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3 Effect of Post-natal Protein
Malnutrition and Intrauterine
Growth Retardation on
Immunity and Risk of Infection
RANJIT KUMAR CHANDRA *
Janeway Child Health Centre, Room 2J740, 300 Prince Philip Drive,
St John’s, Newfoundland, Canada A1B 3V
Introduction
In spite of projections and plans announced by both politicians and profession-
als in the last 25 years, protein–energy malnutrition (PEM) continues to be
widely prevalent, particularly in Asia and Africa. This is associated with consid-
erable morbidity due to infectious illness. Work during the last 30 years has
demonstrated the important pathogenetic role of impaired immune responses
in the two-way interaction between malnutrition and infection. Similarly,
intrauterine growth retardation (IUGR) resulting from a variety of maternal and
fetal factors is associated with impaired immune responses and enhanced sus-
ceptibility to infection. Unlike the reversibility of reduced immunity in post-natal
PEM, decreased immunity in small-for-gestational-age (SGA) infants is pro-
longed and may last for months, even years.
Protein–Energy Malnutrition
The clinical spectrum of PEM is somewhat varied, depending upon the age of
occurrence, the concurrent presence of infection and the area of the world where
it occurs. The same applies, to some extent, to the immunological effects of PEM.
From a historical perspective, it is useful to cite the clinical stimulus that led
to the first comprehensive examination of the immune system in PEM
(Chandra, 1972). Interest in nutrition–immune interactions was kindled by the
story, with an unhappy ending, of a child. Eighteen-month-old Kamala was
thin, her skin pale as wax and her lungs screaming for air. She wore a spectral
© CAB International 2002. Nutrition and Immune Function (eds P.C. Calder, C.J. Field and H.S. Gill) 41
*Other affiliations: Memorial University of Newfoundland and World Health Organization Centre for Nutritional Immunology.
white death-mask in a frame of black hair. Her shrivelled body and swollen legs
were typical of marasmic kwashiorkor, and she had an obvious fulminant infec-
tion. Lung aspirate revealed the opportunistic organism Pneumocystis carinii.
Despite our best efforts, we lost the child. We speculated that malnutrition had
robbed Kamala of her defences against infection and led to her premature
demise. Against this background in 1969, I applied the available techniques to
study the immunocompetence of undernourished children. To convey a sense
of time, the discipline of immunology did not even involve the general use of
terms such as cell-mediated immunity, lymphocyte subsets, immunoregulation
and so on. In malnourished patients, we found a number of impaired immune
responses, including delayed cutaneous hypersensitivity, lymphocyte-prolifera-
tion responses to mitogens, complement activity and secondary antibody
responses to some antigens. These findings were soon confirmed by several
investigators (Anon., 1987).
Any discussion of the effects of nutritional deficiencies on immune
responses must be prefaced by emphasizing the complexities and heterogeneity
of both clinical malnutrition and immune responses. The critical role of nutri-
tion in modulation of immune responses is based on physiological considera-
tions. The severity and extent of dysfunction caused by malnutrition in various
organ systems depend on several factors, including the rate of cell proliferation,
the amount and rate of protein synthesis and the role of individual nutrients in
metabolic pathways. Lymphoid tissues are very vulnerable to marked involu-
tion as a result of nutritional deficiency. Many cells of the immune system are
known to depend for their function on metabolic pathways that employ various
nutrients as critical cofactors. Numerous enzymes require micronutrients.
The consistent impairment of immunity in PEM and the recognized
increase in infections in patients with primary immunodeficiencies are compati-
ble with the hypothesis that a depressed immune system in malnutrition
enhances the risk and severity of infection. The work on children has now been
extended to other age-groups and to other parts of the world, including the
malnourished groups seen in hospitals and in underprivileged communities in
industrialized affluent countries. For example, the cellular immune changes
seen in young children with PEM in developing countries are replicated to a
large extent in subjects with primary or secondary PEM in industrialized coun-
tries, such as those with anorexia nervosa (for a review, see Marcos et al. ,
2001). It should be pointed out that malnutrition is a complex syndrome where
several deficiencies exist simultaneously. Even in laboratory animals deprived
of a single nutrient, the functional effects may be the consequence of changes
in the absorption or body stores of other substances. Thus, what is observed in
an undernourished individual is the sum of the contributions and responses of
many components of the immune system that have been altered by one or
more nutrient deficiencies.
