Keratomalacia

Micronutrient deficiencies and infectious diseases often coexist and exhibit complex interactions leading to the vicious cycle of malnutrition and infections among underprivileged populations of the developing countries, particularly in preschool children. Several micronutrients such as vitamin A, beta-carotene, folic acid, vitamin B12, vitamin C, riboflavin, iron, zinc, and selenium, have immunomodulating functions and thus influence the susceptibility of a host to infectious diseases and the course and outcome of such diseases. Certain of these micronutrients also possess antioxidant functions that not only regulate immune homeostasis of the host, but also alter the genome of the microbes, particularly in viruses, resulting in grave consequences like resurgence of old infectious diseases or the emergence of new infections. These micronutrient infection and immune function interactions and their clinical and public health relevance in developing countries are briefly reviewed in this article.

Introduction

Severe micronutrient deficiencies often occur as multiple deficiencies and coexist with severe protein-energy malnutrition (PEM) in humans. However, single and less severe or subclinical micronutrient deficiencies occur in apparently normal or even well-nourished children, causing several subtle but important functional disturbances. Their complex and mutually adverse interactions with infections constitute the major determinants of childhood morbidity and mortality among the underprivileged preschool children in several developing countries. Reversal of these effects following specific nutrient supplementation suggests a causal role for micronutrient deficiencies in determining infection-related morbidity.

Several micronutrients are significant immunomodulators and thus are critical in determining the outcome of host microbe interactions.1 Infections, in turn, aggravate micronutrient deficiencies by reducing nutrient intake, increasing losses, and interfering with utilization by altering the metabolic pathways. These interactions are of particular significance in poor children whose micronutrient status is already marginal, and they account for a high disease burden in poor communities.

Vitamin A, vitamin C, iron, zinc, folic acid, vitamin B12, and other B-complex vitamins are some of the micronutrients that have been shown to influence host resistance mechanisms, thus altering the susceptibility to infectious diseases. Knowledge of the immune-modulating effects of micronutrients and their interactions with common childhood infections is of great importance in planning comprehensive strategies to promote child health and survival in developing countries.

Vitamin A, Infection, and Immunity

Vitamin A has widespread physiological functions in the body. Apart from its effects on vision, the role of vitamin A in maintaining the structural and functional integrity of mucosal epithelial cells is important. Through its actions on gene expression, vitamin A controls cellular proliferation and differentiation, and thus has significant effects on the immune system.2 These functions of vitamin A have profound significance, particularly in determining maternal and child health in situations where vitamin A deficiency is widely prevalent.

Vitamin A and Infections

As early as 1928, Green and Mellanby named vitamin A as an anti-infective vitamin.3 Subsequently, several epidemiologic, clinical, and experimental studies have demonstrated a close association between severe vitamin A deficiency and increased infection-related morbidity and mortality in children.4 Recent studies suggest that even mild vitamin A deficiency plays a role in infections and related mortality in preschool children.5 The limited information available also suggests a role for vitamin A in modulating susceptibility to reproductive tract infections in women.6-8

Immunologic Effects of Vitamin A Deficiency

Vitamin A-deficient children have significantly lower numbers of T cells in circulation with a proportionate decrease in T4, T8 subsets.9 Contrary to observations in experimental animals, vitamin A deficiency in children appears to have no significant effects on humoral immune mechanisms.10,11 The effect of vitamin A deficiency on innate immune mechanisms has also been found to vary. Phagocytic cell functions, such as hydrogen peroxide (H^sub 2^O^sub 2^) and superoxide (O^sub 2^-) generation by neutrophils and cytotoxicity and interleukin- 1 (IL-1) production by macrophages, were found to be unaffected in children having subclinical vitamin A deficiency.9 However, both plasma and leukocyte lysozyme content was found to be low in vitamin A-deficient children.12

Epithelial Changes in Vitamin A Deficiency

Keratinizing metaplasia with decreased mucus production caused by disappearance of goblet cells is the most important change observed on epithelial linings in vitamin A-deficient children.13 Such a change has been shown to increase bacterial adherence, thus promoting colonization and subsequent invasion by pathogenic microbes.14

Immune Adjuvant Effects of Vitamin A

The immune potentiating effects of large doses of vitamin A are of immense clinical and public health relevance. Administration of 100,000 to 200,000 IU of vitamin A as a single dose has been found to enhance phagocytic functions such as hydrogen peroxide generation by neutrophils and IL-1 production and cytotoxic functions in macrophages. Antibody response to various antigens was potentiated even among children having normal vitamin A status.15 Enhancement of seroconversion rates to measles vaccine when coadministered with vitamin A (84%) is of importance in developing countries situated in tropical climates where basal seroconversion to measles vaccine is suboptimal (63%) under the field conditions of routine immunization16 (Figure 1). The immunopotentiating effects of large dose administrations of vitamin A have led to their routine use in reducing the severity and complications of infectious diseases like measles and diarrhea.17 Supplementation of beta-carotene or vitamin A in HIV-positive pregnant women was also found to reduce vertical transmission of the virus.18 The effects of vitamin A administration in reducing the load of malarial parasitemia in countries having endemic malaria is of clinical relevance.19

