Vitamin A deficiency predisposes children to infection by suppression of humoral and cell mediated immunity as well as changes in the respiratory epithelium(1). Infection in turn reduces the absorption of vitamin A further depleting vitamin A stores and making the child more susceptible to infections resulting in a vicious cycle of events. Though vitamin A supplementation did not appear to be associated with a significant decrease in mortality from acute respiratory infections(2), supplementation to children in Australia with recurrent respiratory infections and no clinical evidence of vitamin A deficiency was shown to reduce the number of episodes of respiratory infections(3). Thus, it is likely that vitamin A supplementation may reduce morbidity due to respiratory infections, though it has no effect on mortality. Since vitamin A deficiency is common in India, we hypothesized that the protective effect of vitamin A in children with recurrent respiratory infections is likely to be more pronounced here. The present trial was therefore designed to evaluate the effect of vitamin A supplementation in children with recurrent respiratory infections.

This study was conducted in the outpatient clinic of our hospital. Children aged 12 to 60 months, with a history of recurrent respiratory infections were enrolled in the study with informed consent from the parents.

Respiratory infection was defined as pre-sence of rhinorrhea or cough with or without fever, tachypnea or chest indrawing(4,5). Recurrent respiratory infection was defined as 3 or more separate episodes of respiratory illnesses or more than 15 days of respiratory symptoms in the past 3 months(3). Children with mild or moderate persistent asthma were excluded. However, episodes of wheezing triggered by ARI (i.e., preceding rhinorrhea, cough, fever) were counted. Children who were on vitamin supplements or who had received a massive dose of vitamin A in the previous 6 months, those with pre-existing congenital heart disease, chronic lung disease, pulmonary tuberculosis or immunodeficiency disorders, those on immunosuppressive drugs and those with clinically apparent vitamin A deficiency were excluded.

All the included children were followed up monthly in the outpatient clinic using a standard follow-up protocol. The parents were given a monthly calendar and were instructed to record the occurrence of any of the following symptoms daily; runny or blocked nose, sore/scratchy throat, dry cough, chesty or moist cough, wheezy breathing, shortness of breath and fever. Details of doctor or outpatient visits and hospital admissions during the study period were also recorded. During each monthly follow-up visit, the entries in the monthly calendar were reviewed with the parent.

Blood sample for estimation of serum retinol was collected before administration of vitamin A/placebo and again 3 months later. The sera were separated and stored at –70º C and analyzed for serum retinol levels using high performance liquid chromato-graphy. Paired sera from each child were tested in the same batch.

The primary outcome was the number of episodes of respiratory infection during the 6-months follow up period. For the purpose of analysis, an episode was defined as one or more days of symptoms preceded by 2 or more symptom free days.

Statistical analysis was carried out using the SPSS PC+ programme. Student’s ‘t’ test and the Chi-square test were used to determine the statistical significance of the differences detected between the two groups.

Sixty-one children, 37 boys and 24 girls, were included in the study. Table I shows the characteristics of children in the two groups at entry. Of the 61 included children, seven (three in the placebo group and four in vitamin A group) did not return for follow-up. The mean duration of follow-up for the remaining 54 children was 154 ± 35 days; 26 children completed 180 days of follow-up.

On follow up, no significant difference was found in the mean number of ARI episodes or mean days of respiratory symptoms between the children in the two groups (Table II).

At recruitment, 15 (27.8%) children, seven in the control group and eight in the treatment group had serum retinol <10 µg /ml. At the end of 12 weeks, 14(25.9%) children (8 placebo and 6 vitamin A) still had serum retinol levels <10 µg/ml. The mean ±SD pre-supplement serum retinol levels in children who received placebo and vitamin A were 25.91 ± 11.8 and 26.6 ± 14.0, respectively, (p = 0.84) and the post- supplement levels were 32.3 ± 7 and 33.9 ± 10.5, respectively. In the vitamin A group the post- supplement level was significantly higher than the pre-supplement level (p = 0.044). The post- supplement serum retinol levels between the two groups were not significantly different (p = 0.457).

There was no difference between the groups even when the children were stratified by pre-supplementation vitamin A level or wheezing episodes (data not shown). There was also no significant difference in the mean number of outpatient clinic visits for inter-current illnesses (2.1 ± 2.4 vs l.34 ± 1.4, p = 0.17) or in the mean weight gain between the two groups (0.6679 ± 0.66 vs 0.7385 ± 0.78 Kg, p = 0.72 placebo vs vitamin A).

The study did not show any effect of vitamin A supplementation on the frequency or duration of recurrent respiratory infections. Though the sample size achieved was slightly below that intended, we do not believe that this could be the reason for the lack of effect. This was despite the fact that the pre-supple-mentation levels of vitamin A were consider-ably lower in these children than in the Australian children in whom a benefit was demonstrated(3).

Table I - Baseline Characteristics of Children Receiving Placebo or Vitamin A

Table II - Frequency and Duration of Respiratory Symptoms During Follow-up

We could also not demonstrate the efficacy of vitamin A supplementation in the subgroup of children with subclinical vitamin A deficiency at inclusion into the study or a correlation between baseline serum retinol levels and subsequent infection. It is possible that factors other than vitamin A deficiency contributed to susceptibility to respiratory infection in this group.

A surprising finding in the study was that the mean serum retinol levels done 12 weeks after placebo administration was also higher than pre-supplement levels. This could be due to the decrease in the serum retinol activity in the pretreatment samples with storage since all the sera were tested together 6 months after supplementation. Seasonal changes in the diet also may have contributed to the increase in the serum retinol levels in the placebo group. Also, post-supplement levels in the vitamin A supplemented group were not significantly higher than the placebo group. A similar observation was noted by Pereira and Begum who noted that after a loading dose of 50,000 µg of vitamin A, serum vitamin A levels came back to below 15 µg/ml at 18 weeks(8). However, it is known that serum levels need not necessarily reflect the body vitamin A status as most of the vitamin A after a large dose gets stored in the liver. Frequent respiratory infections by themselves have been shown to prevent a rise in serum retinol levels(9). Hence, it is possible that the dose of vitamin A as administered in the National Vitamin A Prophylaxis Programme was not adequate to raise the retinol levels and protect children with frequent ARI.

It is likely that a combination of factors may have resulted in the lack of efficacy of vitamin A supplementation in our study. Trials evaluating different dosages, frequency of administration and formulations of vitamin A are required to delineate supplementation regimes which may result in sustained improvement in the retinol levels and thereby have a better clinical effect.

Funding: Field research grant, Christian Medical College and Hospital, Vellore.
Competing interests: None stated.

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