The interaction between malnutrition and infection is bidirectional: one aggra-
vates the other. Scrimshaw et al. (1968) proposed the interesting concept of syner-
gism and antagonism between the host’s nutritional status and the microbe’s
ability to produce disease; the direction of interaction is more often synergistic,
namely, PEM increases the incidence, duration and severity of infectious illness.
42 R.K. Chandra
44 R.K. Chandra
Fig. 3.1. In PEM, most of the host defence mechanisms are breached, allowing microbes to invade and produce clinical infections that are more severe and prolonged (copyright ARTS Biomedical Publishers 1981).
10
8
6
4
2
<
r = 0.
70 80 90 100
Lean body mass (% standard)
r = 0.
Induration (mm)
Fig. 3.2. Correlation between the diameter of maximum skin induration, in response to delayed hypersensitivity challenge, and lean body mass. Those with a negative response, defined as induration of less than 5 mm (shaded box), had a lean body mass of 80% of standard for age or less.
and the production of various cytokines. There is a significant reduction in the
number of mature, fully differentiated T lymphocytes, which can be recognized
by the classical technique of rosette formation or by the newer method of fluo-
rescent labelling with monoclonal antibodies. The reduction in serum thymic-
factor activity observed in primary PEM, including in adolescents with anorexia
nervosa (Wade et al. , 1985), may underlie the impaired maturation of T lym-
phocytes. There is an increase in deoxynucleotidyl transferase activity in leuco-
cytes (Chandra, 1983a), a feature of immaturity. The proportion of
helper/inducer T lymphocytes, recognized by the presence of CD4+ antigen on
the cell surface, is markedly decreased in PEM (Fig. 3.3; Chandra, 1983c).
There is a moderate reduction in the number of suppressor/cytotoxic CD8+
cells. Thus the ratio CD4+/CD8+ is significantly decreased compared with that
in well-nourished controls.
The proliferative response to mitogens and microbial antigens is decreased.
The synthesis of DNA is reduced, especially when autologous patient’s plasma
is used in cell cultures. This may be the result of the presence of inhibitory fac-
tors, as well as deficiency of essential nutrients in the patient’s plasma (Beatty
and Dowdle, 1978). Another aspect of lymphocyte function that changes in
PEM is the traffic and ‘homing’ pattern (Chandra, 1991a). For example, lym-
phocytes derived from mesenteric lymph nodes of immunized rodents normally
revert back to the intestine in large numbers, whereas in malnutrition this hom-
ing is reduced.
Co-culture experiments have shown a reduction in the number of
antibody-producing cells in malnutrition (Fig. 3.4) and in the amount of
immunoglobulin secreted (Chandra, 1983c). These observations may reflect
the amount of ‘help’ provided by T-cells, since the impairment is reversed when
T-cells are derived from well-nourished controls.
Post-natal Protein Malnutrition and Immunity 45
CD4+ CD8+
40
30
20
10
40
30
20
10
Lymphocytes (%)
Well-nourished Malnourished
Fig. 3.3. The proportion of T lymphocyte subsets in children with PEM and well-nourished controls matched for age and gender. The CD4/CD8 ratio is decreased.
There is very little work on the effect of malnutrition on the integrity of phys-
ical barriers, quality of mucus or several other innate immune defences.
However, lysozyme levels are decreased, largely as a result of reduced produc-
tion by monocytes and neutrophils, but also due to increased excretion in the
urine (Chandra et al. , 1977a). Adherence of bacteria to epithelial cells is a first
step before invasion and infection can occur. The number of bacteria adhering
to respiratory epithelial cells is increased in PEM (Fig. 3.6; Chandra and Gupta,
1991). Work in laboratory-animal models of PEM has demonstrated a reduction
in ciliary movement, particularly in the presence of mucosal infection (Fig. 3.7).
