Ending preventable child deaths from pneumonia and diarrhoea by 2025. Development of the integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea.

Despite the existence of low-cost and effective interventions for childhood pneumonia and diarrhoea, these conditions remain two of the leading killers of young children. Based on feedback from health professionals in countries with high child mortality, in 2009, WHO and Unicef began conceptualising an integrated approach for pneumonia and diarrhoea control. As part of this initiative, WHO and Unicef, with support from other partners, conducted a series of five workshops to facilitate the inclusion of coordinated actions for pneumonia and diarrhoea into the national health plans of 36 countries with high child mortality. This paper presents the findings from workshop and post-workshop follow-up activities and discusses the contribution of these findings to the development of the integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea, which outlines the necessary actions for elimination of preventable child deaths from pneumonia and diarrhoea by 2025. Though this goal is ambitious, it is attainable through concerted efforts. By applying the lessons learned thus far and continuing to build upon them, and by leveraging existing political will and momentum for child survival, national governments and their supporting partners can ensure that preventable child deaths from pneumonia and diarrhoea are eventually eliminated.

Efficacy of early neonatal supplementation with vitamin A to reduce mortality in infancy in Haryana, India (Neovita): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Vitamin A supplementation in children aged 6 months to 5 years has been shown to reduce mortality. The efficacy of neonatal supplementation with vitamin A to reduce mortality in the first 6 months of life is plausible but not established. We aimed to assess the efficacy of neonatal oral supplementation with vitamin A to reduce mortality between supplementation and 6 months of age. METHODS: We undertook an individually randomised, double-blind, placebo-controlled trial in Haryana, India. We identified pregnant women through a surveillance programme undertaken every 3 months of all female residents in two districts of Haryana, India, aged 15-49 years, and screened every identified livebirth. Eligible participants were neonates whose parents consented to participate, were likely to stay in the study area until at least 6 months of age, and were able to feed orally at the time of enrolment. Participants were randomly assigned to receive oral capsules containing vitamin A (retinol palmitate 50,000 IU plus vitamin E 9·5-12·6 IU) or placebo (vitamin E 9·5-12·6 IU) within 72 h of birth. Randomisation was in blocks of 20 according to a randomisation list prepared by a statistician not otherwise involved with the trial. Investigators, participants' families, and the data analysis team were masked to treatment allocation. The primary outcome was mortality between supplementation and 6 months of age. Analysis included all participants assigned to study groups. This trial is registered with ClinicalTrials.gov, number NCT01138449, and the Indian Council of Medical Research Clinical Trial Registry, number CTRI/2010/091/000220. FINDINGS: Between June 24, 2010, and July 1, 2012 we screened 47,777 neonates and randomly assigned 44,984 to receive vitamin A (22,493) or placebo (22,491). Between supplementation and 6 months of age, 656 infants died in the vitamin A group compared with 726 in the placebo group (29·2 per 1000 vs 32·3 per 1000; difference -3·1 per 1000, 95% CI -6·3 to 0·1; risk ratio 0·90, 95% CI 0·81 to 1·00). We noted no significant interactions between the intervention effect and sex on mortality at 6 months (p=0·409). Supplementation with 50,000 IU vitamin A within the first 72 h of life was generally safe and well tolerated, with the exception of a small excess risk of transient bulging fontanelle (205 cases in the vitamin A group confirmed by physician vs 80 cases in the placebo group, risk ratio 2·56 [95% CI 1·98-3·32]). INTERPRETATION: The findings of this study, done in a population in which vitamin A deficiency is a moderate public health problem, are consistent with a modest reduction in mortality between supplementation and 6 months of age. These findings must be viewed together with similar trials in other populations to enable determination of appropriate public health policy. FUNDING: Bill & Melinda Gates Foundation to WHO.

Efficacy of early neonatal vitamin A supplementation in reducing mortality during infancy in Ghana, India and Tanzania: study protocol for a randomized controlled trial.

