ZINC FOR CHILD HEALTH IMPLICATIONS OF RESEARCH FINDINGS

Chandyo R K * , Strand T A ** Malnutrition and various micronutrient deficiencies are widespread in developing countries. Although the role of vitamin A and iron in child health has been acknowledged for a long time, the importance of zinc has not been recognized until recently. Indeed, zinc is a micronutrient of great public health importance. Recent research has indicated that prevention of zinc deficiency among young children in developing countries could have a significant impact on health as well as the economy. In the near future, the World Health Organization (WHO) will recommend oral zinc for the treatment of acute and persistent diarrhea in young children. The WHO has also proposed to include zinc in its essential medicine list. Several key issues regarding zinc research and the impact of zinc on child health will be discussed in this paper.


INTRODUCTION
Zinc is an essential micronutrient and zinc deficiency is common in many developing countries leaving those affected more vulnerable to illness and death from infectious diseases. 1,2n many developing countries the intake of zinc dense foods such as meat and seafood is low and the intake of foods with zinc inhibitors such as phytate in cereals and legumes, is high. 3- 5Frequent infections further impair the zinc status and worsen its consequences.This vicious cycle of sub-optimal nutrition and repeated infection results in a high burden of zinc deficiency in the developing countries, such as Nepal.The severe form of zinc deficiency leading to acrodermatitis enteropathica is not common, but marginal and moderate zinc deficiency is a widespread problem and is thought to affect more than 90% of the population in South Asia. 6,7In Nepal, two thirds of young children are malnourished. 8There is compelling evidence from animal and human studies that zinc

TOXICITY OF ZINC
Zinc is a non-toxic mineral and excess dietary intake is not absorbed and stored in body.However, some studies have reported increased vomiting due to zinc supplementation. 12,14his increased vomiting was not serious and did not affect the long-term health of the children.

ZINC FOR GROWTH AND DEVELOPMENT
Zinc is thought to enhances growth and development through several potential mechanisms, which are presented in Fig. 1. [15][16][17] In a meta-analysis undertaken by Brown et al, it was found that zinc supplementation resulted in a substantial increase in height and weight, the mean change in SD units height for age and weight for age was 0.35 (95% CI 0.19, 0.51) and 0.31 (0.18, 0.44), respectively. 18The effect of zinc supplementation was larger among children who were malnourished (stunted).

PREVENTION OF DIARRHEA AND PNEUMONIA WITH ZINC
Clinical trials in children of developing countries have shown that routine zinc supplementation reduces the incidence and prevalence of diarrhea. 19,20A pooled analysis of zinc supplementation trials from developing countries assessed the efficacy of daily zinc administration on diarrheal morbidity.This analysis showed an 18% (95% CI 7%, 28%) lower incidence rate and a 25% (95% CI 12%, 37%) lower prevalence of diarrhea. 21This pooled analysis also included data for pneumonia from four trials [22][23][24][25] and showed that routine zinc supplementation reduced the odds of pneumonia by 41% (95% CI 17, 69%).In a subsequent study involving 2500 Indian children, Bhandari et al confirmed this protective effect of daily zinc administration on pneumonia. 19In this study there was no effect of zinc supplementation on mild pneumonia, but the effect was seen among those with severe pneumonia that usually included fever.The main preventive zinc supplementation trials and their effects on infectious diseases and mortality prevalence are presented in Table I.

TREATMENT OF DIARRHEA WITH ZINC
Sachdev and coworkers were the first to assess the therapeutic effects of zinc during diarrhea. 26In a study on acute diarrhea they found that children who were given 40 mg of daily elemental zinc had shorter diarrheal duration and lower stool frequency than the controls.Following this publication, several trials on zinc supplementation during acute and persistent diarrhea have been conducted and the results from many of these trials have been summarized in two pooled analyses. 27he analysis that included children with acute diarrhea showed that there was a 15% reduction of the duration in children receiving zinc (Table II) (Hazard ratio: 0.85, 95% CI 0.76, 0.95).In the trials that enrolled children with persistent diarrhea, therapeutic zinc reduced the time till recovery of diarrhea by 24% (Hazard ratio: 0.76, 95% CI 0.63, 0.91) and the risk of treatment failure or death by 42% (95% CI 10, 63%) (Table III).

