Breaking the infection pathway for childhood diarrhoea
Authors: Richard Lilford
Journal: The Lancet Global Health (2024)

Large-scale water, sanitation, and hygiene (WASH) trials over the past 6 years have shown null or small effects on children's health in terms of survey-based diarrhoea or child growth. Given that the germ theory of disease holds, two hypotheses have been proposed to explain the unimpressive findings from intervention studies. First, it has been suggested that WASH interventions, notwithstanding their considerable costs, were of insufficient intensity or coverage. Second, children might acquire gastrointestinal disease by a route that is not interrupted by WASH interventions (from food perhaps). In The Lancet Global Health Andrew Mertens and colleagues1Mertens A Arnold BF Benjamin-Chung J et al.Is detection of enteropathogens and human or animal faecal markers in the environment associated with subsequent child enteric infections and growth: an individual participant data meta-analysis.Lancet Glob Health. 2024; 12: e433-e444Google Scholar provide evidence for the first of these hypotheses. The study builds on the authors' previous work,2Mertens A Arnold BF Benjamin-Chung J et al.Effects of water, sanitation, and hygiene interventions on detection of enteropathogens and host-specific faecal markers in the environment: a systematic review and individual participant data meta-analysis.Lancet Planet Health. 2023; 7: e197-e208Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar which capitalised on microbiological samples collected from the environment (water, hands, food, soil, and flies) in studies nested within recent WASH trials. The authors analysed the individual participant records from these nested studies. The authors found, using state of the science microbiological techniques, that the WASH interventions evaluated in the trials had little effect on levels of environmental contamination with pathological organisms. This finding suggests that the interventions simply failed to achieve sufficient intensity or coverage to break the infection pathway. The authors now report a study based on this individual participant data. In this study they pool observations across intervention and control groups, to examine the effect of contamination in the environment on child health in terms of diarrhoea and child growth. They conducted two substudies. In the first substudy, enteric pathogens were treated as a group thereby dichotomising the exposure variable into any enteric pathogen found versus no pathogen found. The authors found that environmental contamination with (one or more) enteric pathogens was associated with slightly lower linear growth in children. There was, however, no association between environmental contamination and survey-based diarrhoea rates. The second substudy was based on the fact that some of the original studies had collected samples of children's stool, which enabled Mertens and colleagues to look for specific associations between an organism in the environment and in the gut. The authors found concordance. However, most of the data (and all the statistically significant correlations) applied to parasites and viruses, rather than bacteria. Also, as mentioned by the authors, it could be that a colonised child contaminates the environment rather than the environment contaminating the child. That said, there is evidence from outside this study, for example, in connection with open defecation,3Lilford RJ The most important applied research paper this year? Perhaps any year?.https://clahrcwmblog.wordpress.com/2014/09/19/the-most-important-applied-research-paper-this-year-perhaps-any-year/Date: Sept 19, 2014Date accessed: January 16, 2024Google Scholar, 4Spears D Ghosh A Cumming O Open defecation and childhood stunting in India: an ecological analysis of new data from 112 districts.PLoS One. 2013; 8e73784 Crossref Google Scholar that environmental contamination does indeed increase infant risk. The study is therefore consistent with the theory that, at least for some pathogens, environmental contamination leads to human infection or infestation. Taken together, the two substudies provide evidence that environmental contamination was a source of infection and that the interventions were not sufficiently effective to improve rates of diarrhoea. How, then did these interventions improve child growth? A further finding in the data from Mertens and colleagues' study must be considered to understand this enigma. The authors found discordance between pathogen detection in stool and survey-based diarrhoea. This finding is in line with a 2021 study showing that survey-based diarrhoea is neither a sensitive nor a specific indicator for pathogens in the gut.5Rego R Watson S Alam MAU et al.A comparison of traditional diarrhoea measurement methods with microbiological and biochemical indicators: a cross-sectional observational study in the Cox's Bazar displaced persons camp.EClinicalMedicine. 