Zinc supplementation for diarrhoea treatment
Diarrhoea remains a leading cause of death among children under five years of age around the world (1). Young children experience on average 2.9 episodes of diarrhoea per year in low- and middle-income countries, which leads to stunting and increases the risk for other infectious disease such as respiratory infections (2-4). The prevention and treatment of diarrhoea is relatively simple. With current technology and available prevention and treatment interventions, it is estimated that 92% of diarrhoea deaths could be prevented with near universal coverage of these interventions (5).
Zinc for the treatment of diarrhoea is a critical treatment intervention and since 2004, zinc has been recommended by WHO and UNICEF as the only treatment to be coupled with oral rehydration salts for the treatment of all diarrhoea episodes (6). The WHO/UNICEF recommendation, which includes zinc as part of routine diarrhoea treatment, was developed after extensively reviewing the results of numerous randomized placebo-controlled trials (RCTs), demonstrating the benefits of zinc on shortening and decreasing the overall severity of the diarrhoea episode. Since the 2004 recommendation there have been several new RCTs and effectiveness studies enabling us to evaluate the effects of zinc for diarrhoea treatment in a less controlled environment.
In this commentary we provide an overview of three recent systematic reviews (7-9). Lamberti et al (7) and Lazzerini & Ronfani (8) provide systematic reviews and meta-analyses of randomized controlled trials assessing the efficacy of zinc for the treatment of diarrhoea. Both reviews sought studies of children under five years of age, though the Cochrane review by Lazzerini & Ronfani further defined this as one month to five years of age. Both reviews included only randomized placebo-controlled trials of zinc supplementation with at least 5 mg zinc/day. The reviews included the outcome of diarrhoea duration for both acute and persistent episodes, as well as the number of acute episodes progressing beyond three and seven days, stool frequency, stool output and hospitalizations. The Cochrane review also included the number of episodes at five days post treatment, deaths, and adverse outcomes. Both reviews used standard abstraction procedures and presented clear search criteria and analytic techniques for conducting meta-analyses. As studies published in the Chinese literature have never been included in any systematic review, Lamberti et al included an exhaustive search of the Chinese literature.
The third review (9) we conducted as part of the standardized review process for all child survival interventions to feed into the Lives Saved Tool (LiST) and was thus designed to go beyond the more traditional previously-published reviews. In this paper we conducted a systematic review of all studies assessing efficacy or effectiveness of zinc for the treatment of diarrhoea. We went beyond RCTs and included cluster randomized trials with the objective of quantifying the effect of zinc for diarrhoea treatment on severe diarrhoea outcomes and diarrhoea mortality. We used a standardized abstraction and grading procedure to qualitatively and quantitatively assess the evidence supporting the effect of zinc for the treatment of diarrhoea on diarrhoea hospitalizations, prolonged diarrhoea and diarrhoea mortality, and proposed an overall effect size for the effect of zinc on diarrhoea mortality.
There were 89 Chinese and 15 non-Chinese studies included in the Lamberti et al review (7) and 24 studies included in the Lazzerini and Ronfani review (8). For the purposes of this commentary we are interested in assessing the comparability of results to present within the larger body of evidence supporting zinc for the treatment of diarrhoea, so will not compare and contrast included and excluded studies by outcome. For the outcome of diarrhoea duration, the Cochrane review (8) found zinc to reduce duration by 12.6 hours (95% CI: 4.2 – 21 hours) when looking at the studies that included all ages. Lamberti et al reported a reduction in duration among zinc supplemented children of 3.8 hours (p<0.05) in non-Chinese studies and 1.7 days (p<0.05) in the Chinese studies (7). Lazzerini and Ronfani found great heterogeneity by age with a statistically significant effect in older children and no effect among infants less than six months of age when looking solely at this age group; Lamberti et al (7) did not stratify by age. While stool output and stool frequency can be a measure of severity, the number of episodes lasting beyond seven days is indicative of children most at risk for a severe outcome (i.e. hospitalization or death). Lamberti et al (7) found a relative risk reduction of 0.74 (95% CI: 0.55–0.99) for children who received zinc compared with those who received placebo in the non-Chinese studies and a relative risk reduction of 0.75 (95% CI: 0.42 – 1.37) in the Chinese studies. This is similar to the risk ratio of 0.82 (95% CI: 0.72–0.94) recorded in the Cochrane review (8) for all studies.
