May 2002: (II)S40 S45

Micronutrient Malnutrition, Infection, and Immunity:

An Overview
Padbidri Bhaskaram, M.D.
Micronutrient de ciencies 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
B 1 2, vitamin C, ribo avin, iron, zinc, and selenium,
have immunomodulating functions and thus in uence 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 brie y reviewed in this article.
2002 International Life Sciences Institute

Introduction
Severe micronutrient de ciencies often occur as multiple
de ciencies and coexist with severe protein-energy malnutrition (PEM) in humans. However, single and less
severe or subclinical micronutrient de ciencies 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 speci c nutrient supplementation suggests a causal role for micronutrient de ciencies
in determining infection-related morbidity.
Dr. Bhaskaram is with the National Institute of
Nutrition (Indian Council of Medical Research), JamaiOsmania P.O., Hyderabad- 500 007, Andhra Pradedsh, India.
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Several micronutrients are signi cant immunomodulators and thus are critical in determining the outcome of host microbe interactions.1 Infections, in turn,
aggravate micronutrient de ciencies by reducing nutrient
intake, increasing losses, and interfering with utilization
by altering the metabolic pathways. These interactions
are of particular signi cance 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 in uence 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 signi cant effects
on the immune system.2 These functions of vitamin A
have profound signi cance, particularly in determining
maternal and child health in situations where vitamin A
de ciency 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
de ciency and increased infection-related morbidity and
mortality in children.4 Recent studies suggest that even
mild vitamin A de ciency plays a role in infections and
related mortality in preschool children.5 The limited
information available also suggests a role for vitamin A
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in modulating susceptibility to reproductive tract infections in women.68

Immunologic Effects of Vitamin A De ciency
Vitamin A de cient children have signi cantly lower
numbers of T cells in circulation with a proportionate
decrease in T4, T8 subsets.9 Contrary to observations in
experimental animals, vitamin A de ciency in children
appears to have no signi cant effects on humoral immune mechanisms.10,11 The effect of vitamin A de ciency on innate immune mechanisms has also been
found to vary. Phagocytic cell functions, such as hydrogen peroxide (H2O2) and superoxide (O2-) generation by
neutrophils and cytotoxicity and interleukin-1 (IL-1) production by macrophages, were found to be unaffected in
children having subclinical vitamin A de ciency.9 However, both plasma and leukocyte lysozyme content was
found to be low in vitamin A de cient children.12
Epithelial Changes in Vitamin A De ciency
Keratinizing metaplasia with decreased mucus production caused by disappearance of goblet cells is the most
important change observed on epithelial linings in vitamin A de cient 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 eld 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
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Figure 1. Seroconversion of measles vaccine with and without

co-administration of vitamin A. Source: reference 16.

In addition, the bene cial effects of vitamin A in

immunocompromised states such as after burns and surgery are well documented.20,21 The recently reported
bene cial effects of such supplements during pregnancy
to reduce maternal morbidity and mortality need to be
con rmed.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 rst 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 ef cacy 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.16,2528
Effects of Infection on Vitamin A Status
Infections, in turn, have a profound in uence on vitamin
A status, and the consequences assume greater signi cance 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 de ciency are
also well established as signi cant contributors to childS41

Figure 2. Acute-phase corneal lesions in measles. For details, see text.

hood 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 signi cantly during measles.
These low levels are associated with the development of
distinct lesions of super cial punctate keratopathy,
which are characteristic of vitamin A de ciency. Further,
the epitheliotropic measles virus invades the conjunctival
and corneal epithelium causing the typical lesions of
super cial 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 SIgA 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 de ciency leading to keratomalacia.
These events are presented in Figures 2 and 3.
These adverse interactions assume greater signi cance in developing countrieswhere measles is still
endemic and vitamin A de ciency is widely prevalent
and call for the development and implementation of
innovative strategies to prevent vitamin A de ciency as
well as measles.
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Iron, Infection, and Immunity

Anemia due to iron de ciency is widespread among all
age groups of the population in most developing countries and depleted iron status is observed even among the
populations of af uent 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 de ciency in children and pregnant women are of public health importance in developing countries.
Effects of Iron De ciency on Infection
Anemia and infection are coexistent among underprivileged populations and several epidemiologic, clinical,
and experimental studies have linked their association