2021; 42101205 Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar This finding is not surprising because survey-based diarrhoea is subject to considerable classification error.5Rego R Watson S Alam MAU et al.A comparison of traditional diarrhoea measurement methods with microbiological and biochemical indicators: a cross-sectional observational study in the Cox's Bazar displaced persons camp.EClinicalMedicine. 2021; 42101205 Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 6Rego R Watson S Ishengoma P Langat P Otieno HP Lilford R Effectiveness of SMS messaging for diarrhoea measurement: a factorial cross-over randomised controlled trial.BMC Med Res Methodol. 2020; 20: 174Crossref Scopus (5) Google Scholar As a result, studies based on this outcome are strongly biased towards the null.7Watson SI Rego RTT Hofer T Lilford RJ Evaluations of water, sanitation and hygiene interventions should not use diarrhoea as (primary) outcome.BMJ Glob Health. 2022; 7e008521 Crossref Google Scholar This finding, that survey-based diarrhoea is a poor signal for enteropathogens in the gut, has important corollaries, and would explain Mertens and colleagues finding of no correlation between any type of pathogen in the environment and survey-based diarrhoea. Survey-based diarrhoea should not be relied on as an important outcome in WASH evaluations.7Watson SI Rego RTT Hofer T Lilford RJ Evaluations of water, sanitation and hygiene interventions should not use diarrhoea as (primary) outcome.BMJ Glob Health. 2022; 7e008521 Crossref Google Scholar In future WASH studies, pathogens should be measured in stool (or sewage run off), because gut contamination is an important mediating variable for child population health.7Watson SI Rego RTT Hofer T Lilford RJ Evaluations of water, sanitation and hygiene interventions should not use diarrhoea as (primary) outcome.BMJ Glob Health. 2022; 7e008521 Crossref Google Scholar, 8Brown J Cumming O Stool-based pathogen detection offers advantages as an outcome measure for water, sanitation, and hygiene trials.Am J Trop Med Hyg. 2020; 102: 260-261Crossref PubMed Scopus (15) Google Scholar Studies should collect rare but relevant outcomes like child growth, admission for diarrhoea, and child death from diarrhoea, even if these studies are individually not large enough to measure these outcomes with high precision. The importance of the last corollary is exemplified by a 2014 individual patient meta-analysis across WASH trials.9Wolf J Prüss-Ustün A Cumming O et al.Systematic review: assessing the impact of drinking water and sanitation on diarrhoeal disease in low- and middle-income settings: systematic review and meta-regression.Trop Med Int Health. 2014; 19: 928-942Crossref PubMed Scopus (342) Google Scholar By combining study findings in a meta-analysis, the authors showed that WASH interventions, especially those which included the water component of WASH,9Wolf J Prüss-Ustün A Cumming O et al.Systematic review: assessing the impact of drinking water and sanitation on diarrhoeal disease in low- and middle-income settings: systematic review and meta-regression.Trop Med Int Health. 2014; 19: 928-942Crossref PubMed Scopus (342) Google Scholar, 10Lilford RJ Childhood diarrhoeal diseases – update of the famous Wolf review.https://clahrcwmblog.wordpress.com/2018/10/19/childhood-diarrhoeal-diseases/Date: Oct 19, 2018Date accessed: January 16, 2024Google Scholar were indeed effective in reducing infant death. Future studies should examine the causal chain from intervention to clinical outcome including analysis of stool or effluent and, where affordable, effects on environmental pathogens.11Watson SI Asamane E Lilford R et al.Protocol for a cluster randomised trial to evaluate a community-level complementary-food safety and hygiene and nutrition intervention in Mali: the MaaCiwara study.medRxiv. 2021; (published online March 31.) (preprint)https://doi.org/10.1101/2021.12.15.21267512Google Scholar This approach will allow us to learn what interventions are most effective and why, thereby enabling future policy makers to select the most propitious interventions at the right intensity and coverage. I declare no competing interests. Is detection of enteropathogens and human or animal faecal markers in the environment associated with subsequent child enteric infections and growth: an individual participant data meta-analysisOur findings support a causal chain from pathogens in the environment to infection to growth faltering, indicating that the lack of WASH intervention effects on child growth might stem from insufficient reductions in environmental pathogen prevalence. Studies measuring enteropathogens in the environment should subsequently measure the same pathogens in stool to further examine theories of change between WASH, faecal contamination, and health. Given that environmental pathogen detection was predictive of infection, programmes targeting specific pathogens (eg, vaccinations and elimination efforts) can environmentally monitor the pathogens of interest for population-level surveillance instead of collecting individual biospecimens. Full-Text PDF Open Access