The effect of acute malnutrition on enteric pathogens, moderate-to-severe diarrhoea, and associated mortality in the Global Enteric Multicenter Study cohort: a post-hoc analysis.

BACKGROUND: Host vulnerabilities associated with acute malnutrition could facilitate the ability of specific enteric pathogens to cause diarrhoea and associated mortality. Using data from the Global Enteric Multicenter Study, we assessed whether acute malnutrition modifies the association between common enteric pathogens and moderate-to-severe diarrhoea, and whether associations between enteric pathogens and death were modified by acute malnutrition. METHODS: Children with moderate-to-severe diarrhoea and age-matched and community-matched controls were included in this post-hoc analysis if their mid-upper arm circumference had been measured and if they were older than 6 months of age. Acute malnutrition was defined as mid-upper arm circumference below 12·5 cm, capturing both severe acute malnutrition (<11·5 cm) and moderate acute malnutrition (≥11·5 cm and <12·5 cm). We tested whether acute malnutrition modified associations between enteric pathogens and moderate-to-severe diarrhoea in conditional logistic regression models. Among children with moderate-to-severe diarrhoea, Cox proportional hazards regression evaluated the modifying effect of acute malnutrition on the relationship between pathogens and 60-day fatality rate. FINDINGS: The age, site, and co-infection adjusted odds ratios (aORs) for moderate-to-severe diarrhoea associated with typical enteropathogenic Escherichia coli among children aged 6-11 months was 2·08 (95% CI 1·14-3·79) in children with acute malnutrition, and 0·97 (0·77-1·23) in children with better nutritional status, compared with healthy controls. Enterotoxigenic E coli producing heat-stable toxin among children aged 12-23 months also had a stronger association with moderate-to-severe diarrhoea in children with acute malnutrition (aOR 7·60 [2·63-21·95]) than among similarly aged children with better nutritional status (aOR 2·39 [1·76-3·25]). Results for Shigella spp, norovirus, and sapovirus suggested they had a stronger association with moderate-to-severe diarrhoea than other pathogens among children with better nutritional status, although Shigella spp remained associated with moderate-to-severe diarrhoea in both nutritional groups. 92 (64%) of 144 children with moderate-to-severe diarrhoea who died had acute malnutrition. Pathogen-specific 60-day fatality rates for all pathogens were higher among children with acute malnutrition, but no individual pathogen had a significantly larger increase in its relative association with mortality. INTERPRETATION: Acute malnutrition might strengthen associations between specific pathogens and moderate-to-severe diarrhoea. However, the strong link between acute malnutrition and mortality during moderate-to-severe diarrhoea in children is not limited to specific infections, and affects a broad spectrum of enteric pathogens. Interventions addressing acute malnutrition could be an effective way to lower the mortality of both childhood malnutrition and diarrhoea. FUNDING: The Bill & Melinda Gates Foundation.

Defining Pediatric Diarrhea in Low-Resource Settings.

Differences in definitions of acute pediatric diarrhea result in variable estimates of morbidity and mortality, treatment coverage, and associations with risk factors and outcomes. We reviewed published literature and guidelines focused on acute pediatric diarrhea in low- and middle-income countries. Clinical guidelines most commonly defined diarrhea in terms of quantity of loose or watery stool with consideration of normal stool patterns, whereas research studies often relied exclusively on a quantitative definition. The most commonly used quantitative definition, ≥3 loose or watery stools in a 24-hour period, has been compared to gold standards of caregiver perception and visual inspection of stool, with variable agreement. Age, breast-feeding status, and setting (facility vs household-based) influence the performance of quantitative diarrhea definitions in children. Universal adoption of a set of valid gold standard definitions specifically aligned with various programmatic and research goals will lead to more accurate coverage estimates and better-informed resource prioritization.

A Systematic Review of the Effect of Rotavirus Vaccination on Diarrhea Outcomes Among Children Younger Than 5 Years.