BACKGROUND: Vitamin A supplementation of 6-59 month old children is currently recommended by the World Health Organization based on evidence that it reduces mortality. There has been considerable interest in determining the benefits of neonatal vitamin A supplementation, but the results of existing trials are conflicting. A technical consultation convened by WHO pointed to the need for larger scale studies in Asia and Africa to inform global policy on the use of neonatal vitamin A supplementation. Three trials were therefore initiated in Ghana, India and Tanzania to determine if vitamin A supplementation (50,000 IU) given to neonates once orally on the day of birth or within the next two days will reduce mortality in the period from supplementation to 6 months of age compared to placebo. METHODS/DESIGN: The trials are individually randomized, double masked, and placebo controlled. The required sample size is 40,200 in India and 32,000 each in Ghana and Tanzania. The study participants are neonates who fulfil age eligibility, whose families are likely to stay in the study area for the next 6 months, who are able to feed orally, and whose parent(s) provide informed written consent to participate in the study. Neonates randomized to the intervention group receive 50,000 IU vitamin A and the ones randomized to the control group receive placebo at the time of enrollment. Mortality and morbidity information are collected through periodic home visits by a study worker during infancy. The primary outcome of the study is mortality from supplementation to 6 months of age. The secondary outcome of the study is mortality from supplementation to 12 months of age. The three studies will be analysed independent of each other. Subgroup analysis will be carried out to determine the effect by birth weight, sex, and timing of DTP vaccine, socioeconomic groups and maternal large-dose vitamin A supplementation. DISCUSSION: The three ongoing studies are the largest studies evaluating the efficacy of vitamin A supplementation to neonates. Policy formulation will be based on the results of efficacy of the intervention from the ongoing randomized controlled trials combined with results of previous studies.

Scaling up diarrhea prevention and treatment interventions: a Lives Saved Tool analysis.

BACKGROUND: Diarrhea remains a leading cause of mortality among young children in low- and middle-income countries. Although the evidence for individual diarrhea prevention and treatment interventions is solid, the effect a comprehensive scale-up effort would have on diarrhea mortality has not been estimated. METHODS AND FINDINGS: We use the Lives Saved Tool (LiST) to estimate the potential lives saved if two scale-up scenarios for key diarrhea interventions (oral rehydration salts [ORS], zinc, antibiotics for dysentery, rotavirus vaccine, vitamin A supplementation, basic water, sanitation, hygiene, and breastfeeding) were implemented in the 68 high child mortality countries. We also conduct a simple costing exercise to estimate cost per capita and total costs for each scale-up scenario. Under the ambitious (feasible improvement in coverage of all interventions) and universal (assumes near 100% coverage of all interventions) scale-up scenarios, we demonstrate that diarrhea mortality can be reduced by 78% and 92%, respectively. With universal coverage nearly 5 million diarrheal deaths could be averted during the 5-year scale-up period for an additional cost of US$12.5 billion invested across 68 priority countries for individual-level prevention and treatment interventions, and an additional US$84.8 billion would be required for the addition of all water and sanitation interventions. CONCLUSION: Using currently available interventions, we demonstrate that with improved coverage, diarrheal deaths can be drastically reduced. If delivery strategy bottlenecks can be overcome and the international community can collectively deliver on the key strategies outlined in these scenarios, we will be one step closer to achieving success for the United Nations' Millennium Development Goal 4 (MDG4) by 2015.

Effectiveness of zinc supplementation plus oral rehydration salts for diarrhoea in infants aged less than 6 months in Haryana state, India.

OBJECTIVE: To determine if educating caregivers in providing zinc supplements to infants < 6 months old with acute diarrhoea is effective in treating diarrhoea and preventing acute lower respiratory infections (ALRIs), and whether it leads to a decrease in the use of oral rehydration salts (ORS). METHODS: In this retrospective subgroup analysis of infants aged < 6 months, six clusters were randomly assigned to intervention or control sites. Care providers were trained to give zinc and ORS to children with acute diarrhoea at intervention sites, and only ORS at control sites. Surveys were conducted at 3 and 6 months to assess outcomes. Differences between intervention and control sites in episodes of diarrhoea and ALRI in the preceding 24 hours or 14 days and of hospitalizations in the preceding 3 months were analysed by logistic regression. FINDINGS: Compared with control sites, intervention sites had lower rates of acute diarrhoea in the preceding 14 days at 3 months (odds ratio, OR: 0.60; 95% confidence interval, CI: 0.43-0.84) and 6 months (OR: 0.72; 95% CI: 0.54-0.94); lower rates of acute diarrhoea in the preceding 24 hours at 3 months (0.66; 95% CI: 0.50-0.87) and of ALRI in the preceding 24 hours at 6 months (OR: 0.59; 95% CI: 0.37-0.93); and lower rates of hospitalization at 6 months for all causes (OR: 0.40; 95% CI: 0.34-0.49), diarrhoea (OR: 0.34; 0.18-0.63) and pasli chalna or pneumonia (OR: 0.36; 95% CI: 0.24-0.55). CONCLUSION: Educating caregivers in zinc supplementation and providing zinc to infants < 6 months old can reduce diarrhoea and ALRI. More studies are needed to confirm these findings as these data are from a subgroup analysis.