Figure 3. Development of postmeasles keratomalacia. For

details, see text. PEM
protein-energy malnutrition.
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with increased susceptibility to infections.31 Studies

demonstrating the reversal of such susceptibility following correction of iron de ciency 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 de ciency in promoting morbidity due to
infections.32
Effects of Iron De ciency on Immune Function
Iron de ciency has been demonstrated to signi cantly
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 signi cantly impaired in children having iron
de ciency and anemia.3336 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-de cient children.39
These effects of iron de ciency 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 de ciency.
Pregnant women having iron de ciency anemia
were observed to have impaired cell-mediated immunity.40 The effects of prenatal iron de ciency on the
immune competence of newborns are not well documented in humans. However, the irreversible immunosuppressive effects demonstrated among the offspring of
iron-de cient mothers in experimental situations raise
concerns regarding child health in countries having a
high prevalence of iron de ciency in pregnant women.41
Iron de ciency 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 signi cantly altered.43,44
Effect of Infection on Iron Status
The effect of infection on iron status assumes practical
signi cance in situations where infections are endemic
and coexist with iron de ciency.
Clear knowledge of the mechanisms involved in the
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pathogenesis of the anemia of infection is essential to

evolve comprehensive programs to reduce the load of
iron de ciency, as well as to evaluate the ongoing national programs such as iron supplementation to pregnant
women and children and food forti cation 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 de ciency. STfR levels were restored to basal level following the control of infection,
suggesting that anemia of infection could be due to
aggravation of iron de ciency.38 These observations
raise the important issue of controlling infections to
achieve the best results from iron supplementation programs in communities where iron de ciency 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 in uence on the course and
outcome of infections is being increasingly recognized in
recent years.
Severe acquired zinc de ciency coexists with severe
protein-energy malnutrition. However, the extent of mild
to moderate de ciency has not been de ned, mainly
because of lack of a sensitive and speci c tool to precisely de ne the zinc status of the population. Zinc
de ciency 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 cerealbased diets.
Effects of Zinc De ciency on Infections
Several investigators reported a signi cant association
between low plasma zinc levels and respiratory tract
infections in children.46,47 Administration of zinc supplements has been found to signi cantly 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 De ciency on Immune Function
As a cofactor, zinc in uences thymulin secretion, and
thus regulates cell-mediated immune function. Zinc-deS43

 cient 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 CD3, CD4, populations with
an increase in CD4/CD8 ratio in children.51
Effects of zinc de ciency 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 De ciency, Infection,
and Immunity
Micronutrients such as beta-carotene, vitamin C, selenium, copper, and ribo avin are powerful antioxidants
and are found to signi cantly in uence infection-related
morbidity in humans. Beck and Levander in their recent
critical review describe the possibility of serious effects
of antioxidant-de cient status on viral infections. Dietary
antioxidant de ciency is found to adversely in uence the
cytokine pro le 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 micronutrientde cient, 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.
1.

2.

3.
4.
5.

6.

7.

S44

Scrimshaw NS, Taylor CE, Gordon JE. Effects of

infection on nutritional status. In: Interactions of
nutrition and infection. Geneva: World Health Organization, Monograph Series 57 1968:44 6
Olson JA. Physiological and metabolic basis of major signs of vitamin A de ciency. In : Bauernfeind
JC, ed. Vitamin A de ciency and its control. New
York: Academic Press Inc., 1986:19 67
Green HM, Mellanby E. Vitamin A as an anti infective
agent. BMJ 1928;2:6912
Mc Laren DS, Shirajan E, Tchalian M. Xerophthalmia
in Jordan. Am J Clin Nutr 1965;17:11730
Sommer A, Tarwotjo I, Djunaedi E, et al. Impact of
vitamin A supplementation on childhood mortality. A
randomised controlled community trial. Lancet
1986;1:1169 73
Mostad SB, Overbaugh J, Devange DM, et al. Hormonal contraception, vitamin A de ciency and other
risk factors for shedding of HIV-1infected cells
from the cervix and vagina. Lancet 1997;350:9227
Semba RD, Miotti PG, Chiphanguwi JD, et al. Maternal vitamin A de ciency and mother-to-child
transmission of HIV-1. Lancet 1994;343:15937

8.
9.

10.
11.
12.
13.
14.
15.

16.

17.
18.

