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BackgroundUnderstanding pathogen-specific relationships with climate is crucial to informing interventions under climate change.MethodsWe matched spatiotemporal temperature, precipitation, surface water, and humidity data to data from a trial in rural Bangladesh that measured diarrhea and enteropathogen prevalence in children 0-2 years from 2012-2016. We fit generalized additive models and estimated percent changes in prevalence using projected precipitation under Shared Socio-Economic pathways describing sustainable development (SSP1), middle of the road (SSP2), and fossil fuel development (SSP5) scenarios.FindingsAn increase from 15°C to 30°C in weekly average temperature was associated with 5.0% higher diarrhea, 6.4% higher Norovirus, and 13.0% higher STEC prevalence. Above-median precipitation was associated with 1.27-fold (95% CI 0.99, 1.61) higher diarrhea; higher Cryptosporidium, tEPEC, ST-ETEC, STEC, Shigella, EAEC, Campylobacter, Aeromonas, and Adenovirus 40/41; and lower aEPEC, Giardia, Sapovirus, and Norovirus prevalence. Other associations were weak or null. Compared to the study period, diarrhea prevalence was similar under SSP1 (7%), 3.4% (2.7%, 4.3%) higher under SSP2, and 5.7% (4.4%, 7.0%) higher under SSP5. Prevalence of pathogens responsible for a large share of moderate-to-severe diarrhea in this setting (Shigella, Aeromonas) were 13-20% higher under SSP2 and SSP5.InterpretationHigher temperatures and precipitation were associated with higher prevalence of diarrhea and multiple enteropathogens; higher precipitation was associated with lower prevalence of some enteric viruses. Under likely climate change scenarios, we projected increased prevalence of diarrhea and enteropathogens responsible for clinical illness. Our findings inform pathogen-specific adaptation and mitigation strategies and priorities for vaccine development.FundingBill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases, National Heart, Lung, And Blood Institute, Stanford University School of Medicine, Chan Zuckerberg BiohubResearch in ContextEvidence before this studyWe searched Google Scholar and Scopus for studies published from January 1, 2000 to present using the following three queries: 1) child; and diarrhea OR “enteric infection”; and meteorological OR environmental OR “surface water” OR “standing water”; and risk AND/OR factors; 2) Climate AND change AND project* AND diarrhea OR diarrhoea; 3) climate AND change AND project* OR model AND enter* AND infect* AND E. coli. Studies generally focused on individual risk factors for diarrhea transmission or enteric infection, with an emphasis on temperature and precipitation. Studies found that higher temperatures were associated with higher incidence of bacterial diarrhea and lower incidence of viral diarrhea; few studies have investigated associations between temperature and parasitic diarrhea. Heavy rainfall, particularly after dry periods, was associated with higher diarrhea prevalence, though heavy rainfall during rainy seasons was found to protect against diarrhea incidence. Similarly, flooding of surface water and shallow wells was also associated with higher diarrhea prevalence. Very few studies investigated associations between diarrhea or enteropathogen carriage and surface water presence, or humidity. A recent individual participant meta-analysis of studies in 19 low- and middle-income countries found that higher precipitation was associated with a small decrease in enterotoxigenic E. coli (ETEC) and Campylobacter spp. prevalence and no difference in Shigella, Cryptosporidium, or Giardia, or enteric virus prevalence. Weekly average temperature increases of 10-40° C within the study period were associated with higher risk of Campylobacter, ETEC, Shigella, Cryptosporidium, Giardia, and adenovirus, and lower risk of sapovirus and rotavirus, and generally, associations were stronger. Higher humidity was associated with higher risk of enteric bacterial infections and lower risk of enteric virus infection. A small number of studies have projected diarrhea under climate change in low- and middle-income countries. Studies have estimated a 15-20% increase in global diarrhea risk in 2040-2069 relative to 1961-1990, up to 21% increase in diarrhea incidence in northern India from 2013 to the 2040s, 3-10% increase in diarrhea cases in the Gaza Strip associated with 1.5° to 2°C increases in temperature, and an 8% increase in diarrhea burden by 2050 in Nepal. One study estimated an additional 1,625,073 ETEC diarrhea cases in Bangladesh from 2046-2065 due to climate change. No studies estimated changes in the presence of multiple enteropathogens under possible climate change scenarios.Added value of this studyThis study matched remote sensing data on precipitation, temperature, surface water, and humidity to data on diarrhea and enteropathogen carriage in children under 2 years from a trial in rural Bangladesh. We fit flexible models to investigate potentially non-linear relationships between each climate and environmental risk factor and each health outcome. In addition, we predicted the prevalence of each outcome under three possible climate change scenarios. Our predictions leveraged the spatiotemporal distributions of both climate precipitation projections and diarrhea and enteropathogen carriage in the trial. To our knowledge, this is the first study to predict prevalence under climate change scenarios for both diarrhea and multiple enteropathogens in a rural, low-resource south Asian setting. Our study sheds light on how climate change may impact diarrhea and enteropathogen carriage in Bangladesh, which is highly vulnerable to climate change due to its low altitude and seasonal flooding.Implications of all the available evidenceWe found that both higher temperatures and precipitation were associated with higher diarrhea prevalence, consistent with prior studies. Compared to prior studies, which have primarily found associations between diarrhea and heavy rainfall following a dry period, we found that moderate levels of weekly precipitation were associated with higher diarrhea prevalence. Relationships between climatic and environmental variables and enteropathogen carriage varied by taxa, as other studies have found, but for some pathogens and risk factors, we observed associations in different directions than prior studies. Under middle of the road and fossil fuel-based development climate change scenarios, we projected increased diarrhea prevalence and taxa-specific changes in enteropathogen prevalence. Our findings suggest that climate change may exacerbate diarrhea burden in rural Bangladesh in the absence of sustainable development and inform prioritization of pathogen-specific mitigation and/or adaptation interventions (e.g., vaccines) for young children in rural, South Asian settings under climate change.