Zinc and low osmolarity oral rehydration salts for diarrhoea: a renewed call to action.

In 2004, WHO and the United Nations Children's Fund (UNICEF) released a joint statement recommending a new lower osmolarity oral rehydration salts (ORS) formulation and zinc supplementation for diarrhoea management. More than 5 years later, diarrhoea remains the second leading cause of death and few children in developing countries are receiving these life-saving interventions. Many countries are stalled in the technicalities of adapting national policy, while others struggle to find the funds for start-up activities. For nearly all countries, zinc supplements for children are not available locally; thus, zinc procurement continues to be a major obstacle. Global resources have not been sufficient to bring diarrhoea management to the forefront; thus, the introduction of these new recommendations has remained slow. Revitalizing diarrhoea management must become an international priority if we are going to reduce the burden of diarrhoea deaths and overall child mortality around the world.

Effect of zinc supplementation on morbidity and growth in hospital-born, low-birth-weight infants.

BACKGROUND: Low-birth-weight infants may have impaired zinc status, but little is known about the effect of zinc supplementation. OBJECTIVE: The objective was to investigate the effect of daily zinc supplementation on morbidity and anthropometric status in hospital-born, low-birth-weight infants. DESIGN: In a double-blind, randomized, placebo-controlled trial, 2052 hospital-born term infants with a birth weight < or =2500 g were randomly assigned to receive zinc or placebo. The zinc group received elemental zinc: 5 mg/d for those infants between ages 2 wk and 6 mo and 10 mg/d for those infants aged >6 mo. All-cause hospitalizations, prevalence of diarrhea, acute lower respiratory tract infections, visits to health care providers, weights, and lengths were ascertained at 3, 6, 9, and 12 mo of age. RESULTS: The supplement was consumed for >85% of the follow-up period. Mean plasma zinc at 12 mo of age was higher in the zinc group (100.2 microg/dL) than in the control group (73.3 microg/dL) (difference in means: 26.9; 95% CI: 19.6, 34.2). The 24-h and 7-d prevalence of diarrhea and acute lower respiratory tract infections was similar at 3, 6, 9, and 12 mo. Care-seeking for illness was significantly lower in the zinc group (difference in proportions: -5.7; 95% CI: -9.9, -1.4; P < 0.05) at 9 mo. The numbers of hospitalizations, weights, and lengths were all similar at all 4 assessments. CONCLUSION: Hospital-born, term, low-birth-weight infants do not seem to benefit substantially from zinc supplementation that meets the Recommended Dietary Allowance for zinc in terms of morbidity or physical growth during infancy in this setting. This trial was registered at www.clinicaltrials.gov as NCT00272142.

Achievements, challenges, and promising new approaches in vitamin and mineral deficiency control.

Micronutrient deficiencies (MNDs) contribute significantly to the world's disease and mortality burden. Global efforts addressing MNDs have achieved significant yet heterogeneous progress across and within regions and countries. For vitamin A and iodine interventions, enhancing achievements in coverage require further political and financial commitment and targeting of hard-to-reach populations. Anemia control must focus on prevention among preschoolers and adolescent women and on integrated public health programs. Current international guidelines on iron supplementation and cut-off values for anemia need revision. For zinc, advocacy to accelerate the application of revised diarrhea management guidelines is critical, as are efficacy studies on food-based interventions and preventive supplementation.

Operational issues and trends associated with the pilot introduction of zinc for childhood diarrhoea in Bougouni district, Mali.