Lazzerini & Rofani found the only two recorded possible side effects to be vomiting and decreased copper absorption (8). While vomiting is reported more often in zinc supplemented children (Risk Ratio 1.71, 95% CI: 1.27–1.99), significant heterogeneity among studies does exist supporting the theory that the rates of vomiting may vary depending on the quality of the zinc supplement provided to the children and is thus not an adverse reaction expected from all products. Decreased copper absorption has not been shown to be a sequela of a short course of zinc supplementation for diarrhoea management (8).
In our review, we included 13 studies of various study designs that included data on the effect of zinc on severe diarrhoea and mortality outcomes (9). Four studies reported the effect of zinc for diarrhoea treatment on all-cause mortality with an overall relative reduction of 46% (95% CI: 12–68%). In areas where routine zinc supplementation was offered in a community-based programme, diarrhoea hospitalizations were decreased by 23% (95% CI: 15–31%, n=2). Given the small number of deaths (less than 50 total) recorded in the studies included in the mortality meta-analysis (i.e. the number of events which resulted in the 46% reduction), we chose the effect size for hospitalization, which was based on substantially more events and also represented the more conservative estimate. The final estimated effect to be included in the LiST program planning tool was chosen as 23%, i.e. zinc supplementation for the treatment of diarrhoea has the potential to reduce diarrhoea mortality by 23% if widely implemented.
Applicability of the results
The results from the three systematic reviews presented here consistently show a benefit of zinc for the treatment of acute and persistent diarrhoea, leading to decreased duration and severity, fewer hospitalizations and lower child mortality (7-9). There are numerous other quality systematic reviews that have been published with all reporting the benefit of zinc for diarrhoea treatment (10–14). Though effect size varies by inclusion and exclusion criteria and statistical approach, the conclusion has remained consistent in that zinc is an effective treatment. The studies included in the reviews were conducted in generalized populations of children with diarrhoea under five years of age. While diarrhoea can be caused by numerous infectious pathogens, these studies did not differentiate between pathogens therefore increasing the applicability of the results to all children under five with diarrhoea.
In a recent review of the heterogeneity between studies, Patel et al pointed out that there the heterogeneity for some outcomes is very strong and argued that this be explored further to determine if subgroups of children might respond better (or worse) to zinc treatment than others (10). Age above or below six months does appear to be one obvious subgroup analysis worth further investigation. While the effect sizes between infants greater or less than six months of age presented in the two RCT reviews varied greatly by age, the difference has not been observed in the larger effectiveness studies (15, 16). Subgroup analyses such as pathogen-specific responses to zinc may be interesting scientifically, but the practical applicability of such results are rarely discussed from the implementation or programmatic side of intervention delivery strategies.
Implementation in settings with limited resources
Zinc for the treatment of diarrhoea is not yet a widespread intervention in most low- and middle-income countries. This is unfortunate because it is the only promoted adjunct treatment to oral rehydration salts for all childhood diarrhoea episodes. In addition to being effective and safe, it is also inexpensive and has been touted as one of the “best buys” in child health (17). Countries should be including zinc on their national Essential Medicines List and thus incorporating zinc as part of the routine public sector care offered to children with diarrhoea. Zinc has already been included in all Integrated Management of Childhood Illnesses (IMCI) manuals and trainings, and programme guidelines for introducing zinc are available in many languages (http://www.who.int/child_adolescent_health/documents/en/). In many countries the cost of buying zinc to the consumer in the private sector is similar to what they are currently being charged for ineffective antibiotics and, unlike antibiotics, zinc treatment can decrease the risk for severe disease resulting in cost-savings as expensive hospital stays and lost parent wages are avoided.
While zinc has been proven effective in many different populations we still lack the knowledge with regard to the best delivery strategies and how to introduce zinc into a health system that already struggles to treat children with basic oral rehydration salts on a regular basis. When supply chains are broken or mismanaged and diarrhoea treatment is not a priority, the addition of zinc is not a quick fix. Additional research is needed as to how to best overcome many of these obstacles. As countries begin to introduce zinc there will be new questions that arise such as how do programmes ensure the treatment is reaching the poorest people, and what messages best encourage compliance with the full 10–14 day treatment. Answers to these operations research questions will greatly improve the quality of new programmes as they tackle the early intervention challenges.
It is critical to ensure that zinc and oral rehydration salts are widely available within the community and promoted as a community-based treatment within all sectors of the health-care system. For most episodes of diarrhoea, case management does not need to be complex and home-based care with zinc and oral rehydration salts is adequate. Country programmes that quickly adopt and promote zinc for the treatment of diarrhoea will ensure that quick strides are made to reducing child morbidity and mortality from diarrhoea.
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The named authors alone are responsible for the views expressed in this document.
Declarations of interests
Conflict of interest statements were collected from all named authors and no conflicts were identified.