In addition, the beneficial effects of vitamin A in immunocompromised states such as after burns and surgery are well documented.20,21 The recently reported beneficial effects of such supplements during pregnancy to reduce maternal morbidity and mortality need to be confirmed.22

Biannual administration of a large dose of vitamin A to children 1 to 5 years of age as a prophylaxis for nutritional blindness has been practiced in several developing countries. To achieve cost effectiveness, WHO has recommended the linking of this program with a universal immunization program.23 The WHO recommends that the first dose of vitamin A supplements be given when measles vaccines are administered to 9-month-old infants. It has also been recommended that vitamin A supplements be given to young infants along with DPT. The safety and efficacy of administering vitamin A together with live viral vaccines has been widely debated.24 However, studies reported from India and other countries have demonstrated that such a schedule is not only safe and effective, but also feasible.16,25-28

Effects of Infection on Vitamin A Status

Infections, in turn, have a profound influence on vitamin A status, and the consequences assume greater significance in individuals already having marginal vitamin A status. The complex interactions of vitamin A status and measles, resulting in malnutrition and blindness, are well established and serve as a typical example for immunologic interactions between micronutrient malnutrition and infection.

In a prospective study among preschool children living in slum areas of Hyderabad, 4% of children with measles were found to develop corneal lesions (corneal xeroxis to ulcer) during the acute illness.29 In addition to acute lesions, postmeasles malnutrition and development of classic keratomalacia due to vitamin A deficiency are also well established as significant contributors to childhood blindness. Development of corneal lesions during the acute phase of measles is a complex phenomenon resulting from multiple factors acting on the cornea. Serum retinol levels drop significantly during measles. These low levels are associated with the development of distinct lesions of superficial punctate keratopathy, which are characteristic of vitamin A deficiency. Further, the epitheliotropic measles virus invades the conjunctival and corneal epithelium causing the typical lesions of superficial punctate keratitis in at least 50-60% of the affected children. Both these lesions devitalize''the corneal surface and make it vulnerable to any further insult. Besides the well-established systemic immunosuppressive effects, measles infection also compromises the local immunity of ocular surfaces as demonstrated by depleted levels of SIg^sub A^and lysozyme content of tears. Enhanced pathogenic microbial invasion of the immunocompromised eye, along with colonization of the microbes on the devitalized corneal epithelium, triggers the process of ulceration with subsequent progression to keratomalacia if unchecked.30 Several systemic immunosuppressions due to measles cause recurrent morbidity during the postmeasles period, resulting in malnutrition and vitamin A deficiency leading to keratomalacia. These events are presented in Figures 2 and 3.

These adverse interactions assume greater significance in developing countries-where measles is still endemic and vitamin A deficiency is widely prevalent-- and call for the development and implementation of innovative strategies to prevent vitamin A deficiency as well as measles.

Iron, Infection, and Immunity

Anemia due to iron deficiency is widespread among all age groups of the population in most developing countries and depleted iron status is observed even among the populations of affluent countries.

Besides being a hemopoietic factor, iron is essential for cell proliferation and oxidative metabolism of various tissues, and its depletion compromises several essential functions. The adverse effects of iron deficiency in children and pregnant women are of public health importance in developing countries.

Effects of Iron Deficiency on Infection

Anemia and infection are coexistent among underprivileged populations and several epidemiologic, clinical, and experimental studies have linked their association with increased susceptibility to infections.31 Studies demonstrating the reversal of such susceptibility following correction of iron deficiency have established a causal role for iron in the predisposal to infections. Simultaneous reversal of immunologic defects following administration of iron supplements further supports the role of iron deficiency in promoting morbidity due to infections.32

Effects of Iron Deficiency on Immune Function

Iron deficiency has been demonstrated to significantly alter cell-mediated immune functions in children as well as in pregnant women. Circulating T-cell number and invitro proliferative responses to mitogenic stimuli were found to be significantly impaired in children having iron deficiency and anemia.33-36 These effects, however, were reversible with adequate iron repletion.37 Recent studies demonstrate lack of interleukin-2 (IL-2) production with a predominant interleukin-4 (IL-4) mRNA expression by in vitro mitogen/antigen stimulated lymphocytes obtained from anemic children, suggesting polarization of T-cell subsets towards Th2 population.38 Sipahi et al. observed decreasing IL-2 and IL-6 concentrations in the serum of iron-deficient children.39

These effects of iron deficiency on the immune system explain the increased susceptibility to predominantly intracellular microbial infections and also raise concerns about the success of immunization programs among children living in communities having widely prevalent iron deficiency.