19.

20.
21.
22.

23.

24.
25.
26.

Christian P, West Kp Jr, Khatry SK, et al. Night

blindness of pregnanc y in rural Nepalnutritional
and health risks. Int J Epidemiol 1998;27:2317
Bhaskaram P. Infection and immunity of vitamin A
and iron de cient children. In: Visser HKA, Bindels,
eds, Child nutrition in South East Asia. London:
Kluwer Academic Publishers, 1990;18597
Mark DA, Nauss KM, Baliga BS, et al. Depressed
transformation response by splenic lymphocytes from
vitamin A de cient rats. Nutr Res 1981;1:489 97
Kitty PM, Mohanram M, Reddy V. Humoral immune
response in vitamin A de cient children. Acta Vitaminol Enzymol 1981;3:2315
Mohanram M, Reddy V, Mishra S. Lysozyme activity
in plasma and leucocytes in malnourished children.
Br J Nutr 1974;32:313 6
Reddy V, Rao VM, Jyothi A, et al. Conjunctival
impression cytology for assessment of vitamin A
status. Am J Clin Nutr 1989;89:2225
Chandra RK. Increased bacterial binding to respiratory epithelial cells in vitamin A de ciency. BMJ
1988;297:834 5
Bhaskaram P, Jyothi SA, Rao KV, et al. Effect of
subclinical vitamin A de ciency and administration
of vitamin A as a single large dose on immune
function in children. Nutr Res 1989;9:101726
Bhaskaram P, Rao KV. Enhancement in seroconversion to measles vaccine with simultaneous administration of vitamin A in 9-months-old Indian
infants. Indian J Pediatr 1997;64:5039
Joint WHO/UNICEF statement on use of vitamin A
for measles. Wkly Epidemiol Rec 1987;62:133 4
Fawzi WW, Msamanga GI, Spiegelman D, et al. Randomised trial of effects of vitamin supplements on
pregnancy outcome and T cell counts in HIV-1infected women in Tanzania. Lancet 1998;351:1477 82
Shankar AH, Genton B, Semba RD, et al. Vitamin A
supplementation as nutrient-based intervention to
reduce malaria related morbidity. Report of the XVIII
International Vitamin A Consultative Group Meeting.
Cairo, Egypt, 2226 September, 1997. ILSI, 1998
Fusi S, Kupper TS, Green DR, et al. Reversal of
postburn immunosuppression by administration of
vitamin A. Surgery 1984;96:330 5
Cohen BE, Gill G, Culler PR, et al. Reversal of
postoperative immunosuppression in man by vitamin A. Surg Gynecol Obstet 1979;149:658 62
West KP Jr, Datz J, Khatry SK, et al. Double blind,
cluster randomised trial of low dose supplementation with vitamin A or beta carotene on mortality
related to pregnancy in Nepal. The NNIPS-2 Study
Group. Br Med J 1999;7183:570 5
WHO/CHD immunization- linked vitamin A supplementation study group. Randomised trial to assess
bene ts and safety of vitamin A supplementation
linked to immunization in early infancy. Lancet 1998;
352:1257 67
Ross D. Vitamin A plus measles vaccination: the
downside of convenienc e? Lancet 1995;345:1317
Semba RD, Akib A, Beeler J, et al. Effect of vitamin
A supplementation on measles vaccination in ninemonth-old infants. Public Health 1997;111:2457
Benn CS Aaby P, Bale C, et al. Randomised trials of
effect of vitamin A supplementation on antibody
Nutrition Reviews , Vol. 60, No. 5

27.

28.

29.

30.
31.
32.
33.
34.

35.
36.

37.
38.
39.
40.

