In this guest blog for IZiNCG, Dr Maxwell A Barffour and Dr Guy-Marino Hinnouho provide insights from a recent publication titled Effects of therapeutic zinc supplementation for diarrhea and two preventive zinc supplementation regimens on the incidence and duration of diarrhea and acute respiratory tract infections in rural Laotian children: A randomized controlled trial.
Background
Over 500,000 young children die from complications of diarrhea each year, with a disproportionately higher burden (>90%) in low- and middle-income countries. Since, 2004, the World Health Organization and UNICEF have recommended the use of therapeutic zinc, along with oral rehydration therapy (ORS), for the treatment of acute diarrhea episodes [1, 2]. This strategy, which requires the use of 20 mg zinc, given daily for 10-14 days during diarrhea episodes, is supported by results of several trials and reviews, which collectively indicate that in children 6 months and older, adjunctive treatment of diarrhea with zinc reduces diarrhea severity. Specifically, the evidence suggests that therapeutic zinc shortens the duration of diarrhea and reduces the number of episodes progressing to persistent diarrhea [3]. Limited evidence also suggests that therapeutic zinc may reduce the incidence of new diarrhea episodes in the 2-3 months following treatment initiation [4].
There are several limitations to a therapeutic approach to zinc supplementation. Because this strategy requires appropriate recognition of diarrhea, motivation to seek treatment and access to a health care facility, coverage is often low [5, 6]. In addition, this strategy has not been shown to affect other functional outcomes related to zinc deficiency, such as physical growth and risk of pneumonia. Hence a goal of this study was to compare the health benefits of therapeutic and preventive strategies for delivering zinc. Furthermore, when delivered as a preventive supplement, zinc may be given as a single zinc-alone supplement, or as part of a multiple micronutrient powder (MNP). Generally, MNP formulations are deemed more desirable because of the ability to target multiple micronutrient deficiencies. However, some evidence suggests that because zinc interacts with other nutrients, zinc delivered as part of MNP may not be as effective as zinc delivered alone. Therefore, an additional goal of this study was to compare two preventive zinc strategies (i.e. zinc alone or MNP) with respect to their effect on diarrhea outcomes.
Photo credit: Sonja Hess
Study Design and Study Population
This blog summarizes a study published in the Journal of Global Health which aimed to assess the benefits of two preventive zinc supplementation regimens and a therapeutic zinc supplementation for diarrhea, on the incidence and duration of diarrhea episodes [7]. The trial was implemented from September 2015 through April 2017 in rural communities in Khammouane Province, Lao PDR. The province was selected because of the high prevalence of stunting [8], a proxy indicator of zinc deficiency. In addition, the province had no existing programs delivering micronutrient interventions at the time of the study. A pilot survey completed in 2015 found that ~62% of children (6- 23 months) were zinc deficient (plasma zinc concentrations <65 μg/dL).
The study included children 6-23 months at enrollment [9]. Children were randomly assigned to one of four groups, namely a preventive zinc group (7mg zinc /d as dispersible tablet), a therapeutic zinc group (20 mg/d for 10 days) given in relation to diarrhea episodes, and a daily preventive MNP group (containing 10 mg zinc, 6 mg iron + 13 other micronutrients). A fourth group, the control group, received a daily placebo powder, and in addition, a placebo tablet during diarrhea episodes. Each child was followed for up to 9 months, or until lost to follow-up. Reported diarrhea episodes were assessed during weekly home visit. Diarrhea was defined as 3 or more lose stools in a 24-hr period.
Photo credit: Maxwell Barffour
Photo credit: Maxwell Barffour
Relevant baseline characteristics and compliance
Overall, 3407 eligible children were enrolled and randomized into one of the four groups (i.e. therapeutic zinc (n=851), preventive zinc (n=852), MNP (n=852) and control (n=852)). About 87% of the children enrolled completed the scheduled 9 months of follow-up. The participants who completed the study were similar to those who did not with respect to age and other baseline characteristics including anemia.
The mean age of participating children was 14 months, and the prevalence of stunting (40%), and anemia (55%) suggested a population with a high prevalence of chronic malnutrition. Most of the children (>70%) were breastfed at the time of the baseline survey. Reported adherence to the daily preventive supplements was 92%. Diarrhea treatment was initiated for ~87% of all diarrhea episodes, and on average, 7 out of the 10 tablets were given to children who needed treatment for diarrhea.
