THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 5, NO.2 47

Editorials

Infections and Vitamin A

Vitamin A deficiency is widely prevalent among children of poor communities inmany developing countries and is often associated with other nutritional defects.Although an inadequate diet is the main cause of the poor nutritional status, theunhygienic environment that these children live in results in a high incidence ofinfections which accentuate the nutritional deficiencies. Thus, malnutrition andinfection have a synergistic interaction with mutually adverse effects. Vitamin A isbelieved to be important in such interactions.

The mechanisms involved are complex and include a decreased intake particu-larly of carotene-rich foods. Malabsorption associated with infection aggravatesthe situation. Sheehy et at. found that Puerto Rican army recruits with severehookworm disease suffered from steatorrhoea and showed a decreased absorptionof vitamin A and xylose.' Reddy and Sivakumar, using 11, 12-3H retinyl acetate andretinyl palmitate, demonstrated absorptive defects in children suffering frombronchopneumonia, diarrhoea and ascariasis." However, the decrease in vitamin Aabsorption was not associated with fat malabsorption.

In 1892, Spicer first observed that clinical signs of xerophthalmia often followedan episode of acute or chronic illness- and in 1917 McCollum described theassociation between vitamin A deficiency and infection in an animal model." Adecade later Green and Mellanby referred to it as the anti-infective vitamin' and in1985 the induction of solitary vitamin A deficiency in experimental animals wasshown to lead to immunosuppression and an increased susceptibility to infection."Children suffering from febrile illnesses and acute infections have been reported tohave low levels of circulating carotenoids and retinol." and recently, Bhaskaram etal? have shown lower levels of serum retinol in children suffering from acuteinfections such as measles, bronchopneumonia and gastroenteritis. In a prospectivestudy of children living in urban slums, the same investigators found a fall in serumretinol and retinol binding protein levels during an acute attack of measles.Interestingly, the fall was greater in children whose pre-measles nutritional statuswas poor.'?

Several epidemiological and clinical studies have demonstrated an increasedmortality and morbidity among children with severe vitamin A deficiency.l':"However, vitamin A deficiency is usually associated with severe protein energymalnutrition in children and these studies failed to define the effect of vitamin Adeficiency alone.

Like other nutritional deficiencies vitamin A deficiency is only an indication ofthe much wider problems of malnutrition. Most apparently normal pre-schoolchildren in India suffer from mild vitamin A deficiency and have serum retinollevels of less than 20 ug/dl with or without clinical signs of xerophthalmia.Sommer et at. were the first to report the adverse effects of mild vitamin Adeficiency on childhood morbidity and mortality.P-" The results of such studieshave important policy implications and the United Nations Subcommittee onNutrition has called for more controlled studies from different parts of the world to

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elucidate the relationship between vitamin A infection and childhood mortality.Several studies have revealed that a certain association exists between mild

vitamin A deficiency and infections, though the pattern of infections was notuniform, While reports from Indonesia indicated an association with respiratoryand gastrointestinal infections," Bloem et al. from Thailand found a greater risk ofrespiratory infections. IS These observations were similar to the results reported byMilton et al. from a retrospective study in India of urban slum children who hadclinical vitamin A deficiency" as well as a later prospective community study byVijayaraghavan et al,"

The Indonesian workers found an association between mild vitamin A defi-ciency and higher childhood mortality rates and reversal of both morbidity andmortality following periodic administration of large doses of vitamin A.14 How-ever, the strong claims made by the Indonesian workers about the relation betweenvitamin A, morbidity and mortality have been subjected to severe criticism" andthe conclusions should be accepted with caution. The major controversies relate to:

-the disregard of other confounding variables;-the lack of a placebo group in the supplementation study;-the effect of the 'contact factor' with the health worker in the experimental group;-how representative the study area was, given the differences in mortality rates of

the control area and the national figures;-the lack of information on the exact age and cause of death.

Subsequent studies from Nepal, India, Bangladesh and Sudan have shownconflicting results. The Nepalese workers support the observations made by theIndonesian group.v-? Daulaire demonstrated that periodic administration of largedoses of vitamin A (ranging from 50000 IU to 200000 IU depending on age)reduced deaths due to diarrhoea, pneumonia and measles in a population ofchildren with high underlying mortality rates and xerophthalmia."

In the two Indian studies, Vijayaraghavan et af. from Hyderabad found that200 000 IU of vitamin A given once in 6 months to rural pre-school children'?produced no significant effect while the community study reported from Madurai"demonstrated a 50% reduction in mortality rates in a double blind controlled studywhere the experimental group of children received 800 IU vitamin A weekly whilethe control group received a placebo. These two studies are not strictly comparablebecause of major differences in the dose and mode of administration of vitamin Aand a higher rapport between the health worker and the test population in the latterstudy. However, both failed to account for other associated factors which mightlead to childhood mortality.

In Bangladesh, Bardhan et af. examined the effect of administering a single doseof vitamin A to the mother and/or infant at birth on the morbidity of breast fedbabies." Morbidity was determined by the number of episodes of diarrhoea orrespiratory infections and this did not differ between the supplemented andunsupplemented infants.

Herrera et al. from Sudan found no significant effect on mortality or morbiditywhen 200 000 IU of vitamin A was given every 6 months to asymptomatic childrenwho did not have clinical signs of xerophthalrnia.P

These investigations have all been carried out on poor children in whom theincreased morbidity could have been attributed to a number of other poverty relatednutritional and non-nutritional factors. However, it is fairly well established thatvitamin A has an effect on the integrity of epithelial tissue" and adjuvant effects onthe immune system, so its deficiency might increase susceptibility to infections.

