Vitamin A supplementation to improve treatment outcomes among children diagnosed with respiratory infections
Biological, behavioural and contextual rationale
Acute lower respiratory tract infections, in particular bronchiolitis and pneumonia which are the most severe forms of acute lower respiratory tract infections, are the leading cause of mortality in children under the age of five1, 2. Pneumonia alone kills 1.8 million infants and young children every year3. Most of these likely preventable deaths occur in low-resource settings and are strongly linked to poverty, inadequate access to health care and undernutrition.
Several nutrition interventions have been shown to be effective in reducing the number of cases of acute lower respiratory tract infections and the potentially deadly outcomes associated with pneumonia. Vitamin A/retinol is involved in the production, growth and differentiation of red cells, lymph cells and antibodies4, and epithelial integrity. Because of its proven effectiveness in protecting against measles-associated pneumonia5, vitamin A supplementation has been investigated as a possible intervention to speed recovery, reduce the severity and prevent against subsequent episodes of acute lower respiratory tract infections6–11. The results have not been at all consistent. Some authors have reported no benefits6, 12–15, while others only described positive effects for specific groups such as underweight children16 or those with pre-existing vitamin A deficiency17. Vitamin A supplementation has also been found to increase the incidence of acute lower respiratory tract infections, mainly among children with better nutrient intakes16, 18.
Children with vitamin A deficiency seem to be at greater risk of illness and death due to respiratory tract infections19. Pre-existing deficiency appears to worsen infection and vitamin A supplementation has been shown to reduce the risk of death in 6–59 month old children by about 23–30%20. In the case of pneumonia that is associated with measles, large doses of vitamin A have a clear protective effect21, 22. Similar effects have not, however, been observed for acute lower respiratory tract infections using high and low doses of vitamin A. For example, lower doses have been associated with decreased risk of respiratory infection16, and high doses have been shown to have a negative effect23. There have been several theories put forward to try and explain the range of results and the possible biological mechanisms involved. For children with adequate vitamin A stores, supplementation with particularly high doses of vitamin A may cause a temporary malfunction in the regulation of immune function. This may result and perhaps lead to an increased susceptibility to infectious diseases18.
Two recent systematic reviews on the role of vitamin A supplementation in the prevention of respiratory infections among children have concluded that supplements should only be given to children with poor nutritional status1. The results also suggest that the dosage and potential adverse effects are important considerations when making recommendations1, 24. Over-dosage of vitamin A can cause toxicity that is associated with nausea, vomiting and loss of appetite that can further reduce nutrient intake. One study that evaluated the effects of a moderate dose of vitamin A found a positive effect among children with sufficient vitamin A intakes and no side effects of the supplementation were reported9. Whether or not these positive effects would be associated with the increased intake of vitamin A containing foods has not yet been examined. In low-resource settings with high rates of acute lower respiratory tract infections3, foods with significant vitamin A content such as animal products (liver, milk, cheese, eggs) or fortified foods may not be frequently eaten. Better access to foods rich in provitamin A, such as mangos and papayas, may therefore be necessary under these circumstances through dietary diversification and homestead food production programmes24–26.
1 Chen H et al. Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age. Cochrane Database of Systematic Reviews, 2008, Issue 1, No.: CD006090.
2 Dekker LH et al. Stunting associated with poor socioeconomic and maternal nutrition status and respiratory morbidity in Colombian schoolchildren. Food and Nutrition Bulletin, 2010, 31(2):242–250.
3 WHO/UNICEF. Global action plan for prevention and control of pneumonia (GAPP). Geneva, World Health Organization, 2009.
4 Olson JA. Vitamin A. In: Ziegler EE, Filer LJ, eds. Present knowledge in nutrition, 7th ed. Washington D.C., International Life Sciences Institute (ILSI) Press, 1996:109–19.
5 Ellison J. Intensive vitamin therapy in measles. British Medical Journal,1932, II:708–711.
6 Fawzi W et al. Vitamin A supplementation and severity of pneumonia in children admitted to the hospital in Dar es Salaam, Tanzania. American Journal of Clinical Nutrition, 1998, 68:187–192.