Zinc for the treatment of childhood diarrhoea was introduced in a pilot area in southern Mali to prepare for a cluster-randomized effectiveness study and to inform policies on how to best introduce and promote zinc at the community level. Dispersible zinc tablets in 14-tablet blister packs were provided through community health centres and drug kits managed by community health workers (CHWs) in two health zones in Bougouni district, Mali. Village meetings and individual counselling provided by CHWs and head nurses at health centres were the principal channels of communication. A combination of methods were employed to (a) detect problems in communication about the benefits of zinc and its mode of administration; (b) identify and resolve obstacles to implementation of zinc through existing health services; and (c) describe household-level constraints to the adoption of appropriate home-management practices for diarrhoea, including administration of both zinc and oral rehydration solution (ORS). Population-based household surveys with caretakers of children sick in the previous two weeks were carried out before and four months after the introduction of zinc supplementation. Household follow-up visits with children receiving zinc from the health centres and CHWs were conducted on day 3 and 14 after treatment for a subsample of children. A qualitative process evaluation also was conducted to investigate operational issues. Preliminary evidence from this study suggests that the introduction of zinc does not reduce the use of ORS and may reduce inappropriate antibiotic use for childhood diarrhoea. Financial access to treatments, management of concurrent diarrhoea and fever, and high use of unauthorized drug vendors were identified as factors affecting the effectiveness of the intervention in this setting. The introduction of zinc, if not appropriately integrated with other disease-control strategies, has the potential to decrease the appropriate presumptive treatment of childhood malaria in children with diarrhoea and fever in malaria-endemic areas.

Effectiveness of zinc supplementation plus oral rehydration salts compared with oral rehydration salts alone as a treatment for acute diarrhea in a primary care setting: a cluster randomized trial.

OBJECTIVE: The purpose of this work was to evaluate whether education about zinc supplements and provision of zinc supplements to caregivers is effective in the treatment of acute diarrhea and whether this strategy adversely affects the use of oral rehydration salts. PATIENTS AND METHODS: Six clusters of 30,000 people each in Haryana, India, were randomly assigned to intervention and control sites. Government and private providers and village health workers were trained to prescribe zinc and oral rehydration salts for use in diarrheal episodes in 1-month-old to 5-year-old children in intervention communities; in the control sites, oral rehydration salts alone was promoted. In 2 cross-sectional surveys commencing 3 months (survey 2) and 6 months (survey 3) after the start of the intervention, care-seeking behavior, drug therapy, and oral rehydration salts use during diarrhea, diarrheal and respiratory morbidity, and hospitalization rates were measured. RESULTS: In the 2 surveys, zinc was used in 36.5% (n = 1571) and 59.8% (n = 1649) and oral rehydration salts in 34.8% (n = 1571) and 59.2% (n = 1649) of diarrheal episodes occurring in the 4 weeks preceding interviews in the intervention areas. In control areas, oral rehydration salts were used in 7.8% (n = 2209) and 9.8% (n = 2609) of episodes. In the intervention communities, care seeking for diarrhea reduced by 34% (survey 3), as did the prescription of drugs of unknown identity (survey 3) and antibiotics (survey 3) for diarrhea. The 24-hour prevalences of diarrhea and acute lower respiratory infections were lower in the intervention communities (survey 3). All-cause, diarrhea, and pneumonia hospitalizations in the preceding 3 months were reduced in the intervention compared with control areas (survey 3). CONCLUSIONS: Diarrhea is more effectively treated when caregivers receive education on zinc supplementation and have ready access to supplies of oral rehydration salts and zinc, and this approach does not adversely affect the use of oral rehydration salts; in fact, it greatly increases use of the same.

Conclusions of the Joint WHO/UNICEF/IAEA/IZiNCG Interagency Meeting on Zinc Status Indicators.