BACKGROUND: Rotavirus is the leading cause of vaccine-preventable diarrhea among children under 5 globally. Rotavirus vaccination has been shown to prevent severe rotavirus infections with varying efficacy and effectiveness by region. METHODS: We sought to generate updated region-specific estimates of rotavirus vaccine efficacy and effectiveness. We systematically reviewed published vaccine efficacy and effectiveness studies to assess the region-specific effect of rotavirus vaccination on select diarrheal morbidity and mortality outcomes in children under 5 years of age. We employed meta-analytic methods to generate pooled effect sizes by Millennium Development Goal region. RESULTS: Rotavirus vaccination was both efficacious and effective in preventing rotavirus diarrhea, severe rotavirus diarrhea and rotavirus hospitalizations among children under 5 across all regions represented by the 48 included studies. Efficacy against severe rotavirus diarrhea ranged from 90.6% [95% confidence interval (CI): 82.3-95.0] in the developed region to 88.4% (95% CI: 67.1-95.9) in Eastern/Southeastern Asia, 79.6% (95% CI: 71.3-85.5) in Latin America and the Caribbean, 50.0% (95% CI: 34.4-61.9) in Southern Asia and 46.1% (95% CI: 29.1-59.1) in sub-Saharan Africa. Region-specific effectiveness followed a similar pattern. There was also evidence of vaccine efficacy against severe diarrhea and diarrheal hospitalizations. CONCLUSION: Our findings confirm the protective efficacy and effectiveness of rotavirus vaccination against rotavirus diarrheal outcomes among children under 5 globally.

Zinc Deficiency in Childhood and Pregnancy: Evidence for Intervention Effects and Program Responses.

Zinc is a key micronutrient of particular importance during childhood and pregnancy. Zinc deficiency has been linked to increased infection and stunting among children and is a risk factor for adverse pregnancy outcomes and preterm delivery. Targeted interventions have the potential to alleviate the adverse effects of zinc deficiency via therapeutic and preventive supplementation, fortification and biofortification, but implementation is challenging. A growing number of low- and middle- income countries have introduced national policies for zinc treatment of diarrhea among children under 5 years in response to mounting evidence of reduced episode duration and severity as well as reduced incidence in the ensuing months, but coverage remains low in the absence of effective scale-up efforts. Implementation of preventive zinc supplementation in young children has also been slow, despite evidence linking routine daily supplementation and treatment regimens with reductions in stunting and the incidence of diarrhea and pneumonia. Acceptance of other zinc interventions, including traditional fortification, fortification with micronutrient powders and biofortification, is hindered by unclear evidence on efficacy. Additional research is therefore warranted to ascertain the efficacy of delivering zinc through fortified and biofortified foods and in combination with other micronutrients in supplements or powders. Operations research is also necessary to establish best practices for scale-up of therapeutic zinc supplementation for diarrhea.

Management of childhood diarrhea among private providers in Uttar Pradesh, India.

BACKGROUND: In Uttar Pradesh (UP), India, a new initiative to introduce zinc and reinvigorate ORS for diarrhea treatment in the public and private sectors was rolled out in selected districts. We conducted an external evaluation of the program that included assessing the knowledge and practices of private sector providers 6 months after the initial program rollout. METHODS: We conducted interviews and direct observations among a randomly selected group of formal and informal private sector providers in 12 districts of UP. We calculated summary statistics for reported provider characteristics, diarrhea treatment knowledge and preferred treatments, as well as the treatments advised during consultation with a child with diarrhea. RESULTS: We interviewed 232 providers, of whom 67% reported receiving a diarrhea treatment training/drug detailing visit. In the interview, 14% of providers reported prescribing zinc to all children with diarrhea and 36% reported prescribing zinc to more than half of diarrhea cases. During direct observation, ORS and zinc were prescribed by 77.3% and 29.9% of providers, respectively. Treatments other than zinc and ORS were also commonly prescribed, including antibiotics (61.9%) and antidiarrheals (17.5%). CONCLUSION: Adequate treatment of childhood diarrhea with zinc and ORS remains a challenge among private sector providers in rural UP, India. Additional training and knowledge transfer activities are needed to curb the overprescription of antibiotics and antidiarrheals and to increase the confidence of private providers in advising zinc and ORS. In addition, policymakers and program implementers must ensure collaborative efforts to target and meaningfully engage informal private providers who play a major role in childhood diarrhea treatment in hard-to-reach areas.

