Vitamin A Deficiency Infection and Mortality in Developing Countries A Recurring Theme

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With improvements in nutrition, hygiene, and living standards, vitamin A deficiency gradually disappeared from Europe and the United States. The Joint Food and Agricultural Organization (FAO)/WHO) Expert Committee on Nutrition focused on vitamin A

deficiency as a public health problem in developing countries in the 1950s. The FAO/ WHO Expert Committee on Nutrition recognized that dried skimmed milk production had increased greatly after World War II, and that it was a "surplus" food being considered for distribution in developing countries in the form of food aid. The expert committee recommended that dried skimmed milk be fortified with vitamin A (85).

In 1948, Vulimiri Ramalingaswami (1921-2001) drew attention to the important association between diarrheal disease and vitamin A deficiency among young children seen at the Nutrition Clinic of the Nutrition Research Laboratories in Coonor, India (86). He noted that diarrheal disease and altered gastrointestinal pathology were consistent features of vitamin A deficiency, both in humans and in experimental animal models, and that the diarrheal disease resolved with administration of vitamin A (48,50,87-91). In a small therapeutic trial involving children with xerophthalmia and diarrheal disease, Ramalingswami divided children into three groups: (1) children with keratomalacia and Bitot spots who received daily high doses of vitamin A, (2) children with Bitot spots who were treated with standard bowel-binding substances such as kaolin and bismuth carbonate, and (3) children with Bitot spots and diarrhea who were treated with sulfa antibiotics. In the first group, keratomalacia and Bitot spots improved and diarrhea resolved with vitamin A treatment. In the latter two groups, diarrhea continued until the children were switched to treatment with vitamin A, after which the diarrhea resolved (86). Ramalingaswami concluded: "From these observations and from a consideration of the literature, it is concluded that a deficiency in vitamin A, diarrhea occurs which responds specifically to vitamin A" (86).

In 1958, the National Institutes of Health organized a conference on beriberi, iodine deficiency, and vitamin A deficiency (92). At the conference, H.A.P.C. Oomen (19021986), who had spent many years working in the field, reported that children with xerophthalmia in Indonesia often had intestinal and respiratory disease, and made an impassioned plea:

"Xerophthalmia has been the most bitter pill for me to swallow during 18 years of doctor's work in Indonesia. The over and over repeated experience of discovering a child, recently blinded, in the arms of the mother; having to tell her that I now could nothing more to save its eyesight; remembering that I could have done so with a few spoonsful of cod-liver oil some days ago; these things still enter my nightmares. They belong to the most vivid examples of what disprivilegedpeople in underdeveloped regions sometimes miss... More printing space nowadays is devoted to a few cases of hypervitami-nosis A, induced by an irresponsible vitamin racket, than to the thousands of small children who die or get blind every year due to the lack of a handful of vitamin A units. What on earth is nutritional science good for, if, even in the atom age, it is not capable to counteract one of the foulest consequences of bad nutrition ?"

In 1962 a world-wide assessment of xerophthalmia was organized by WHO and showed that vitamin A deficiency was a major health problem in many parts of the world, especially in south Asia, southeast Asia, sub-Saharan Africa, and Central America (93). The investigators concluded: "There appears to be a universal relation between infectious disease and xerophthalmia." "Not only may deficiency of vitamin A itself play an important role in lowering the resistance to infection...but infectious diseases themselves predispose to and actually precipitate xerophthalmia" (93). The "survey," a collection of existing data, showed that some 43 countries had significant vitamin A deficiency among preschool children, and this study formed the original basis for WHO's current database for vitamin A deficiency, which is periodically updated as new data become available (94).

Further attention was given to vitamin A deficiency at an international conference held in 1963 in Bellagio, Lake Como, Italy on "How to Reach the Pre-School Child." It was noted that the mortality rates for preschool children in developing countries was sometimes forty times greater than in affluent countries. The participants concluded that there was a real need for emergency action, for a "crash program" to make the world aware of the serious extent of the problem of child mortality and address nutritional needs of children (95). The following year, an international conference on "Prevention of Malnutrition in the Pre-School Child" was held by the National Academy of Sciences in Washington, D.C. Among the conclusions of the conference were that "the mortality rate among malnourished children with xerophthalmia is very high" and "present evidence enforces the ominous conclusion that the incidence of xerophthalmia is increasing" (96). Included in the discussion were pilot schemes for giving large doses of vitamin A to children at risk in countries where xerophthalmia is common (97). Paul Gyorgy (1893-1976) reported the results of an intervention trial in Indonesia in which a teaspoon of red palm oil was given daily to preschool children in pilot villages, regardless of whether they had xerophthalmia or not. After 2 mo, the prevalence of xerophthalmia dropped from 6.5% to 0.6% (95,98). Gyorgy was enthusiastic about the results but cautioned: "As stated in the recommendation of the Como Conference, any 'crash action program' for the pre-school child should dovetail with long-term projects already in progress, such as maternal and child health centers, agricultural extension, community development and nutrition education."