7 Julien et al. A randomized double-blind, placebo-controlled clinical trial of vitamin A in Mozambican children hospitalized with non-measles acute lower respiratory tract infections. Tropical Medicine and International Health, 1999, 4:794–800.
8 Nacul L et al. Randomised, double blind, placebo controlled clinical trial of efficacy of vitamin A treatment in non-measles childhood pneumonia. BMJ, 1997, 315:505–510.
9 Rodriguez A et al. Effects of moderate doses of vitamin A as an adjunct to the treatment of pneumonia in underweight and normal-weight children: a randomized, double-blind, placebo-controlled trial. American Journal of Clinical Nutrition, 2005, 82:1090–1096.
10 Stevensen C et al. Adverse effects of high-dose vitamin A supplements in children hospitalized with pneumonia. Pediatrics, 1998, 101:1–8.
11 Cameron C et al. Neonatal vitamin A deficiency and its impact on acute respiratory infections among preschool Inuit children. Canadian Journal of Public Health, 2008, 99(2):102–106.
12 Long KZ et al. Supplementation with vitamin A reduces watery diarrhoea and respiratory infections in Mexican children. British Journal of Nutrition, 2007, 97: 337–343.
13 Donnen P et al. Randomised placebo-controlled clinical trial of the effect of a single high dose or daily low doses of vitamin A on the morbidity of hospitalized, malnourished children. American Journal of Clinical Nutrition, 1998, 68:1254–1260.
14 Kjolhede C et al. Clinical trial of vitamin A as adjuvant treatment for lower respiratory tract infections. Journal of Pediatrics, 1995, 126:807–812.
15 The Vitamin A and Pneumonia Working Group. Potential interventions for the prevention of childhood pneumonia in developing countries: a meta-analysis of data from field trials to assess the impact of vitamin A supplementation on pneumonia morbidity and mortality. Bulletin of the World Health Organization, 1995, 73:609–619.
16 Sempertegui F et al. The beneficial effects of weekly low-dose vitamin A supplementation on acute lower respiratory infections and diarrhea in Ecuadorian children. Pediatrics, 1999, 104(1):e1.
17 Si NV et al. High dose vitamin A supplementation in the course of pneumonia in Vietnamese children. Acta Paediatrica, 1997, 86:1052–1055.
18 Grotto I et al. Vitamin A supplementation and childhood morbidity from diarrhea and respiratory infections: a meta-analysis. Journal of Pediatrics, 2003, 142:297–304.
19 Ross A. In: Sommer A, West K, eds. Vitamin A deficiency: health, survival and vision. New York, Oxford University Press, 1996:251–273.
20 Glasziou PP, Mackerras DE. Vitamin A supplementation in infectious diseases: a meta-analysis. BMJ, 1993, 306:366–370.
21 Hussey GD, Klein M. A randomized controlled trial of vitamin A in children with severe measles. New England Journal of Medicine, 1990, 323:160–164.
22 Barclay AIG et al. Vitamin A supplements and mortality related to measles: a randomized clinical trial. British Medical Journal, 1987, 294:294–296.
23 Wu T et al. Vitamin A for non-measles pneumonia in children. Cochrane Database of Systematic Reviews, 2005, Issue 3, No.: CD003700.
24 Global prevalence of vitamin A deficiency in populations at risk 1995-2005: WHO global database on vitamin A deficiency. Geneva, World Health Organization, 2009.
25 de Pee S et al. Orange fruit is more effective than are dark-green, leafy vegetables in increasing serum concentrations of retinol and beta-carotene in schoolchildren in Indonesia. American Journal of Clinical Nutrition, 1998, 68:1058–67.
26 de Pee S, Bloem MW. The bioavailability of (pro) vitamin A carotenoids and maximizing the contribution of homestead food production to combating vitamin A deficiency. International Journal for Vitamin and Nutrition Research, 2007, 77:182–92.