Vitamin A supplementation as therapy—are the benefits disease specific?

The report by Fawzi et al (1) in this issue of the Journal describes the results of a randomized, double-blind, placebocontrolled study conducted in a hospital in Dar es Salaam, Tanzania, to test whether vitamin A can reduce the severity of pneumonia. In this study, 687 children between 6 and 60 mo of age who were admitted to the hospital for nonmeasles pneumonia were randomly assigned to receive 100 000 IU (30 mg retinol equivalents; infants < 1 y of age) or 200 000 IU (60 mg retinol equivalents) vitamin A, or a placebo, on 2 consecutive days. The evaluation included mortality, duration of hospitalization, and the clinical severity of the pneumonia as assessed by a variety of symptoms. The report is important for being a carefully randomized, well-monitored, relatively large study conducted within an urban hospital setting to evaluate vitamin A as a treatment for an existing infectious disease. The authors report that vitamin A did not reduce mortality from nonmeasles pneumonia [relative risk (RR) = 1.63]. The 63% greater mortality in vitamin A‐treated children was based on small numbers of children (13 in the vitamin A group compared with 8 in the placebo group) and was not statistically significant ( P = 0.28). The lack of any beneficial effect and a trend toward increased mortality after vitamin A treatment is consistent with the results of community vitamin A supplementation trials in which there was no apparent beneficial effect (2), or with studies in Indonesia (3) and Nepal (4), in which high-dose vitamin A supplementation increased symptoms of respiratory illness (3) and mortality in infants (4). It is now widely accepted that improving the vitamin A status of preschool-age children in populations at risk of vitamin A deficiency is an effective, low-cost means of improving child survival (5‐7). Reductions in all-cause mortality after the administration of vitamin A have been shown in several communitybased intervention studies. However, using data combined from several large trials, Beaton et al (6) calculated that vitamin A had no effect on mortality from respiratory diseases (RR of vitamin A compared with control = 0.99). This value is striking when compared with the highly significant reduction by vitamin A of all-cause mortality (RR = 0.73, P < 0.000) and of mortality associated with diarrhea (RR = 0.68, P < 0.000) and measles (RR = 0.74, P = 0.083) (6). A further meta-analysis of field trial data to assess the effect of vitamin A supplementation on pneumonia morbidity and mortality likewise led to the conclusion that, despite a significant reduction in all-cause mortality in both infants and children, there was no significant effect on pneumonia incidence (RR = 0.95) or pneumonia-related mortality (RR = 0.99) (2). The lack of benefit of vitamin A in pneumonia is all the more surprising because the epithelia of the trachea and respiratory tree are among the first tissues to show histologic changes characteristic of vitamin A deficiency. One possible explanation for the lack of effect of vitamin A in Fawzi et al’s hospital study could be that the Tanzanian children in this study were not sufficiently vitamin A deficient to respond to treatment with vitamin A. The authors have begun an analysis of dietary intake that is reported in part in this issue (1). Most children had vitamin A intakes that were not far below the US recommended dietary allowance (8). Children in the lowest decile of vitamin A intake consumed about one-third of the recommended dietary allowance, but nevertheless, their outcomes did not differ from those of children whose vitamin A intakes were higher. Thus, the vitamin A status of most of these children