Background We evaluated the impact of low-cost water, sanitation, and handwashing (WSH) and child nutrition interventions on enteropathogen carriage in the WASH Benefits cluster-randomized controlled trial in rural Bangladesh. Methods We analyzed 1411 routine fecal samples from children 14 ± 2 months old in the WSH (n = 369), nutrition counseling plus lipid-based nutrient supplement (n = 353), nutrition plus WSH (n = 360), and control (n = 329) arms for 34 enteropathogens using quantitative polymerase chain reaction. Outcomes included the number of co-occurring pathogens; cumulative quantity of 4 stunting-associated pathogens; and prevalence and quantity of individual pathogens. Masked analysis was by intention-to-treat. Results Three hundred twenty-six (99.1%) control children had 1 or more enteropathogens detected (mean, 3.8 ± 1.8). Children receiving WSH interventions had lower prevalence and quantity of individual viruses than controls (prevalence difference for norovirus: –11% [95% confidence interval {CI}, –5% to –17%]; sapovirus: –9% [95% CI, –3% to –15%]; and adenovirus 40/41: –9% [95% CI, –2% to –15%]). There was no difference in bacteria, parasites, or cumulative quantity of stunting-associated pathogens between controls and any intervention arm. Conclusions WSH interventions were associated with fewer enteric viruses in children aged 14 months. Different strategies are needed to reduce enteric bacteria and parasites at this critical young age.

ImportanceA regulated stress response is essential for healthy trajectories, but the integrated effects of early childhood environmental and nutritional interventions on stress physiology are unknown.ObjectiveTo assess the effects of a combined nutritional, water, sanitation, and handwashing intervention on physiological stress response, oxidative stress, and DNA methylation.Design, Setting, and ParticipantsIn a trial in rural Bangladesh, we randomized geographical clusters of pregnant women and their in-utero children into either the combined nutritional, water, sanitation, and handwashing intervention or the control group. Physiological stress response, oxidative stress, and methylation levels of 757 children were measured at ages one and two years. Analysis was intention-to-treat.InterventionsThe intervention group received combined nutritional counseling and lipid-based nutrient supplements, chlorinated drinking water, upgraded sanitation, and handwashing with soap (N+WSH). The control group did not receive interventions.Main Outcomes and MeasuresWe measured four isomers of urinary F2-isoprostanes [iPF(2α)-III; 2,3-dinor-iPF(2α)-III; iPF(2α)-VI; 8,12-iso-iPF(2α)-VI] at year one. At year two, we measured pre- and post-stressor concentrations of salivary alpha-amylase and cortisol, overall methylation of the glucocorticoid receptor (NR3C1) exon 1F promoter including methylation levels at the nerve growth factor-inducible protein A (NGFI-A) binding site, mean arterial pressure, and resting heart rate.ResultsChildren in the N+WSH group had lower levels of F2-isoprostanes compared to controls (difference -0.16 to -0.19 log ng/mg of creatinine, PPP=0.023) in the N+WSH group. Children in the N+WSH group exhibited decreased logit-transformed methylation of the NGFI-A transcription factor binding site (−0.04; 95% CI, -0.08 to 0; P=0.037).Conclusions and RelevanceA nutritional, water, sanitation, and handwashing intervention reduced oxidative stress, enhanced hypothalamic-pituitary-adrenocortical axis activity, and reduced methylation levels in a transcription factor binding site of the glucocorticoid receptor gene. A targeted environmental and nutritional intervention affected the set point, reactivity, and regulation of the physiological stress system in early childhood, which may have implications for long-term health and developmental trajectories.Trial RegistrationClinicalTrials.govNCT01590095Key PointsQuestionDo intensive nutritional and environmental interventions alter physiological stress response, oxidative stress levels, and epigenetic programming during the first two years of life?FindingsIn this cluster randomized clinical trial of 757 children, a combined nutritional, drinking water, sanitation, and handwashing intervention significantly reduced oxidative stress, enhanced the cortisol response, and reduced methylation levels in a transcription factor binding site of the glucocorticoid receptor gene.MeaningThe integrated nutritional, drinking water, sanitation, and handwashing intervention enhanced adaptive responses of the physiological stress system in early childhood, which may have implications for long-term health and developmental trajectories.