Main results
Overall, 2013 children (representing ~60% of the study population) experienced at least one diarrhea episode during the course of the follow-up. The overall incidence of acute diarrhea was low ( <1 episode per 100 days at risk) and each episode lasted about 2 days. There was no overall difference in either the diarrhea incidence or duration across the four groups. Because previous studies have established that the impact of zinc on diarrhea tended to vary by age, a goal of this study was to also assess evidence of such age variation. We found that older children (i.e. those 18 months of age and above) tended to benefit from the therapeutic zinc supplementation. In this age group, the duration of diarrhea was significantly lower in those who received the therapeutic zinc compared to the control group. Similarly, the incidence of recurrent diarrhea episodes (i.e. episodes occurring after a prior diagnosis) was significantly reduced among the therapeutic zinc group compared to the control group. The preventive zinc and the MNP had no impact on diarrhea incidence or duration, regardless of the child’s age. Also, noteworthy, the MNP was not associated with an overall adverse effect on diarrhea incidence or duration.
Concluding remarks
Finding of this study suggest that therapeutic zinc may confer protective benefits against diarrhea in this population, especially if delivered to older children. It is plausible that the observed impact seen in older children may be due to a zinc-dependent enhancement in adaptive immune response. Contrary to evidence from several prior studies and systematic reviews, preventive zinc did not have an impact on diarrhea in this population. This lack of effect may have been due to the fact that the overall incidence of diarrhea in this population was relatively lower than those observed in other populations. Finally, the MNP, which contained a daily iron dose of 6 mg was not associated with an overall increase in the diarrhea incidence. It is worth mentioning that in children with genetic hemoglobinopathies, the MNP was associated with a small increase in diarrhea incidence. Overall, the findings from this study highlight the need for continuing research to find optimal strategies for improving nutritional and health status in this population.
Additional findings from the Lao Zinc Study
The Lao zinc study was also designed to assess treatment effect on micronutrient status, anemia and physical growth. Below is a summary of findings as published in the Journal of Pediatrics [10]:
Therapeutic zinc had no impact on zinc, iron or vitamin A status.
Preventive zinc significantly improved zinc status.
MNP improved zinc and iron status.
MNP had a marginal positive impact on hemoglobin and anemia, with a significant impact among children who were anemic at baseline.
Photo credit: Maxwell Barffour
Relevant references
1. WHO, U., Clinical management of acute diarrhoea in children: WHO/UNICEF joint statement. Geneva: World Health Organization; 2004. http://www.who.int/maternal_child_adolescent/documents/who_fch_cah_04_7/en/, 2004.
2. World Health Organization; UNICEF., Zinc supplementation in the management of diarrhoea.http://www.who.int/elena/titles/zinc_diarrhoea/en/ 2016. Accessed 2016 September 28.
3. Lazzerini, M. and H. Wanzira, Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev, 2016. 12: p. Cd005436.
4. Baqui, A.H., et al., Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial. BMJ, 2002. 325(7372): p. 1059.
5. Sabot, O., et al., Scaling up oral rehydration salts and zinc for the treatment of diarrhoea. Bmj, 2012. 344: p. e940.
6. Ram, P.K., et al., Declines in case management of diarrhoea among children less than five years old. Bull World Health Organ, 2008. 86(3): p. E-f.
7. Barffour MA, Hinnouho GM, Wessells KR, et al. Effects of therapeutic zinc supplementation for diarrhea and two preventive zinc supplementation regimens on the incidence and duration of diarrhea and acute respiratory tract infections in rural Laotian children: A randomized controlled trial. J Glob Health. 2020;10(1):010424. doi:10.7189/jogh.10.010424
8. Bureau., M.o.H.a.L.S., Lao People's Democratic Republic Special, 2011–12 - Lao Social Indicator Survey (MICS/DHS) Final Report (English) Vientiane: Ministry of Health and Lao Statistics Bureau. 2012.
9. Wessells, K.R., et al., Comparison of two forms of daily preventive zinc supplementation versus therapeutic zinc supplementation for diarrhea on young children’s physical growth and risk of infection: study design and rationale for a randomized controlled trial. BMC Nutrition, 2018. 4(1): p. 39.
10. Barffour, M.A., et al., Effects of Daily Zinc, Daily Multiple Micronutrient Powder, or Therapeutic Zinc Supplementation for Diarrhea Prevention on Physical Growth, Anemia, and Micronutrient Status in Rural Laotian Children: A Randomized Controlled Trial. J Pediatr, 2018.
Contact:
Maxwell A Barffour, Missouri State University, MaxwellABarffour@missouristate.edu
Read more on this topic:
Preventive zinc supplementation in children
Zinc as part of the treatment of diarrhea