Adherence to zinc supplementation guidelines for the treatment of diarrhea among children under-five in Uttar Pradesh, India.

BACKGROUND: There is limited evidence on adherence to the recommended dose and duration of zinc supplementation for diarrheal episodes in children under five years of age. In selected districts of Uttar Pradesh, India, we sought to assess adherence to the nationally advised zinc treatment regimen (ie, 10 mg/day for ages 2-6 months and 20 mg/day for ages 7-59 months for 14 days) among caregivers of zinc-prescribed children. METHODS: We identified and conducted follow-up visits to children advised zinc for the treatment of diarrhea. At the initial visit, we collected data on the treatment instructions received from providers. Caregivers were asked to record treatments administered on a pictorial tracking form and were asked to retain all packaging for collection at follow-up. We quantified the average dose and duration of zinc therapy and built logistic regression models to assess the factors associated with caregiver adherence to national guidelines. RESULTS: Caregivers administered zinc for an average of 10.7 days (standard deviation (SD) = 3.9 days; median = 13 days), and 47.8% continued treatment for the complete 14 days. Among children receiving zinc syrups and tablets respectively, the age appropriate dose was received by 30.8% and 67.3%. Adherence to age appropriate dose and continuation of zinc for 14 days were highly associated with having received appropriate provider instructions. CONCLUSIONS: Our results indicate moderate-to-good adherence to national zinc treatment guidelines for diarrhea among caregivers in rural India. Our findings also highlight the importance of provider guidance in ensuring adherence to zinc dose and duration. Programs aiming to scale-up zinc treatment for childhood diarrhea should train providers to successfully communicate dosing instructions to caregivers, while also addressing the tendency of caregivers to terminate treatment once a child appears to have recovered from an acute diarrheal episode.

An external evaluation of the Diarrhea Alleviation through Zinc and ORS Treatment (DAZT) program in Gujarat and Uttar Pradesh, India.

BACKGROUND: To address inadequate coverage of oral rehydration salts (ORS) and zinc supplements for the treatment of diarrhea among children under-five, the Diarrhea Alleviation through Zinc and ORS Treatment (DAZT) program was carried out from 2011-2013 in Gujarat and from 2011-2014 in Uttar Pradesh (UP), India. The program focused on improving the diarrhea treatment practices of public and private sector providers. METHODS: We conducted cross-sectional household surveys in program districts at baseline and endline and constructed state-specific logistic regression models with generalized estimating equations to assess changes in ORS and zinc treatment during the program period. RESULTS: Between baseline and endline, zinc coverage increased from 2.5% to 22.4% in Gujarat and from 3.1% to 7.0% in UP; ORS coverage increased from 15.3% to 39.6% in Gujarat but did not change in UP. In comparison to baseline, children with diarrhea in the two-weeks preceding the endline survey had higher odds of receiving zinc treatment in both Gujarat (odds ratio, OR = 11.2; 95% confidence interval (CI) 6.4-19.3) and UP (OR = 2.4; 95% CI 1.4-3.9), but the odds of receiving ORS only increased in Gujarat (OR = 3.6; 95% CI 2.7-4.8; UP OR = 0.9; 95% CI 0.7-1.2). Seeking care outside the home, especially from a public sector source, was associated with higher odds of receiving ORS and zinc. CONCLUSIONS: During the duration of the DAZT program, there were modest improvements in the treatment of diarrhea among young children. Future programs should build upon and accelerate this trend with continued investment in public and private sector provider training and supply chain sustainability, in addition to targeted caregiver demand generation activities.

Public sector scale-up of zinc and ORS improves coverage in selected districts in Bihar, India.