Pregnant women having iron deficiency anemia were observed to have impaired cell-mediated immunity.40 The effects of prenatal iron deficiency on the immune competence of newborns are not well documented in humans. However, the irreversible immunosuppressive effects demonstrated among the offspring of iron-deficient mothers in experimental situations raise concerns regarding child health in countries having a high prevalence of iron deficiency in pregnant women.41 Iron deficiency has also been demonstrated to reduce the bactericidal effects of neutrophils and may partly contribute to their reduced content of myeloperoxidase enzyme, which is an essential component of the bactericidal system in neutrophils.42 Cytotoxicity and IL-1 production by macrophages, and antibody response to certain antigens like diphtheria and tetanus, however, do not appear to be significantly altered.43,44

Effect of Infection on Iron Status

The effect of infection on iron status assumes practical significance in situations where infections are endemic and coexist with iron deficiency.

Clear knowledge of the mechanisms involved in the pathogenesis of the anemia of infection is essential to evolve comprehensive programs to reduce the load of iron deficiency, as well as to evaluate the ongoing national programs such as iron supplementation to pregnant women and children and food fortification programs aimed at improving the iron status of the population. In a recent study, an increase in the frequency of anemia was observed among children with infection and was associated with a simultaneous rise in serum transferrin receptor (STfR) concentration, a sensitive parameter for assessing early iron deficiency. STfR levels were restored to basal level following the control of infection, suggesting that anemia of infection could be due to aggravation of iron deficiency.38 These observations raise the important issue of controlling infections to achieve the best results from iron supplementation programs in communities where iron deficiency is widely prevalent and infections are endemic.

Zinc, Infection, and Immunity

Zinc is essential for DNA synthesis and is also a cofactor for several enzymes involved in various physiologic and metabolic functions of the body.45 The role of zinc in immune modulation and its influence on the course and outcome of infections is being increasingly recognized in recent years.

Severe acquired zinc deficiency coexists with severe protein-energy malnutrition. However, the extent of mild to moderate deficiency has not been defined, mainly because of lack of a sensitive and specific tool to precisely define the zinc status of the population. Zinc deficiency is presumed to be widely prevalent in developing countries based on the low intake of zinc due to food inadequacy and its poor bioavailability from plant foods among populations subsisting mainly on cereal-- based diets.

Effects of Zinc Deficiency on Infections

Several investigators reported a significant association between low plasma zinc levels and respiratory tract infections in children.46,47 Administration of zinc supplements has been found to significantly reduce the infection-related disease burden in children.48 The potential for such supplements in ameliorating disease in developing countries needs to be carefully evaluated vis-a-vis the adverse interactions of long-term zinc supplements with other micronutrients, particularly iron, copper, and calcium.

Effects of Zinc Deficiency on Immune Function

As a cofactor, zinc influences thymulin secretion, and thus regulates cell-mediated immune function. Zinc-deficient individuals have been observed to exhibit decreased thymulin levels and impaired cell-mediated immune functions. 49,50 Zinc supplementation of children has been shown to improve CD^sub 3^, CD^sub 4^, populations with an increase in CD^sub 4^/CD^sub 8^ ratio in children.51

Effects of zinc deficiency on the differentiation and function of B cells and the reversal of the effects following zinc supplementation have been reported in experimental animals.52 Nevertheless, such information is not available from human studies.

Antioxidant Micronutrient Deficiency, Infection, and Immunity

Micronutrients such as beta-carotene, vitamin C, selenium, copper, and riboflavin are powerful antioxidants and are found to significantly influence infection-related morbidity in humans. Beck and Levander in their recent critical review describe the possibility of serious effects of antioxidant-deficient status on viral infections. Dietary antioxidant deficiency is found to adversely influence the cytokine profile of host T cells and also to alter the genome of the virus. These effects are alarming and suggest an increase in the virulence of mildly pathogenic strains of existing viruses or the emergence of new strains of pathogenic viruses, which could result in pandemics of viral diseases sweeping the micronutrient-- deficient, immunocompromised populations of the world.53

Thus, micronutrient nutrition and infectious disease interactions are complex and operate through altering immune mechanisms of the host. The consequences of such interactions are of immense clinical and public health relevance in developing countries where the two disorders often coexist.

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Padbidri Bhaskaram, M.D.

Dr. Bhaskaram is with the National Institute of Nutrition (Indian Council of Medical Research), Jamai-- Osmania P.O., Hyderabad-500 007, Andhra Pradedsh, India.

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