Zinc is an essential micronutrient associated with over 300 biological functions. Marginal zinc deficiency states are common among children living in poverty and exposed to diets either low in zinc or high in phytates that compromise zinc uptake. These children are at increased risk of morbidity due to infectious diseases, including diarrhoea and respiratory infection. Children aged less than five years (under-five children) and those exposed to zinc-deficient diets will benefit from either daily supplementation of zinc or a 10 to 14-day course of zinc treatment for an episode of acute diarrhoea. This includes less severe illness and a reduced likelihood of repeat episodes of diarrhoea. Given these findings, the World Health Organization/United Nations Children’s Fund now recommend that all children with an acute diarrhoeal illness be treated with zinc, regardless of aetiology. ICDDR.B scientists have led the way in identifying the benefits of zinc. Now, in partnership with the Ministry of Health and Family Welfare, Government of Bangladesh and the private sector, the first national scaling up of zinc treatment has been carried out. Important challenges remain in terms of reaching the poorest families and those living in remote areas of Bangladesh.

INTRODUCTION

It is now over a decade since the publication of the landmark articles by Sazawal et al. and Roy et al. which demonstrated the efficacy of orally-administered zinc in the treatment of acute childhood diarrhoea (1,2). Since then, several randomized hospital- and community-based trials have consistently demonstrated the efficacy of zinc treatment for acute or persistent diarrhoea in children aged less than five years (under-five children) (3-6). Pooled analyses of published data demonstrate that zinc reduces the duration and severity of acute diarrhoea and the likelihood of a prolonged episode (7,8). Results from these efficacy trials were then replicated by a community-based, effectiveness trial of zinc treatment for acute childhood diarrhoea carried out in the ICDDR, B rural field site in Matlab. In this trial in which children received daily zinc treatment for each episode of diarrhoea, children in the zinc intervention group had a shorter duration of illness, a reduced likelihood of a repeat episode of diarrhoea, and non-injury mortality. The reduction in mortality was very substantial (50%) (9). This study and several more-cited investigations were carried out by scientists at ICDDR, B who continue to study the effects of zinc on diarrhoeal and other illnesses, most notably childhood pneumonia.

The World Health Organization (WHO) has estimated the global annual burden of mortality attributable to zinc deficiency to be 750,000 deaths (10). It is anticipated that over one-half of these deaths could be averted through the successful application of zinc as a treatment for childhood diarrhoea (11). Given this potential reduction in mortality and the strength of the evidence at hand in support of zinc treatment, the WHO/United Nations Children’s Fund (UNICEF) issued, in May 2004, a joint statement on updated guidelines for the management of childhood diarrhoea (12). This includes the recommendation that all under-five children be treated with zinc (20 mg/day if age is 6-59 months and 10 mg/day if age is less than six months) for 10-14 days. This recommendation is now a policy of the Ministry of Health and Family Welfare, Government of Bangladesh, with a slight modification to include children starting at two months of age.

• Zinc deficiency is estimated to be related to 750,000 deaths annually.
• WHO and UNICEF now recommend 10-14 days of zinc treatment for under-five children with each diarrhoea illness.
• Zinc treatment is inexpensive, safe, and easy.
• Zinc treatment shortens the diarrhoea episode, reduces the risk of episode being persistent, and reduces the risk of future diarrhoea or pneumonia.
• Zinc treatment reduces overall mortality.
• Now the task is to provide zinc treatment to every child in Bangladesh with each episode of diarrhoea.

This paper summarizes our understanding of zinc deficiency in children, its relationship with childhood morbidity and mortality, the strategies that have been tested to supplement zinc, and the bene-fits of these interventions. This is followed by a discussion of future research priorities and their applicability to health policy and planning.

ZINC DEFICIENCY IN EARLY CHILDHOOD

Population-based estimates of the occurrence of zinc deficiency in young children are hindered by the lack of an accurate measure of zinc status. Current estimates are based upon one or a combination of zinc-deficiency indicator(s). These include rates of stunting, the amount of zinc in national food supplies, serum zinc levels, and histories of dietary intake.

Despite the limitations in accurately estimating zinc levels, it is now recognized that mild-to-moderate zinc deficiency due to inadequate dietary intake is prevalent in all parts of the world. The higher prevalence of zinc deficiency in developing countries is due primarily to low intake of zinc from animal sources, high dietary phytate content (that limits the bioavailability of zinc), and inadequate food intake (13). A population-level analysis from national food-balance sheets has estimated that 21% of the world population is at risk of inadequate zinc intake; however, the percentages are much higher in least-developed countries (14,15). These children are especially prone to zinc deficiency because of poor dietary quality and increased faecal loss of zinc due to repeated gastrointestinal infections (8). Children with modest levels of chronic zinc deficiency do not manifest any observable clinical signs that would alert clinicians to its presence, thus making it a hidden disorder. Bangladesh has one of the highest prevalence levels in the world, affecting over 50% of all under-five children (15).