Intrauterine Growth Retardation
There is much clinical evidence that neonates have suboptimal immune
responses and are susceptible to infection. When growth retardation and nutri-
tional deficiency complicate the picture, as in low-birth-weight (LBW) infants,
impairment of immunocompetence and risk of infection are more marked and
longer-lasting (Chandra, 1991b). This results in higher morbidity (Ashworth,
2001; Table 3.1), enhanced occurrence of admission to hospital and increased
mortality (Ashworth, 2001; Table 3.2).
The worldwide incidence of LBW, defined as a weight less than 2500 g,
varies considerably from one population group to another, from 8% in some
industrialized countries to 41% in some developing countries of Africa. In the
former, the majority are preterm appropriate for gestational age (AGA),
whereas, in the latter, the majority are SGA. The aetiology of fetal growth retar-
dation includes maternal malnutrition.
Post-natal Protein Malnutrition and Immunity 47
8
6
4
2
Control
Log reciprocal geometric mean
Supplemented
Fig. 3.5. Antibody response to influenza virus vaccine in the elderly given a nutritional supplement and in controls on a placebo.
48 R.K. Chandra
14
12
10
8
6
4
2
0
Adherence (bacteria per cell)
Weight-for-height (% standard)
50 60 70 80 90
r = 0. P < 0.
Fig. 3.6. Correlation between the number of Klebsiella adhering to tracheal epithelial cells and nutritional status, assessed by weight-for-height.
Well-nourished Malnourished
Ciliary movements (beats s
)^ PBS
PBS
Bordetella
Bordetella
0 15 30 45 60 Incubation period (min)
Fig. 3.7. Movement of tracheal-cell cilia in dogs with PEM and well-nourished controls. The experiment was run with phosphate-buffered saline (PBS) and after infection with Bordetella sp.
50 R.K. Chandra
Table 3.2.
Low birth weight and risk of morbidity.
Age
Sample
Birth weight
Risk ratio
Country
Design
Gestation
(months)
size
(g)
(95% CI)
Outcome
Ethiopia
Cohort
Term
All infections
Brazil
Cohort
Term
a^
Diarrhoea
India
Cohort
Term
Diarrhoea
ALRI
Guatemala
Cohort
Term
2 days–
Mostly sepsis
3 months
and ALRI
Papua New Guinea
Cohort
Term + preterm
a^
Diarrhoea
a^
a^
Brazil
Case–control
Term + preterm
Pneumonia
a^
(1.1 to 8.9)
India
Cohort
Term + preterm
ARI
Uruguay
Cohort
Term + preterm
ARI
UK
Cohort
Term + preterm
ALRI
aAdjusted for confounders.ARI, acute respiratory-tract infection; CI, confidence interval; ALRI, acute lower respiratory-tract infection.See Ashworth (2001) for references.
LBW is associated with higher mortality. Whereas the total proportion of
infants who die or are handicapped is similar in AGA and SGA groups, the
former are at a higher risk of death in the immediate post-natal period,
whereas the latter are at a higher risk of morbidity in the first year of life
(Chandra, 1984). Infection is one of the recognized causes of increased ill-
ness in SGA infants. Upper and lower respiratory-tract infections are three
times more frequent in SGA infants compared with AGA infants (Chandra,
1984). It appears that the morbidity pattern in the former group shows a
bimodal distribution; about two-thirds exhibit a near-normal rate of illness,
comparable to that of healthy full-term infants, whereas one-third have an
increased illness rate – almost three times that of the full-term infants
(Chandra, 1984). The SGA group is also at risk of developing infection with
opportunistic microorganisms, such as P. carinii , as observed in post-natal
malnutrition (Chandra, 1984).
SGA infants show atrophy of the thymus and prolonged impairment of
cell-mediated immunity (Chandra, 1975c; Moscatelli et al. , 1976). Delayed
cutaneous hypersensitivity to a variety of microbial recall antigens, as well as to
the strong chemical sensitizer 2,4-dinitrochlorobenzene, is impaired. Serum
thymic-factor activity is lower in SGA infants tested at 1 month of age or later.
In contrast to AGA LBW infants, who recover immunologically by about 2–
months of age, SGA infants continue to exhibit impaired cell-mediated immune
responses for several months or even years (Chandra et al. , 1977b; Chandra,
1980). This is particularly true of those infants whose weight-for-height is less
than 80% of standard. The prolonged immunosuppression in some SGA
infants correlates with clinical experience of infectious illness (Chandra, 1991b)
and thus may have considerable biological significance. In animal models of
intrauterine nutritional deficiency, PEM results in reduced immune responses in
the offspring (Chandra, 1975d).