ZINC
After these pooled analyses were published, more studies on the therapeutic use of zinc in diarrhea have been completed. 12,14,28,29The findings from these studies were presented in a WHO meeting in New Delhi in 2001 and the report from this meeting 30 states: "Based on the results of this review, it is concluded that there is now enough evidence demonstrating the efficacy of zinc supplementation on the clinical course of diarrhea, with regard to the severity and duration of the episode".

Table III : Studies evaluating therapeutic effects of zinc on episodes of prolonged diarrhea (>7 days)
promising and is supported by a recently published clusterrandomized trial in Bangladeshi children. 32This study also showed that there was a 50% reduction in mortality in clusters where children were given zinc along with standard treatment against diarrhea.It should be noted that there were only 40 fatalities and that children in the clusters that received zinc also had a higher intake of ORS. 30

ZINC AS ADJUVANT THERAPY FOR THE TREATMENT OF PNEUMONIA
Studies on routine zinc supplementation for the prevention of disease indicated substantial reductions in the prevalence of acute lower respiratory infection (ALRI).There is, however, limited information on zinc as adjuvant therapy for the treatment of ALRI.In a pneumonia study with Indian children there was an effect of zinc among boys, but not among girls. 33nother recently published study from Bangladesh among 270 young children with severe pneumonia indicated that zinc supplementation reduced the duration ?relative hazard (RH)= 0.70 (0.51, 0.98)? and hospital stay ?(RH 0.75 (0.57-0.99)?. 34 Currently, we are undertaking a randomized clinical trial in Bhaktapur involving 2500 young children with WHO defined pneumonia to evaluate the effect of zinc as an adjuvant therapy.The main outcome is time till recovery and proportion with treatment failure.

ZINC SUPPLEMENTATION FOR THE TREATMENT AND PREVENTION OF MALARIA
The results from studies evaluating the relation between zinc supplementation for the prevention and treatment of malaria are still inconclusive.Studies from Gambia and Papua New Guinea 35 revealed reductions of about one-third in the rate of visits to health facilities due to malaria among zinc supplemented children.However, a multicenter trial in Ecuador, Uganda and Zambia that assessed zinc as adjuvant therapy during plasmodium falciparum malaria in 1087 young children concluded that, "Zinc does not appear to provide a beneficial effect in the treatment of acute, uncomplicated falciparum malaria". 36

ZINC AND IMMUNITY
Zinc supplementation has been shown to improve cell mediated immunity (CMI) in children. 208][39] The size of thymus, which is a central organ for maturation and differentiation of T-lymphocytes also decrease during zinc deficiency, a process that is reversed after zinc supplementation. 40,41Although both acquired and innate immunity seems to play an important role in the effect of zinc during infections, 42,43 the relative importance of these parts of the immune system remains to be determined.Furthermore, zinc metabolism is altered in infectious diseases.During inflammation, the plasma zinc is shifted into the liver causing depletion in other tissues. 44Children who have poor zinc nutriture may thus be at a high risk of entering a vicious cycle of infection and zinc depletion.Breaking this vicious cycle is probably of great importance and may be the mechanism behind the beneficial effect on reduction of childhood morbidity and mortality.

ZINC FOR THE REDUCTION OF CHILDHOOD MORTALITY
As mentioned above, zinc administration in children of developing countries have shown a substantial reduction in the prevalence and severity of common infectious diseases such as pneumonia and diarrhea.Pneumonia and diarrhea are still major causes of under five-childhood mortality, so it is logical to consider that there will be a reduction in childhood mortality with a correction of zinc deficiency.Indeed, the Bellagio child survival study estimates that 5% of under five deaths can be averted by the implementation of a preventive zinc interventions program. 45This figure is supported by the findings from a trial in 1,154 small for gestational age children where zinc supplementation resulted in a 68% reduction in the risk of dying. 46A reduced death risk was also found among children belonging to clusters that received zinc as adjuvant therapy for acute diarrhea trial in Bangladesh. 32The WHO has followed up the promising results of these trials and is currently supporting three large clinical trials in India, Zanzibar and Nepal to evaluate the effect of zinc supplementation on childhood mortality.Thus, there is compelling evidence that zinc is beneficial for the improvement of child health, particularly in developing countries where zinc deficiency is estimated to be a widespread public health problem.Oral zinc should be included in routine treatment for acute diarrhea and actions to improve zinc nutriture should be pursued.These actions would include dietary diversification / modification to enhance the availability, access and utilization of zinc dense foods, food fortification, supplementation, and most importantly, poverty reduction.

Fig. 1 :?
Fig. 1 : The mechanisms of zinc for growth and development (Reproduced from reference 15)