Being a micronutrient component in many metallo-enzymes and poly-ribosomes involved in cellular function, zinc supports normal growth and development during pregnancy, childhood, and adolescence (16). It is essential for metabolism, cellular growth, and immune function (17). Despite its essential role, overt clinical syndromes associated with zinc deficiency in humans are rare.

The first published description of clinically-evident zinc deficiency due to nutritional causes in otherwise normal humans was documented in the Middle East in the 1960s among adolescent boys, characterized by stunted growth and delayed sexual maturation that were reversible with supplementation of zinc (18). One well-known zinc-deficiency disorder with overt clinical signs is acrodermatitis enteropathica, a genetic autosomal recessive disease with an inborn defect in metabolism that results in reduced intestinal absorption of zinc (19). The discovery of this genetic disorder and its rapid resolution when treated with zinc alerted clinicians to the potential impact of zinc as a clinical deficiency disorder in humans. Not long after this discovery, zinc deficiency was also found to occur in adult patients on total parenteral nutrition, which was attributable to the failure to add zinc in the intravenous infusates (20,21). These individuals suffered from loss of memory, skin disorders, loss of taste, and increased susceptibility to infection—all of which disappeared when zinc was added.

It is now well-known that mild-to-moderate zinc deficiency due to inadequate dietary intake is pre-valent in all parts of the world, with higher pre-valence in developing countries, due primarily to low intake of zinc from animal sources, high dietary phytate content, and inadequate food intake (13).

ZINC, INFECTION, AND IMMUNITY

Closely linked to these effects is the important role it plays in maintaining normal immune function. Results of studies have suggested that zinc deficiency impairs cell regeneration, epithelial barrier functions, and linear growth (22). Zinc deficiency also impairs immunocompetence with reduced cell-mediated immune responses, decreased T-lymphocytes, abnormal T-helper and/or suppressor functions, impaired macrophage function, and reduced killer cells and antibody-dependent cytotoxicity (23,24). The levels of complement in blood increases with supplementation of zinc in children with acute diarrhoea (Qadri F. Personal communication, 2006). Zinc levels also modulate the function of monocytes, macrophages, and neutrophils polymorphs and in the release of reactive free radicals from phagocytes (23). These impairments in immune function occur even with modest levels of zinc deficiency.

The possible mechanisms of the effect of zinc treatment on the duration and severity of diarrhoea include improved absorption of water and electrolytes by the intestines (25-27), regeneration of gut epithelium (28-31), increased levels of enterocyte brush-border enzymes (32,33), and enhanced immunologic mechanisms for the clearance of infection. Supplementation of zinc improves immunity (34-36) and may, hence, promote rapid clearance of diarrhoeal pathogens from the intestine.

Innate immunity is the body’s first line of defence to pathogens, and its functions are also disturbed by altered zinc levels. Natural killer cell numbers and function are dependent on normal levels of serum zinc (37). These levels also modulate the function of monocytes, macrophages, and neutrophils (23). Zinc is also required for the development and activation of T-lymphocytes. When zinc supplements are given to individuals having low levels of zinc, the numbers of T-cell lymphocytes circulating in the blood increase, and the ability of lymphocytes to fight against infection improves.

ZINC DEFICIENCY AND MORBIDITY

Given the numerous biologic functions dependent upon normal levels of zinc, particularly immunity, it is not surprising to find that zinc deficiency is associated with numerous infectious illnesses, but the link between diarrhoea and zinc is especially well-established. Diarrhoea leads to loss of zinc and abnormalities of zinc metabolism. Substantial amounts of zinc are lost during acute diarrhoea: daily losses of zinc during diarrhoea can be as high as 160 µg/kg per day in children (38).

How important are marginal deficiencies in zinc? Clinical and field studies have consistently observed an association between zinc deficiency and morbidity due to infectious diseases, particularly diarrhoea in early childhood (39-41). Marginal zinc deficiency is associated with about a 50% increased risk and number of days with diarrhoea. However, zinc deficiency results in higher rates of other infectious diseases as well, including skin infections, respiratory infections, malaria, and delayed wound healing (17). Overall, zinc-deficient children are at a three-fold increased risk of an acute respiratory infection (40,41).