Phagocyte function is deranged in LBW infants (Chandra, 1975c). There is
a slight reduction in ingestion of particulate matter and a significant reduction
in both metabolic activity and bactericidal capacity.
IgG from the mother, acquired through placental transfer, is the principal
immunoglobulin in cord blood. The half-life of IgG is 21 days and thus all
infants show physiological hypoimmunoglobulinaemia between 3 and 5
months of age. This is pronounced and prolonged in LBW infants (Chandra,
1975c), since their level of IgG at birth is significantly lower compared with that
of full-term infants. There is a progressive rise in IgG concentration with gesta-
tional age and birth weight, especially in infants below 2500 g. All four sub-
classes of IgG are detected in fetal sera as early as 16 weeks of gestation, the
bulk being IgG 1 (Chandra, 1988). In SGA LBW infants, the cord-blood level of
IgG 1 is reduced much more than that of other subclasses (Chandra, 1988).
Thus the infant : maternal ratio is significantly low for IgG 1 but not for IgG 2. The
number of immunoglobulin-producing cells and the amount of immunoglobu-
lin secreted are decreased in SGA infants who are symptomatic, i.e. those who
have recurrent infection (Chandra, 1986). In the second year of life, SGA
infants show a marked reduction in IgG 2 levels and often show infections with
organisms that have a polysaccharide capsule.
Post-natal Protein Malnutrition and Immunity 51
Promotion of breast-feeding should be continued. The anti-infective prop-
erties of human milk are well known and depend in part upon various cellular
and soluble factors, as well as its buffering capacity and several antigen-non-
specific protective factors (see also Brandtzaeg, Chapter 14, this volume).
Secretory IgA antibodies against a variety of common pathogens have been
found in human milk and correlate negatively with morbidity due to specific
diseases, such as cholera (Chandra, 1992). The protective effect is particularly
dramatic in underprivileged communities with poor sanitation, inadequate
housing and contaminated food and water. Furthermore, breast-feeding con-
tributes to birth spacing, an important factor in both maternal and child health.
More effective immunization programmes against the common communi-
cable diseases are required for the majority of the susceptible population. There
are still a large number of children in developing countries who die from or are
disabled by preventable infectious diseases. Immunization programmes should
include universal coverage of all the population at risk. Moreover, there is a
need to develop new vaccines, such as those for malaria, Shigella and
Pneumococcus , and to improve the quality of those against typhoid, cholera
and tuberculosis. In addition, new methods of vaccine preparation, such as
genetic recombination, subunit antigens, synthetic-peptide antigens, anti-idio-
types and host-cell receptor-specific vaccines, show great promise. It would be
ideal to have a single, stable, efficacious, inexpensive vaccine containing immu-
nizing antigens for several infections, which can be given at birth, be easy to
administer and have no serious adverse effects.
Post-natal Protein Malnutrition and Immunity 53
Targeted subsidies
Appropriate weaning foods
Oral rehydration therapy
Growth monitoring
Clean plentiful water
Nutrition and health education
Sanitation Housing
Breast- feeding Immunization^
Agricultural production
Socioeconomic
development
Education
and literacy
Fig. 3.8. Intervention strategies to deal with the conjugate problem of malnutrition and infection. The importance of each measure is indicated by the size of letters. (Copyright ARTS Biomedical Publishers 1990.)
Other useful preventive measures include the availability of plentiful clean
water and improved sanitation and housing. The early and adequate manage-
ment of diarrhoea and respiratory infections using oral rehydration solution
and antibiotics, respectively, has already proved useful and found applicability
worldwide. The early detection of growth faltering, using simple weight and
height charts, together with subsequent dietary advice, will reduce the preva-
lence and severity of malnutrition and its adverse consequences. Lastly, tar-
geted subsidies during times of acute need, such as in famines and wars, and
massive campaigns to eliminate specific nutrient deficiencies, such as those of
vitamin A, iron and iodine, are justified.
References
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