Vitamin A and Viral Infections Including RS
By Hal B. Jenson, MD, FAAP
Vitamin a deficiency is not often recognized to occur in the United States, although Vitamin A given prophylactically may decrease morbidity and mortality associated with diarrheal diseases in children with malnutrition living in the third world.1,2 Vitamin A therapy for certain viral respiratory infections has gained recent attention.
The term Vitamin A encompasses Vitamin A alcohol (A1 or retinol and A2 or 3-dehydroretinol) and the acid and aldehyde derivatives, retinoic acid and retinol. Retinol is found in the eye, and retinoic acid is important in tissue growth and differentiation. Retinol is transported by retinol binding protein (RBP); the RBP-retinol complex is further bound to prealbumin. Vitamin A is a necessary co-factor for non-keratinized epithelial cell integrity and repair and may have a beneficial effect on the immune response.3
Hyporetinemia is present in more than 90% of measles cases in Africa4,5 and in approximately 22-72% of children in the United States, with an apparent inverse correlation of retinol concentration and measles severity.6-8 It is not known whether decreased retinol concentrations predispose to more severe measles, or whether more severe illness results in lower serum retinol concentrations. Serum retinol concentrations in measles return to normal in approximately one week regardless of Vitamin A supplementation, implying that hepatic stores are not exhausted but that there is transient impaired mobilization due to an acute decline of hepatic production of retinol-binding protein and prealbumin, redistribution into extracellular fluids, or increased tissue utilization of bioavailable Vitamin A for repair of respiratory epithelium. The clinical benefit of Vitamin A therapy for measles has been demonstrated in three randomized trials in 429 African children.4-6 In these studies, children who received Vitamin A showed more rapid clinical improvement, had decreased incidence of croup and other complications, spent fewer days in the hospital, and had a two-thirds reduction in overall mortality (3.9% vs 11.7%, for the three studies combined).
Measles virus and respiratory syncytial virus (RSV) are both paramyxoviruses that replicate in respiratory epithelium and produce lower respiratory tract disease. In one study, low serum Vitamin A levels were found in 65% of children with RSV infection, again with the suggestion of an inverse correlation with severity of illness.9 Two recent placebo-controlled studies in a multi-center trial in the United States10 and in well-nourished children in Chile11 evaluated treatment of RSV infection with high-dose oral Vitamin A given within two days of hospital admission. There was no difference in baseline retinol concentrations between the treatment and control groups for either study. In children in the United States, lower retinol concentrations were associated with admission oxygen concentrations of less than 90% (P = 0.01) and the need for mechanical ventilation (P < 0.01). There were no differences in most clinical outcomes, although Vitamin A recipients had statistically slightly longer hospital stays than placebo recipients (5.0 vs 4.4 days; P = 0.01). Vomiting within 72 hours of drug administration occurred in 33% of Vitamin A recipients and 23% of the placebo group (P = 0.12). In children in Chile, there was no overall benefit, although children with significant hypoxemia on admission had more rapid resolution of tachypnea (1 day vs 3 days; P = 0.017) and shorter hospital stays (5.5 vs 9.3 days; P = 0.09).
The American Academy of Pediatrics (AAP) has stated that normal, healthy children receiving a proper diet do not need vitamin supplementation over and above the recommended dietary allowances. Although data are incomplete to determine the need for Vitamin A supplementation for all children with measles, the AAP does recommend that Vitamin A supplementation "should be considered" in selected circumstances, including: 1) patients 6 months to 2 years of age hospitalized for measles and its complications; and 2) patients older than 6 months of age with measles and immunodeficiency, ophthalmologic evidence of Vitamin A deficiency, impaired intestinal absorption, moderate-to-severe malnutrition, or recent immigration from areas with high mortality rates from measles.12 The recommended dosage is a single dose of 100,000 IU orally for children 6 months to 1 year and 200,000 IU for children 1 year and older.
Unlike measles, in which decreased serum retinol concentrations and clinical benefit of Vitamin A supplementation have been shown, the benefit of Vitamin A therapy for RSV infection is dubious, at best. Based on available information, Vitamin A therapy should not be routinely recommended for otherwise healthy children in the United States with RSV infection. Vitamin A therapy may be considered for selected cases of severe RSV infection complicated by pre-existing immunodeficiency, impaired intestinal absorption, or moderate-to-severe malnutrition. (Dr. Jenson is Chief, Pediatric Infectious Diseases, University of Texas Health Sciences Center, San Antonio, TX.)
References
1. Rahmathullah L, et al. Reduced mortality among children in Southern India receiving a small weekly dose of Vitamin A. N Engl J Med 1990;323:929-935.
2. Daulaire NM, et al. Childhood mortality after a high dose of Vitamin A in a high risk population. BMJ 1992;304:207-210.
3. Coutsoudis A, et al. Vitamin A supplementation enhances specific IgG antibody levels and total lymphocyte numbers while improving morbidity in measles. Pediatr Infect Dis J 1992;11:203-209.
4. Barclay AJG, et al. Vitamin A supplements and mortality related to measles. BMJ 1987;294:294-296.
5. Hussey GD, Klein M. A randomized, controlled trial of Vitamin A in children with severe measles. N Engl J Med 1990;323:160-164.
6. Coutsoudis A, et al. Vitamin A supplementation reduces measles morbidity in young African children: A randomized, placebo-controlled, double-blind trial. Am J Clin Nutr 1991;54:890-895.
7. Frieden TR, et al. Vitamin A levels and severity of measles. New York City. Am J Dis Child 1992; 146:182-186.
8. Butler JC, et al. Measles severity and serum retinol (Vitamin A) concentration among children in the United States. Pediatrics 1993;91:1176-1181.
9. Neuzil KM, et al. Serum Vitamin A levels in respiratory syncytial virus infection. J Pediatr 1994;124: 433-436.
10. Bresee JS, et al. Vitamin A therapy for children with respiratory syncytial virus infection: A multi-center trial in the United States. Pediatr Infect Dis J 1996;15:777-782.
11. Dowell SF, et al. Treatment of respiratory syncytial virus infection with Vitamin A: A randomized placebo-controlled trial in Santiago, Chile. Pediatr Infect Dis J 1996;15:782-786.
12. Committee on Infectious Diseases, American Academy of Pediatrics. Vitamin A treatment of measles. Pediatrics 1993;91:1014-1015.
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