopus (64) Google Scholar and in volunteers,5Hanevik K Chen WH Talaat KR Porter C Bourgeois L The way forward for ETEC controlled human infection models (CHIMs).Vaccine. 2019; 37: 4794-4799Crossref PubMed Scopus (6) Google Scholar in children of low-income and middle-income countries, their epidemiological pathogenicity differs and seems to be age dependent. High-quality studies2Kotloff KL Nataro JP Blackwelder WC et al.Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study.Lancet. 2013; 382: 209-222Summary Full Text Full Text PDF PubMed Scopus (2116) Google Scholar, 3Platts-Mills JA Babji S Bodhidatta L et al.Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED).Lancet Glob Health. 2015; 3: e564-e575Summary Full Text Full Text PDF PubMed Scopus (520) Google Scholar, 6Valentiner-Branth P Steinsland H Fischer TK et al.Cohort study of Guinean children: incidence, pathogenicity, conferred protection, and attributable risk for enteropathogens during the first 2 years of life.J Clin Microbiol. 2003; 41: 4238-4245Crossref PubMed Scopus (80) Google Scholar, 7Mansour A Shaheen HI Amine M et al.Pathogenicity and phenotypic characterization of enterotoxigenic Escherichia coli isolates from a birth cohort of children in rural Egypt.J Clin Microbiol. 2014; 52: 587-591Crossref PubMed Scopus (13) Google Scholar show that most strains producing only LT (LT ETEC) are not associated with diarrhoea, except on the first encounter,6Valentiner-Branth P Steinsland H Fischer TK et al.Cohort study of Guinean children: incidence, pathogenicity, conferred protection, and attributable risk for enteropathogens during the first 2 years of life.J Clin Microbiol. 2003; 41: 4238-4245Crossref PubMed Scopus (80) Google Scholar, 7Mansour A Shaheen HI Amine M et al.Pathogenicity and phenotypic characterization of enterotoxigenic Escherichia coli isolates from a birth cohort of children in rural Egypt.J Clin Microbiol. 2014; 52: 587-591Crossref PubMed Scopus (13) Google Scholar but many of those that express ST, irrespective of whether they also produce LT, are pathogenic, even in older children. This is the main reason the Global Enteric Multicenter Study (GEMS) and MAL-ED combine all ST producers, irrespective of whether they also produce LT, into one category (ST ETEC).2Kotloff KL Nataro JP Blackwelder WC et al.Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study.Lancet. 2013; 382: 209-222Summary Full Text Full Text PDF PubMed Scopus (2116) Google Scholar, 3Platts-Mills JA Babji S Bodhidatta L et al.Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED).Lancet Glob Health. 2015; 3: e564-e575Summary Full Text Full Text PDF PubMed Scopus (520) Google Scholar But, the ability to distinguish between subtypes is important to give more accurate estimates of ORs, as Baker and colleagues point out in their Article.1Baker JM Hasso-Agopsowicz M Pitzer VE et al.Association of enteropathogen detection with diarrhoea by age and high versus low child mortality settings: a systematic review and meta-analysis.Lancet Glob Health. 2021; 9: e1402-e1410Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar The only three high-quality epidemiological studies that distinguish STh from STp8Porat N Levy A Fraser D Deckelbaum RJ Dagan R Prevalence of intestinal infections caused by diarrheagenic Escherichia coli in Bedouin infants and young children in Southern Israel.Pediatr Infect Dis J. 1998; 17: 482-488Crossref PubMed Scopus (57) Google Scholar, 9Steinsland H Valentiner-Branth P Perch M et al.Enterotoxigenic Escherichia coli infections and diarrhea in a cohort of young children in Guinea-Bissau.J Infect Dis. 2002; 186: 1740-1747Crossref PubMed Scopus (80) Google Scholar, 10Vidal RM Muhsen K Tennant SM et al.Colonization factors among enterotoxigenic Escherichia coli isolates from children with moderate-to-severe diarrhea and from matched controls in the Global Enteric Multicenter Study (GEMS).PLoS Negl Trop Dis. 2019; 13e0007037Crossref PubMed Scopus (31) Google Scholar show that SThLT ETEC have ORs exceeding 2, while it is closer to 0·5 for STpLT ETEC—the seeming protection probably resulting from this microbial bystander being diluted in the stools of children with diarrhoea of another cause. Pooling SThLT and STpLT ETEC into one category therefore underestimates the true OR. Many studies that use molecular detection methods unnecessarily refrain from reporting on the distinction between STh and STp. Meta-analyses, including the SRMA,1Baker JM Hasso-Agopsowicz M Pitzer VE et al.Association of enteropathogen detection with diarrhoea by age and high versus low child mortality settings: a systematic review and meta-analysis.Lancet Glob Health. 2021; 9: e1402-e1410Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar rely on their findings and might therefore underestimate the true ETEC disease burden. Systematic reviews must strike a balance between inclusiveness to represent bigger and more representative populations versus restriction to high-quality studies. Acknowledging the authors’ transparency in presenting study characteristics, it seems they err towards inclusiveness, possibly at the expense of quality, with one-quarter of the studies having a validity score of less than 3.1Baker JM Hasso-Agopsowicz M Pitzer VE et al.Association of enteropathogen detection with diarrhoea by age and high versus low child mortality settings: a systematic review and meta-analysis.Lancet Glob Health. 2021; 9: e1402-e1410Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar Their estimates might therefore not be more appropriate than those generated by large multicountry studies such as GEMS2Kotloff KL Nataro JP Blackwelder WC et al.Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study.Lancet. 2013; 382: 209-222Summary Full Text Full Text PDF PubMed Scopus (2116) Google Scholar and MAL-ED.3Platts-Mills JA Babji S Bodhidatta L et al.Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED).Lancet Glob Health. 2015; 3: e564-e575Summary Full Text Full Text PDF PubMed Scopus (520) Google Scholar It is, however, reassuring that the data from these two studies are given substantial weight in the SRMA.1Baker JM Hasso-Agopsowicz M Pitzer VE et al.Association of enteropathogen detection with diarrhoea by age and high versus low child mortality settings: a systematic review and meta-analysis.Lancet Glob Health. 2021; 9: e1402-e1410Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar More such high-quality studies should be carried out and count heavily when future SRMAs synthesise data. Better diagnostics, treatment, and prevention should first be developed for the enteric infections that are responsible for the bulk of impeded child development and premature death. By focusing on more severe diarrhoea, studies such as GEMS can quantify each enteropathogen's ability to inflict a nutritional insult and kill.2Kotloff KL Nataro JP Blackwelder WC et al.Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study.Lancet. 2013; 382: 209-222Summary Full Text Full Text PDF PubMed Scopus (2116) Google Scholar, 11Nasrin D, Blackwelder WC, Sommerfelt H, et al. Pathogens associated with linear growth faltering in children with diarrhea and impact of antibiotic treatment: the Global Enteric Multicenter Study. J Infect Dis (in press).Google Scholar Such studies and the SRMAs which synthesise their data will provide even stronger evidence for prioritising interventions to promote child health, development and survival in low-income and middle-income countries. I declare a patent for an ETEC vaccine component. Association of enteropathogen detection with diarrhoea by age and high versus low child mortality settings: a systematic review and meta-analysisIncorporating effect estimates from diverse data sources into diarrhoeal disease cause and burden of disease models is needed to produce more representative estimates. Full-Text PDF Open Access