In 1965, the Western Hemisphere Nutrition Congress was organized by the American Medical Association, and W. Henry Sebrell (1901-1992), the former director of the National Institutes of Health, noted "vitamin A deficiency... is becoming increasingly recognized as a serious condition which is widespread in some parts of this hemisphere. Vitamin A deficiency accounts for widespread blindness or impaired vision and to a large extent contributes to high mortality" (99). The Interdepartmental Committee on Nutrition for National Defense of the US National Institutes of Health conducted surveys in which data on vitamin A deficiency were collected. Vitamin A deficiency was considered a major health problem in many countries, including Jordan (100), Ethiopia (101), Vietnam (102), Thailand (103), Lebanon (104), and East Pakistan (105). These surveys defined vitamin A deficiency as a public health problem if more than 5% of the population had plasma or serum vitamin A concentration <0.35 pmol/L or more than 15% had concentrations <0.70 pmol/L (106). A high prevalence of Bitot spots was described among children in Lebanon (104), East Pakistan (now Bangladesh) (105), and Ethiopia (101). In 1966, photographs of the stages of vitamin A deficiency, including conjunctival xero-sis, Bitot spots, corneal xerosis, corneal ulceration, keratomalacia, corneal staphyloma, and scarring were published in the Bulletin of the World Health Organization (107).

From 1959 to 1965, the Interdepartmental Committee on Nutrition for National Defense conducted dietary surveys in eight South American countries and the West Indies. The Office of International Research (formerly the Interdepartmental Committee on Nutrition for National Defense), in collaboration with the Institute of Nutrition of Central America and Panama, made similar studies in the six Central American countries from 1965 to 1967. A technical group meeting was held at the Pan American Health Organization in

1968 in which it was stated: "From experiments in animals... it can be assumed that prolonged low intake of vitamin A and its precursors may have serious effects on growth and development and on resistance to infectious diseases." "The regular occurrence of xerophthalmia cases in an area is indicative of a very serious preschool public health nutrition problem. The high case fatality rate of at least 25 per cent contributes to underestimation of its magnitude. The severity of the eye lesions and the fatality are inversely related to age, and are greater in males than females" (108). At this meeting in 1968, the technical group at the Pan American Health Organization made comprehensive recommendations for the control of vitamin A deficiency, including the administration of oral high-dose vitamin A one to four times per year to infants and preschool children where vitamin A deficiency is a public health problem, oral high-dose vitamin A to lactating women immediately after delivery, fortification of foods such as dried skim milk with vitamin A, and promotion of nutrition education, increased agricultural production of vitamin A-rich food sources, and greater professional training in regard to vitamin A deficiency (108).

With the growing interest in the relationship between nutrition and infection, in 1965, an expert committee at WHO recommended a systematic review of the literature, and this resulted in an influential work, Interactions of Nutrition and Infection, published in 1968 (109). Nevin Scrimshaw, Carl Taylor, and John Gordon reviewed the large body of clinical and experimental evidence that had accumulated and concluded: "One of the first recognized features of avitaminosis A, increased susceptibility to infection, has had strong confirmation" (109). As shown in this section, the scientific conferences, expert committee meetings, and reviews conducted during the 1950s and 1960s indicate that most scientists had little doubt that vitamin A deficiency played an important role in blindness, increased morbidity from infectious diseases, and death.

Indonesia appeared to be one of the countries with the highest prevalence of vitamin A deficiency in the world (107). Early work by Dutch and Indonesian investigators such as C. D. Ouwehand, Johannes Tijssen (1881-1948), Sie Boen Lian, and others showed that xerophthalmia and keratomalacia were common in the Netherland East Indies (110113). In the 1950s, H.A.P.C. Oomen provided detailed descriptions of xerophthalmia in Indonesia (114), and during the late 1960s, Johanna ten Doesschate (1912-1989) conducted epidemiological investigations in Indonesia that identified risk factors for xeroph-thalmia, including inadequate dietary intake of vitamin A and carotenoids, Ascaris infection, diarrheal disease, tuberculosis, measles, artificial feeding, prematurity, and lower socioeconomic status (115). The main cause of blindness among infants and young children in Indonesia was vitamin A deficiency, and follow-up of small children who had become blind showed that about 30% had subsequently died (115).

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