IJE Advance Access originally published online on August 25, 2008
International Journal of Epidemiology 2008 37(5):938-940; doi:10.1093/ije/dyn178
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Cochrane Column
South African Cochrane Centre, South African Medical Research Council, PO Box 19070, Tygerberg 7505, South Africa. E-mail: taryn.young{at}mrc.ac.za
The aim of the Column is to highlight Cochrane Reviews of relevance to public health, and to stimulate debate on relevance, feasibility and acceptability. This month we feature the review by Lazzerini et al. on oral zinc for treating diarrhoea in children.
The Cochrane Collaboration (http://www.cochrane.org) is an international, non-profit organization that prepares and disseminates up-to-date systematic reviews on the effects of healthcare interventions in order to help people make well-informed decisions. Systematic reviews aim to answer focused healthcare questions by systematically identifying and evaluating all relevant research studies and synthesizing their results.
If you are interested in contributing to the Cochrane Column or The Cochrane Collaboration, contact me at the South African Cochrane Centre.
Oral zinc for treating diarrhoea in children
Unit of Research on Health Services and International Health, WHO Collaborating Centre for Maternal and Child Health, Via dei Burlo 1,34123, Trieste, Italy
Diarrhoea is the leading cause of death in children under 5 years, outside the neonatal period, in many developing countries. Each year, several million children suffer from this disease, and about 2 million die.
Zinc influences the activity of over 200 enzymes, for a wide range of functions and plays a central role in cellular growth, differentiation and metabolism. It is found in red meat, fish and dairy products, which are expensive and also in short supply in many developing countries. For this reason, zinc deficiency is common in many countries with low resources. Nearly 30% children in the world are considered to be zinc deficient.
This review on zinc supplements for treating acute or persistent diarrhoea identified 18 eligible trials involving nearly 6200 children. The studies were generally of good quality and most had been done in countries with a high risk of zinc deficiency. Thirteen trials studied acute diarrhoea, five focused on persistent diarrhoea.
Among children over 6 months of age, zinc was effective. The risk of acute diarrhoea at day 3 and 5 was reduced by 31 (RR 0.69, 95% CI 0.59–0.81; 1073 children, two trials) and 45% (RR 0.55, 95% CI 0.32–0.95; 346 children, two trials), respectively. Evidence was robust and clinically relevant especially for reduction of acute diarrhoea at day 7, an indicator for the risk of persistent diarrhoea: seven trials in 4087 children shown a 29% (RR 0.71, 95% CI 0.52–0.98) reduction in the risk of diarrhoea at day 7. Subgroup analyses did not show a modification of effect by nutritional status, geographic region, background zinc deficiency, zinc type and study setting. Zinc also reduced the duration of persistent diarrhoea. Among children under 6 months zinc was not superior to placebo from two large trials enrolling more than 1300 children under 6 months.
Zinc was associated with an increase in vomiting. This might be due to its metallic taste, and might be tackled through the use of a palatable formulation.
In conclusion, this Cochrane Review shows the benefits of using zinc supplements for children aged from 6 to 59 months who are suffering from diarrhoea and highlights the relevance of this finding to low resources countries.
The trials were not designed to look at hospitalization and mortality, but given these results it is expected that a policy of zinc supplementation to all children over 6 months with diarrhoea in developing countries could also reduce hospitalization rate and help to fight child mortality.
The full text of the Cochrane Review is available in The Cochrane Library: Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD005436. DOI: 10.1002/14651858.CD005436.pub2.
Commentary: Oral zinc for treating diarrhoea in children
School of Child and Adolescent Health, Groote Schuur Hospital, Cape Town, South Africa
The recently published Cochrane review by Lazzerini and Ronfani evaluates the impact of oral zinc supplementation for treatment of children with acute or persistent diarrhoea on disease duration and severity.1
Diarrhoea is a major cause of childhood morbidity and mortality and is responsible for around 2 million deaths of children <5 years annually.2 It is responsible for 18% of all childhood deaths worldwide. The burden of diarrhoeal disease still occurs mainly in poorer countries where malnutrition is an ongoing problem and the underlying cause of 61% of childhood deaths due to diarrhoea globally. Zinc deficiency, more common in the situation of poor nutrition, has been related to increased disease severity in acute diarrhoea and pneumonia. It has been estimated that zinc treatment for diarrhoea could prevent 354 000 diarrhoea related deaths annually.3 Therefore, zinc treatment for diarrhoea has the potential to be a major public health intervention. Consequently in May 2004 UNICEF and WHO recommended zinc supplementation for all children with diarrhoea.4 Lazzerini and Ronfani's review supports this, showing a shorter duration of diarrhoea (mean difference 12.27 h, 95% CI –23.02 to –1.52 h) in children receiving zinc supplementation vs children receiving placebo. This occurred in the setting of both acute and persistent diarrhoea.