BACKGROUND: In Bihar, India, a new initiative to enhance diarrhea treatment with zinc and ORS in the public sector was rolled out in selected districts. We conducted an external evaluation to measure changes in diarrhea careseeking and treatment in intervention districts. METHODS: We conducted baseline and endline household surveys among caregivers of children 2-59 months of age. We calculated summary statistics for household characteristics, knowledge, careseeking and treatments given to children with a diarrhea episode in the last 14 days and built logistic regression models to compare baseline and endline values. RESULTS: Caregivers named a public health center as an appropriate source of care for childhood diarrhea more often at endline (71.3%) compared to baseline (38.4%) but did not report increased careseeking to public sector providers for the current diarrhea episode. In logistic regression analyses, the odds of receiving zinc, with or without oral rehydration salts (ORS), increased at endline by more than 2.7 as compared to baseline. Children who were taken to the public sector for care were more likely to receive zinc (odds ratio, OR = 3.93) and zinc in addition to ORS (OR = 6.10) compared to children who were not taken to the public sector. CONCLUSION: Coverage of zinc and ORS can improve with public sector programs targeted at training and increasing product availability, but demand creation may be needed to increase public sector careseeking in areas where the private sector has historically provided much of the care.

The Influence of Episode Severity on Caregiver Recall, Care-seeking, and Treatment of Diarrhea Among Children 2-59 Months of Age in Bihar, Gujarat, and Uttar Pradesh, India.

Increased diarrheal episode severity has been linked to better 2-week recall and improved care-seeking and treatment among caregivers of children under five. Using cross-sectional data from three Indian states, we sought to assess the relationship between episode severity and the recall, care-seeking, and treatment of childhood diarrhea. Recall error was higher for episodes with onset 8-14 days (31.2%) versus 1-7 days (4.8%) before the survey, and logistic regression analysis showed a trend toward increased severity of less recent compared with more recent episodes. This finding indicates that data collection with 2-week recall underestimates diarrhea prevalence while overestimating the proportion of severe episodes. There was a strong correlation between care-seeking and dehydration, fever, vomiting, and increased stool frequency and duration. Treatment with oral rehydration salts was associated with dehydration, vomiting, and higher stool frequency, and trends were established between therapeutic zinc supplementation and increased duration and stool frequency. However, state and care-seeking sector were stronger determinants of treatment than episode severity, illustrating the need to address disparities in treatment quality across regions and delivery channels. Our findings are of importance to researchers and diarrhea management program evaluators aiming to produce accurate estimates of diarrheal outcomes and program impact in low- and middle-income countries.

The Association between Provider Practice and Knowledge of ORS and Zinc Supplementation for the Treatment of Childhood Diarrhea in Bihar, Gujarat and Uttar Pradesh, India: A Multi-Site Cross-Sectional Study.

INTRODUCTION: Programs aimed at reducing the burden of diarrhea among children under-five in low-resource settings typically allocate resources to training community-level health workers, but studies have suggested that provider knowledge does not necessarily translate into adequate practice. A diarrhea management program implemented in Bihar, Gujarat and Uttar Pradesh, India trained private sector rural medical practitioners (RMPs) and public sector Accredited Social Health Activists (ASHAs) and Anganwadi workers (AWWs) in adequate treatment of childhood diarrhea with oral rehydration salts (ORS) and zinc. We used cross-sectional program evaluation data to determine the association between observed diarrhea treatment practices and reported knowledge of ORS and zinc among each provider cadre. METHODS: We conducted principal components analysis on providers' responses to diarrhea treatment questions in order to generate a novel scale assessing ORS/zinc knowledge. We subsequently regressed a binary indicator of whether ORS/zinc was prescribed during direct observation onto the resulting knowledge scores, controlling for other relevant knowledge predictors. RESULTS: There was a positive association between ORS/zinc knowledge score and prescribing ORS and zinc to young children with diarrhea among private sector RMPs (aOR: 2.32; 95% CI: 1.29-4.17) and public sector ASHAs and AWWs (aOR 2.48; 95% CI: 1.90-3.24). Controlling for knowledge score, receipt of training in the preceding 6 months was a good predictor of adequate prescribing in the public but not the private sector. In the public sector, direct access to ORS and zinc supplies was also highly associated with prescribing. CONCLUSIONS: To enhance the management of childhood diarrhea in India, programmatic activities should center on increasing knowledge of ORS and zinc among public and private sector providers through biannual trainings but should also focus on ensuring sustained access to an adequate supply chain.

Estimating diarrheal illness and deaths attributable to Shigellae and enterotoxigenic Escherichia coli among older children, adolescents, and adults in South Asia and Africa.