The prevalence of vitamin A deficiency and the mortality rates in a givencommunity appear to be important factors determining the beneficial effects, ifany, of vitamin A administration on morbidity and mortality. The available infor-mation fails to provide unequivocal support for the spin-off benefits of a massivevitamin A prophylactic programme in communities where malnutrition and infec-tious illnesses are widely prevalent. Giving all children regular and massive doses

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of vitamin A to improve their survival may not be cost-effective and the possibleadverse metabolic=-" and immunological effects'? of repeated administration oflarge doses cannot be ignored. It may therefore be prudent to limit the administra-tion of large vitamin A supplements to children at risk.

REFERENCESSheehy TW, Meroney WH, Cox RS Jr, Soler JE. Hookworm disease and malabsorption.Gastroenterology 1962;42: 148-56.

2 Sivakumar B, Reddy V. Absorption of labelled vitamin A in children during infection. Br J Nutr1972;27:299-304.

3 Spicer H. Keratomalacia in young children. Lancet 1892;2:1387.4 McCollum EV. The supplementary dietary relationships among our natural food stuff. JAMA

1917;68:1379.5 Green HN, Mellanby E. Vitamin A as anti-infective agent. Br Med J 1928;2:691-Q.6 Ongsakul M, Sirisinha S, Lamb AJ. Impaired blood clearance of bacteria and phagocytic activity in

vitamin A deficient rats (41999). Proc Soc Exp Bioi Med 1985;178:204-8.7 Araya M, Silink SJ, Nobile S, Walker-Smith JA. Blood vitamin levels in children with gastroenteritis.

Aust NZ J Med 1975;5:239-50.8 Jacobs AL, Leitner ZA, Moore T, Sharman 1M. Vitamin A in rheumatic fever. Am J Clin Nutr

1954;2: 155-{i I.9 Bhaskaram P, Mathur R, Rao V, et al. Pathogenesis of corneal lesions in measles. Hum Nutr Clin Nutr

I986;40(c): 197-204.10 Reddy V, Bhaskaram P, Raghuramulu N, et al. Relationship between measles, malnutrition and

blindness. A prospective study in Indian children. Am J Clin Nutr 1986;44:924-30.II Cohen BE, Elin RJ. Vitamin A induced nonspecific resistance to infection. J Infect Dis

I974;129:597...QOO.12 Chew BP, Luedecke La, Holpuch OM. Effect of dietary vitamin A on resistance to experimental

Staphylococcus marstisli in mice. J Dairy Sri 1984;67:2566-70.13 Sommer A, Katz J, Tarwotjo I. Increased risk of respiratory disease and diarrhoea in children with

pre-existing mild vitamin A deficiency. Am J Clin Nutr 1984;40: 1090-5.14 Sommer A, Tarwotjo I, Djunaedi E, et al. Impact of vitamin A supplementation on childhood

mortality. Lancet 1986;1:1169-73.15 Bloem MW, Wedel M, Schrewis WHP. Mild vitamin A deficiency and risk of respiratory infection

and diarrhoea in preschool and school children in Northeast Thailand. National Symposium and XIIIIVACG Meeting. Kathmandu 1989:88.

16 Milton RC, Reddy V, Naidu AN. Mild vitamin A deficiency and childhood morbidity: An Indianexperience. Am J Clin Nutr 1987;46:827-9.

17 Vijayaraghavan K, Radhaiah G, Prakasam BS, Sarma KVR, Reddy V. Effect of massive dose vitaminA on morbidity and mortality in Indian children. Lancet 1990;336: 1342-4.

18 Gopalan C. Vitamin A deficiency and child mortality. Bull Nutr Foundation India 1986;6-7.19 West KP, Pokhrel RP, Katz J, et al. Efficacy of vitamin A in reducing preschool child mortality in

Nepal. Lancet 1991 ;338:67-70.20 Daulaire NMP. Effect of a single high dose of vitamin A on mortality in a population with high

childhood mortality and xerophthalmia rates. National Symposium and XIII IVACG Meeting.Kathmandu 1989:79.

21 Rahmathullah L, Underwood BA, Thulasi Raj RD, et al. Reduced mortality among children inSouthern India receiving a small weekly dose of vitamin A. N Engl J Med 1990;323:929-35.

22 Bardhan PR, Rahman N, Alam NH, Ahmed T, Alam AN, Khan MU. Impact of oral vitamin Asupplementation on the morbidity of diarrhoeal and acute respiratory disease in breast fedBangladesh children. National Symposium and XIII IVACG Meeting. Kathmandu 1989:94.

23 Herrera MG, Amin AEI, Mohamed KA, Nesles P, Weld L, Fawzi W. Vitamin A supplementation ofasymptomatic children. Effects on morbidity and mortality. XIV IVACG Meeting. Guayaquil1991:77.

24 Olson JA. Vitamin A, retinoids and carotenoids. In: Schils ME, Young VR (eds). Modern nutrition inhealth and disease. Philadelphia: Lea and Febiger, 1988:292-312.

25 Frankel TL, Seshadri MS, McDowall DB, Cornish CJ. Hypervitaminosis A and calcium-regulatinghormones in the rat. J Nutr 1986;116:578-87.

26 Martin BR, Morre OM. Excess vitamin A decreases the specific activity of galactosyl transferase inGolgi apparatus of rat liver. J Nutr 1988;118:968-75.

27 Bhaskaram P, Jyothi SA, Rao KV, Rao BSN. Effects of subclinical vitamin A deficiency andadministration of vitamin A as a single large dose on immune function in children. Nutr Res1989;9:1017-26.

P. BHASKARAM

National Institute of NutritionHyderabad