While studies have speculated that immune function may play a role in how water, sanitation, hygiene, and nutritional (N+WSH) interventions may individually impact child growth and development, the combined effects of these interventions on immune system development are unknown. Here, we report on a trial in rural Bangladesh, where we cluster-randomized pregnant women into control and N+WSH arms. Among the birth cohort, we quantified plasma IL-1β, IL-6, TNF-α, IL-2, IL-12p70, IFN-γ, IL-4, IL-5, IL-13, IL-17A, IL-21, IL-10, and GM-CSF at ages 14 and 28 months. Cytokine ratios were included as prespecified outcomes to examine the net inflammatory environment. We assessed 704 children. After one year, TNF-α/IL-10, IL-12/IL-10, and IL-17A/IL-10 ratios were lower in the intervention group compared to the control group (mean difference: -0.12 to -0.19, p

Background:Previously, we demonstrated that a water, sanitation, handwashing, and nutritional intervention improved linear growth and was unexpectedly associated with shortened childhood telomere length (TL) (Lin et al., 2017). Here, we assessed the association between TL and growth.Methods:We measured relative TL in whole blood from 713 children. We reported differences between the 10th percentile and 90th percentile of TL or change in TL distribution using generalized additive models, adjusted for potential confounders.Results:In cross-sectional analyses, long TL was associated with a higher length-for-age Z score at age 1 year (0.23 SD adjusted difference in length-for-age Z score [95% CI 0.05, 0.42; FDR-corrected p-value = 0.01]). TL was not associated with other outcomes.Conclusions:Consistent with the metabolic telomere attrition hypothesis, our previous trial findings support an adaptive role for telomere attrition, whereby active TL regulation is employed as a strategy to address ‘emergency states’ with increased energy requirements such as rapid growth during the first year of life. Although short periods of active telomere attrition may be essential to promote growth, this study suggests that a longer overall initial TL setting in the first 2 years of life could signal increased resilience against future telomere erosion events and healthy growth trajectories.Funding:Funded by the Bill and Melinda Gates Foundation.Clinical trial number:NCT01590095

BackgroundWe hypothesized that drinking water, sanitation, handwashing (WSH), and nutritional interventions would improve environmental enteric dysfunction (EED), a potential contributor to stunting.MethodsWithin a subsample of a cluster-randomized, controlled trial in rural Bangladesh, we enrolled pregnant women in 4 arms: control, WSH, child nutrition counseling plus lipid-based nutrient supplements (N), and nutrition plus WSH (N+WSH). Among the birth cohort, we measured biomarkers of gut inflammation (myeloperoxidase, neopterin), permeability (alpha-1-antitrypsin, lactulose, mannitol), and repair (regenerating gene 1β) at median ages 3, 14, and 28 months. Analysis was intention-to-treat.ResultsWe assessed 1512 children. At age 3 months, compared to controls, neopterin was reduced by nutrition (-0.21 log nmol/L; 95% confidence interval [CI], -.37, -.05) and N+WSH (-0.20 log nmol/L; 95% CI, -.34, -.06) interventions; similar reductions were observed at 14 months. At 3 months, all interventions reduced lactulose and mannitol (-0.60 to -0.69 log mmol/L). At 28 months, myeloperoxidase was elevated in the WSH and nutrition arms (0.23-0.27 log ng/mL) and lactulose was higher in the WSH arm (0.30 log mmol/L; 95% CI, .07, .53).ConclusionsReductions in permeability and inflammation at ages 3 and 14 months suggest that the interventions promoted healthy intestinal maturation; however, by 28 months, the WSH and nutrition arms showed elevated EED biomarkers. These results underscore the importance of developing a better understanding of EED pathophysiology and targeting interventions early in childhood, when they are likely to have the largest benefit to intestinal health.Clinical trials registrationNCT01590095.