INTRODUCTION: While Shigellae and strains of enterotoxigenic Escherichia coli (ETEC) are important causes of diarrhea-associated morbidity and mortality among infants and young children (<5 years of age), their health impact in older age groups is unclear. We sought to quantify the overall burden of shigellosis and ETEC diarrhea among older children, adolescents, and adults in Africa and South Asia, the two regions with the highest levels of diarrhea-related morbidity and mortality worldwide. METHODS: We employed two distinct methodological approaches to estimate the burden of diarrhea due to Shigellae and ETEC among persons ≥ 5 years of age in the WHO regions of South Asia (SEAR) and Africa (AFR). Under method 1, we conducted a systematic review to identify the median proportion of total deaths due to diarrhea and then applied this figure to the number of all-cause deaths that occurred in 2010 among this age group. To estimate the total number of diarrhea deaths attributable to Shigellae and ETEC, we subsequently applied previously published estimates of the median percentage of diarrhea hospitalizations due to Shigellae and ETEC to the estimated number of diarrhea deaths. For method 2, we applied previously published incidence rates to 2010 population figures and estimated the total number of episodes due to Shigellae and ETEC using published estimates of the average proportion of pathogen-positive outpatients from studies of >4 pathogens. We then estimated the number of pathogen-specific deaths by determining the number of hospitalized patients and applying the case-fatality rate. RESULTS: By method 1, there were 19,451 deaths due to Shigellae and 42,973 due to ETEC in AFR, and 20,691 due to Shigellae and 45,713 due to ETEC in SEAR in 2010. By method 2, there were 15.0 million ETEC episodes and 30.4 million episodes due to Shigellae in AFR, and 28.7 million episodes due to ETEC and 58.1 million episodes due to Shigellae in SEAR in 2010. We were unable to identify published case-fatality rates for ETEC and thus could only estimate Shigellae-related deaths using method 2, by which there were 5,308 and 10,158 Shigellae-related deaths in AFR and SEAR in 2010, respectively. DISCUSSION: Methods 1 and 2 underscore the importance of Shigellae and ETEC as major causes of morbidity and mortality among older children, adolescents, and adults in AFR and SEAR. Understanding the epidemiology of these pathogens is imperative for the development and use of future vaccines and other preventative interventions.

Oral zinc supplementation for the treatment of acute diarrhea in children: a systematic review and meta-analysis.

Evidence supporting the impact of therapeutic zinc supplementation on the duration and severity of diarrhea among children under five is largely derived from studies conducted in South Asia. China experiences a substantial portion of the global burden of diarrhea, but the impact of zinc treatment among children under five has not been well documented by previously published systematic reviews on the topic. We therefore conducted a systematic literature review, which included an exhaustive search of the Chinese literature, in an effort to update previously published estimates of the effect of therapeutic zinc. We conducted systematic literature searches in various databases, including the China National Knowledge Infrastructure (CNKI), and abstracted relevant data from studies meeting our inclusion and exclusion criteria. We used STATA 12.0 to pool select outcomes and to generate estimates of percentage difference and relative risk comparing outcomes between zinc and control groups. We identified 89 Chinese and 15 non-Chinese studies for the review, including studies in 10 countries from all WHO geographic regions, and analyzed a total of 18,822 diarrhea cases (9469 zinc and 9353 control). None of the included Chinese studies had previously been included in published pooled effect estimates. Chinese and non-Chinese studies reported the effect of therapeutic zinc supplementation on decreased episode duration, stool output, stool frequency, hospitalization duration and proportion of episodes lasting beyond three and seven days. Pooling Chinese and non-Chinese studies yielded an overall 26% (95% CI: 20%-32%) reduction in the estimated relative risk of diarrhea lasting beyond three days among zinc-treated children. Studies conducted in and outside China report reductions in morbidity as a result of oral therapeutic zinc supplementation for acute diarrhea among children under five years of age. The WHO recommendation for zinc treatment of diarrhea episodes should be supported in all low- and middle-income countries.

Breastfeeding for reducing the risk of pneumonia morbidity and mortality in children under two: a systematic literature review and meta-analysis.