Zinc deficiency is an important cause of morbidity in developing countries, particularly among young children, yet little information is available on the global prevalence of zinc deficiency. A working group meeting was convened by the World Health Organization (WHO), the United Nations Children's Fund (UNICEF), the International Atomic Energy Agency (IAEA), and the International Zinc Nutrition Consultative Group (IZiNCG) to review methods of assessing population zinc status and provide standard recommendations for the use of specific biochemical, dietary, and functional indicators of zinc status in populations. The recommended biochemical indicator is the prevalence of serum zinc concentration less than the age/sex/time of day-specific cutoffs; when the prevalence is greater than 20%, intervention to improve zinc status is recommended. For dietary indicators, the prevalence (or probability) of zinc intakes below the appropriate estimated average requirement (EAR) should be used, as determined from quantitative dietary intake assessments. Where the prevalence of inadequate intakes of zinc is greater than 25%, the risk of zinc deficiency is considered to be elevated. Previous studies indicate that stunted children respond to zinc supplementation with increased growth. When the prevalence of low height-for-age is 20% or more, the prevalence of zinc deficiency may also be elevated. Ideally, all three types of indicators would be used together to obtain the best estimate of the risk of zinc deficiency in a population and to identify specific subgroups with elevated risk. These recommended indicators should be applied for national assessment of zinc status and to indicate the need for zinc interventions. The prevalence of low serum zinc and inadequate zinc intakes may be used to evaluate their impact on the target population's zinc status.

Adding zinc to supplemental iron and folic acid does not affect mortality and severe morbidity in young children.

Studies have found a substantial reduction in diarrhea and respiratory morbidity in young children receiving zinc supplementation. The impact of daily zinc supplementation administered with iron plus folic acid (IFA) in young children on all-cause hospitalizations and mortality in comparison with IFA alone was evaluated. In a double blind cluster-randomized controlled trial, 94,359 subjects aged 1-23 mo were administered a daily dose of zinc plus IFA or IFA alone for a duration of 12 mo after enrollment. The intervention group tablet contained 10 mg of elemental zinc, 12.5 mg of iron, and 50 microg of folic acid. The control group tablets were similar except that they contained a placebo for zinc. Infants aged <6 mo were administered half a tablet, and those older received 1 tablet dissolved in breast milk or water. Hospitalizations were captured by trained study physicians through the surveillance of 8 hospitals. Deaths and hospitalizations were ascertained through visits to households by study supervisors once every 2 mo. The overall death rates did not differ significantly between the 2 groups when adjusted for cluster randomization (hazard ratio = 1.02, 95% CI 0.87, 1.19). Zinc and IFA supplementation compared with IFA alone did not affect adjusted hospitalization rates (overall rate ratio = 1.08, 95% CI 0.98, 1.19; diarrhea-specific rate ratio = 1.15, 95% CI 0.99, 1.34; or pneumonia-specific rate ratio = 1.09, 95% CI 0.94, 1.25). The lack of impact of zinc on mortality and hospitalization rates in this study may have been due to the use of lower daily zinc dosing than used in some of the morbidity prevention trials or from an interaction between zinc and iron, where the addition of iron may have adversely affected potential effects of zinc on immune function and morbidity. Future research should address iron and zinc interaction effects on important functional outcomes.

Improving antimicrobial use among health workers in first-level facilities: results from the multi-country evaluation of the Integrated Management of Childhood Illness strategy.

OBJECTIVE: The objective of this study was to assess the effect of Integrated Management of Childhood Illness (IMCI) case management training on the use of antimicrobial drugs among health-care workers treating young children at first-level facilities. Antimicrobial drugs are an essential child-survival intervention. Ensuring that children younger than five who need these drugs receive them promptly and correctly can save their lives. Prescribing these drugs only when necessary and ensuring that those who receive them complete the full course can slow the development of antimicrobial resistance. METHODS: Data collected through observation-based surveys in randomly selected first-level health facilities in Brazil, Uganda and the United Republic of Tanzania were statistically analysed. The surveys were carried out as part of the multi-country evaluation of IMCI effectiveness, cost and impact (MCE). FINDINGS: Results from three MCE sites show that children receiving care from health workers trained in IMCI are significantly more likely to receive correct prescriptions for antimicrobial drugs than those receiving care from workers not trained in IMCI. They are also more likely to receive the first dose of the drug before leaving the health facility, to have their caregiver advised how to administer the drug, and to have caregivers who are able to describe correctly how to give the drug at home as they leave the health facility. CONCLUSIONS: IMCI case management training is an effective intervention to improve the rational use of antimicrobial drugs for sick children visiting first-level health facilities in low-income and middle-income countries.