response to measles vaccine in Guinea-Bissau,

West Africa. Lancet 1989;64:512
Bhaskaram P, Balakrishna N. Effect of administration of 200,000 IU of vitamin A to women within 24
hrs after delivery on response to PPV administered
to the newborn. Indian Pediatr 1998;35:2317 22
WHO/CHD immunization linked vitamin A supplementation study group. Randomised trial to assess
bene ts and safety of vitamin A supplementation
linked to immunization in early infancy. Lancet 1998;
352:125763
Reddy V, Bhaskaram P, Raghuramulu N, et al. Relationship between measles, malnutrition, and
blindness: a prospective study in Indian children.
Am J Clin Nutr1986;44:924 30
Bhaskaram P, Mathur R, Rao V, et al. Pathogenesis
of corneal lesions in measles. Hum Nutr Clin Nutr
1986;40C:197204
Cohen E, Elvehjem CA. The relation of iron and
copper to the cytochrome oxidase content of animal tissues. J Biol Chem 1934;107:97
Chandra RK, Grace A. Goldsmith award lecture.
Trace element regulation of immunity and infection.
J Am Coll Nutr 1985;4:516
Bhaskaram C, Reddy V. Cell-mediated immunity in
iron- and vitamin-de cient children. BMJ 1975;3:
522
Bhaskaram P. Immunology of iron de cient subjects. In: Contemporary issues in clinical nutrition.
Nutrition and immunology. Chandra RK, ed. New
York: AR Liss AR, Inc., 1988;11:149 68
Srikantia SG, Prasad JS, Bhaskaram C, et al. Anemia and immune response. Lancet 1976;1:13079
Chandra RK, Vyas D. Functional consequences of
iron de ciency. Non- erythroid effects. In: Chandra
RK, ed. Critical reviews in tropical medicine. New
York: Plenum, 1984;2:93
Bhaskaram P, Prasad JS, Krishnamachari KAV. Anaemia and immune response. Lancet 1977;1:1000
Annual Report 2000 National Institute of Nutrition,
Indian Council of Medical Research, Hyderabad,
India, 1999 2000
Sipahi T, Akar N, Egin T, et al. Serum interleukin-2
and interleukin-6 levels in iron de ciency anemia.
Pediatr Hematol Oncol 1998;15:69 73
Prema K, Ramalakshmi BA, Madhavapeddi R, et al.

Nutrition Reviews , Vol. 60, No. 5

41.
42.
43.
44.
45.
46.

47.

48.

49.
50.
51.

52.

53.

Immune status of anemic pregnant women. Br J

Obstet Gynaecol 1982;89:2225
Kochanowski BA, Sherman AR. Decreased antibody formation of iron de cient rat pups effect of
iron repletion. Am J Clin Nutr 1983;41:278 84
Prasad JS. Leukocyte function in iron-de ciency
anemia. Am J Clin Nutr 1979;32:550 2
Bhaskaram P, Sharada K, Sivakumar B, et al. Effect
of iron and vitamin A de ciencies on macrophage
function in children. Nutr Res 1989;9:3545
Bagchi, Mohanram M, Reddy V. Humoral immune
response in children with iron de ciency anemia.
BMJ 1980;280:1249 51
Sandstead HH, Rinaldi RA. Impairment of deoxyribonucleic acid synthesis by dietary zinc de ciency
in the rat. J Cell Physiol 1969;73:813
Bahl R, Bhandari N, Hambidge KM, et al. Plasma
zinc as a predictor of diarrhoeal and respiratory
morbidity in children in an urban slum setting. Am J
Clin Nutr 1998;68(suppl 2):414S7S
Bhandari N, Bahl R, Hambidge KM, et al. Increased
diarrhoeal and respiratory morbidity in association
with zinc de ciencya preliminary report. Acta
Paediatr 1996;85:148 50
Sazawal S, Black RE, Bhan MK, et al. Ef cacy of
zinc supplementation in reducing the incidence and
prevalence of acute diarrhoeaa communitybased, double- blind, controlled trial. Am J Clin Nutr
1997;66:4138
Prasad AS, Meftah S, Abdalah J, et al. Serum
thymulin in human zinc de ciency. J Clin Invest
1988;82:1202 10
Chandra RK, Au B. Single nutrient de ciency and
cell-mediated immune responses. I. Zinc. Am J Clin
Nutr 1980;33:736 8
Sazawal S, Jalla S, Mazumadar S, et al. Effects of
zinc supplementation on cell-mediated immunity
and lymphocyte subsets in preschool children. Indian J Pediatr 1997;34:589 97
Hambidge KM. Zinc in the nutrition of children in
trace elements. In: Chandra RK, ed. Trace elements
nutrition of children II. Nestle Nutrition Workshop
Series Vol. 23. New York: Raven Press, 1991:6577
Beck MA, Levander OA. Dietary oxidative stress
and potential viral infection. Annu Rev Nutr 1998;
18:93116

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