BACKGROUND: Suboptimal breastfeeding practices among infants and young children <24 months of age are associated with elevated risk of pneumonia morbidity and mortality. We conducted a systematic review and meta-analysis to quantify the protective effects of breastfeeding exposure against pneumonia incidence, prevalence, hospitalizations and mortality. METHODS: We conducted a systematic literature review of studies assessing the risk of selected pneumonia morbidity and mortality outcomes by varying levels of breastfeeding exposure among infants and young children <24 months of age. We used random effects meta-analyses to generate pooled effect estimates by outcome, age and exposure level. RESULTS: Suboptimal breastfeeding elevated the risk of pneumonia morbidity and mortality outcomes across age groups. In particular, pneumonia mortality was higher among not breastfed compared to exclusively breastfed infants 0-5 months of age (RR: 14.97; 95% CI: 0.67-332.74) and among not breastfed compared to breastfed infants and young children 6-23 months of age (RR: 1.92; 95% CI: 0.79-4.68). CONCLUSIONS: Our results highlight the importance of breastfeeding during the first 23 months of life as a key intervention for reducing pneumonia morbidity and mortality.

Systematic review of diarrhea duration and severity in children and adults in low- and middle-income countries.

BACKGROUND: Diarrhea is a leading cause of morbidity and mortality globally; yet the overall burden of diarrhea in terms of duration and severity has not been quantified. As improvements in treatment lead to decreases in diarrhea mortality, it is important to understand the substantial impact of diarrhea morbidity on disability among children and adults worldwide. METHODS: We conducted a systematic review to generate estimates of duration and severity outcomes for individuals 0-59 mos, 5-15 yrs, and ≥ 16 yrs, and for 3 severity indexes: mild, moderate, and severe. RESULTS: We estimate that among children under-five, 64.8% of diarrheal episodes are mild, 34.7% are moderate, and 0.5% are severe. On average, mild episodes last 4.3 days, and severe episodes last 8.4 days and cause dehydration in 84.6% of cases. We estimate that among older children and adults, 95% of episodes are mild; 4.95% are moderate; and 0.05% are severe. Among individuals ≥ 16 yrs, severe episodes typically last 2.6 days and cause dehydration in 92.8% of cases. CONCLUSIONS: Moderate and severe episodes constitute a substantial portion of the total envelope of diarrhea among children under-five (35.2%; about 588 million episodes). Among older children and adults, moderate and severe episodes account for a much smaller proportion of the total envelope of diarrhea (5%), but the absolute number of such episodes is noteworthy (about 21.5 million episodes among individuals ≥ 16 yrs). Hence, the global burden of diarrhea consists of significant morbidity, extending beyond episodes progressing to death.

Breastfeeding and the risk for diarrhea morbidity and mortality.

BACKGROUND: Lack of exclusive breastfeeding among infants 0-5 months of age and no breastfeeding among children 6-23 months of age are associated with increased diarrhea morbidity and mortality in developing countries. We estimate the protective effects conferred by varying levels of breastfeeding exposure against diarrhea incidence, diarrhea prevalence, diarrhea mortality, all-cause mortality, and hospitalization for diarrhea illness. METHODS: We systematically reviewed all literature published from 1980 to 2009 assessing levels of suboptimal breastfeeding as a risk factor for selected diarrhea morbidity and mortality outcomes. We conducted random effects meta-analyses to generate pooled relative risks by outcome and age category. RESULTS: We found a large body of evidence for the protective effects of breastfeeding against diarrhea incidence, prevalence, hospitalizations, diarrhea mortality, and all-cause mortality. The results of random effects meta-analyses of eighteen included studies indicated varying degrees of protection across levels of breastfeeding exposure with the greatest protection conferred by exclusive breastfeeding among infants 0-5 months of age and by any breastfeeding among infants and young children 6-23 months of age. Specifically, not breastfeeding resulted in an excess risk of diarrhea mortality in comparison to exclusive breastfeeding among infants 0-5 months of age (RR: 10.52) and to any breastfeeding among children aged 6-23 months (RR: 2.18). CONCLUSIONS: Our findings support the current WHO recommendation for exclusive breastfeeding during the first 6 months of life as a key child survival intervention. Our findings also highlight the importance of breastfeeding to protect against diarrhea-specific morbidity and mortality throughout the first 2 years of life.