Zinc and Infectious Disease
studies of mice and men
Tor A. Strand, 2003
Zinc is an essential trace element important for almost all biological systems. Zinc nutriture is likely to be suboptimal in many children of developing countries and may contribute to their impaired growth, increased susceptibility to infections and possibly to the high mortality. A large proportion of childhood deaths in developing countries are caused by diarrhea and pneumonia. Impaired zinc nutriture seems to play a role in the increased incidence and severity of these infections.
As a basis for this thesis work, we undertook two randomized placebo controlled trials and two animal experiments to study the effect of zinc in common childhood illnesses. In Nepal, 1,792 children were randomized to receive zinc or placebo. This trial was designed to assess: the efficacy of oral zinc given during acute diarrhea, whether zinc was as effective when given by the caretaker as when given by a trained field worker, whether the effect of zinc was dependent on concomitant vitamin A administration, whether zinc was associated with any adverse effects, and whether there was any beneficial effect of zinc administration beyond the enrollment episode. Furthermore, a blood sample drawn at enrollment enabled us to measure the associations between the plasma zinc concentration and markers of infection severity. In another trial in 2,482 Indian children, we assessed whether daily zinc administration for 4 months reduced the incidence and risk of acute lower respiratory tract infections (ALRI) and pneumonia. Two animal experiments were carried out to assess whether zinc depleted mice had reduced immune responses to pneumococcal antigens, whether they had an increased infection severity following mucosal pneumococcal challenge, and whether immunization of mice with pneumococcal surface protein A (PspA) before challenge could reduce the infection severity and the inflammation-associated depletion of plasma and bone zinc.
Nepalese children that were given zinc during acute diarrhea had a substantial reduced risk of prolonged and persistent diarrhea. This study also demonstrated that the caretakers were excellent providers of zinc and that the effect of zinc was not dependent on vitamin A administration. Zinc administration, however, was not associated with a reduced incidence of ALRI, pneumonia or diarrhea during the month after cessation of the enrollment episode. The plasma zinc concentration was lower in children with elevated axillary temperature, increased plasma C-reactive protein (CRP) concentrations and in those with dysentery upon enrollment. In the trial on routine zinc administration in Indian children, the proportion of children who had ALRI was not different in the two experimental groups. Zinc supplementation, however, substantially reduced the risk of clinical pneumonia. Vomiting was more common in children receiving zinc in both clinical trials.
In the first animal experiment, there was no measurable effect of zinc depletion on the anti-pneumococcal polysaccharide T cell independent IgM response. However, in the second experiment, mice on the zinc deficient diet showed substantially reduced T cell dependent immune responses to PspA, more extensive pneumococcal colonization in the nasal mucosa, more severe infections and an increased risk of death. PspA immunization reduced the risk of severe disease; the reduction in severity was reflected in substantially reduced zinc depletion from bones and plasma but not in a measurable reduction in the death risk.
Zinc administration reduced the incidence and risk of clinical pneumonia, which is a serious infection that causes 2-3 million deaths in young children every year. Another 2-3 million children die of diarrhea every year and most of these deaths are associated with prolonged episodes. Thus, a substantial decrease in the incidence of pneumonia with improvement of zinc nutriture and a reduction in the risk of persistent diarrhea with adjunct zinc therapy may contribute to improving child health and survival in developing countries.