What was interesting in this review was that the effect was not apparent in children <6 months. As breast milk is an adequate source of zinc up until 6 months of age, zinc deficiency usually only develops around 6 months of age. This suggests that the impact of zinc is most evident in the setting of zinc deficiency. Since the release of the WHO recommendations for zinc treatment in childhood diarrhoeal disease there has been an increased interest in the programmatic implementation and impact that such an intervention may have on diarrhoea related morbidity and mortality. Until now the emphasis has been on developing countries who carry the major burden of diarrhoea-related disease. This emphasis is also based on the premise that zinc supplementation is effective in the setting of zinc deficiency and not necessary as a ‘medication’ in zinc sufficient states. Communities in developing countries have a higher prevalence of zinc deficiency. However, some recent work has suggested that zinc plays a therapeutic effect in disease treatment as well as prevention and that it may play a broader and organism specific role in prevention and treatment of diarrhoea disease in both the developing and developed countries.5
Zinc treatment for diarrhoea is a low-cost therapy and should be easy to implement into child care programmes especially if used with oral rehydration fluid. Although there has been a wide acceptance of the WHO recommendations, implementation has been slowed by access to child friendly formulations and initial financial input required at a country level to set up the system.6 However, paediatric zinc products are now readily available and at a cost of approximately $0.20 per full course of treatment, are inexpensive.
Zinc is known to be associated with gastrointestinal intolerance, notably regurgitation and vomiting. Lazzerini and Ronfani reported an increased risk of vomiting after zinc treatment as compared with placebo, a relative risk of 1.71, 95% 1.27–2.30.1 In recently published study assessing the occurrence of adverse events after administration of zinc in Bangladeshi children with acute or persistent diarrhoea, 21.8% of children regurgitated or vomited within 1 h of receiving zinc. Most of the children (90.8%) only had one vomit, no children had persistent symptoms requiring further treatment and the vomiting did not impact on the continuation of treatment.7
A positive effect of zinc treatment on all cause and diarrhoea specific mortality has been suggested in previous studies.8 However, only three trials included in the Cochrane review reported on deaths, with only one death reported in those studies. Hence they were unable to assess impact of zinc treatment on mortality.
We do have strong evidence that zinc treatment is beneficial in children with acute and persistent diarrhoea. It is a cost effective intervention that decreases diarrhoea-associated morbidity and improves overall health. It is recommended for the use in all children >6 months with acute or persistent diarrhoea.
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1 Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev, (2008) 3:CD005436.[Medline]
2 Bryce J, Boschi-Pinto C, Shibuya K, et al. WHO estimates of the causes of death in children. Lancet (2005) 365:1147–52.[CrossRef][Web of Science][Medline]
3 Jones G, Steketee RW, Black RE, et al. How many child deaths can we prevent this year? Lancet (2003) 362:65–71.[CrossRef][Web of Science][Medline]
4 World Health Organisation. Deptartment of Child and Adolescent Health and Development/UNICEF. In: Clinical management of acute diarrhoea: WHO/UNICEF joint statement. (2004) Geneva: World Health Organisation.
5 Crane JK, Hoque KM. Zinc for infectious diarrhoea in developed countries: should we be sprinkling our own lawns? J Pediatr Gastroenterol Nutr (2008) 46:484–5.[Web of Science][Medline]
6 Fischer Walker CL, Black RE. Micronutrients and diarrheal disease. Clin Infect Dis (2007) 45(Suppl 1):S73–77.[CrossRef][Web of Science][Medline]
7 Khan AM, Larson CP, Faruque AS, et al. Introduction of routine zinc therapy for children with diarrhoea: evaluation of safety. J Health Popul Nutr (2007) 25:127–33.[Web of Science][Medline]
8 Sazawal S, Black RE, Ramsan M, et al. Effect of zinc supplementation on mortality in children aged 1–48 months: a community-based randomised placebo-controlled trial. Lancet (2007) 369:927–34.[CrossRef][Medline]
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