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

  • Other affiliations: Memorial University of Newfoundland and World Health Organization Centre for Nutritional Immunology.
  • CAB International 2002. Nutrition and Immune Function (eds P.C. Calder, C.J. Field and H.S. Gill)

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 infection. 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-proliferation 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 nutrition in modulation of immune responses is based on physiological considerations. 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 involution 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 compatible 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 countries, 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 aggravates the other. Scrimshaw et al. (1968) proposed the interesting concept of synergism 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.

Longitudinal prospective studies of infants have shown that reduction in various parameters of immunocompetence preceded clinical infection and growth faltering. Findings such as these suggest, first that altered immune responses are early functional indices of growth failure secondary to latent nutritional deficiency and, second, that episodes of infection worsen the child's nutritional state.

PEM has been documented to increase morbidity and mortality caused by diarrhoea and respiratory illness (James, 1972; Tomkins, 1981; Chandra, 1983a). The incidence of infectious diarrhoea is increased and there is a more profound and consistent effect on the duration of each episode. Victora et al. (1990) studied the synergism between nutritional status and hospital admissions due to diarrhoea and pneumonia in a cohort of 5914 live births in southern Brazil and found that malnutrition was a more important risk factor for pneumonia than for diarrhoea, whereas diarrhoea was a stronger predictor of malnutrition than was pneumonia, the association being strongest in the first 2 years of life. In rural India, there was a significant correlation between weight-for-height as an index of protein-energy status and risk of death from infectious disease (Chandra, 1983b).

The term 'nutritional thymectomy' has been used to dramatize the extensive reduction in the size and weight of the thymus that occurs with malnutrition (see Chandra and Newberne, 1977). Histologically, there is a loss of corticomedullary differentiation, there are fewer lymphoid cells and the Hassal bodies are enlarged, degenerated and, occasionally, calcified. These changes are easily differentiated from findings in primary immune deficiency, such as DiGeorge's syndrome. In the spleen, there is a loss of lymphoid cells around small blood vessels. In the lymph node, the thymus-dependent paracortical areas show depletion of lymphocytes.

The consistent adverse effects of PEM on cell-mediated immunity, production of cytokines, phagocyte function, the complement system and mucosal immunoglobulin A (IgA) antibody responses have been demonstrated in several studies in many countries. These observations have been reviewed several times (see Chandra and Newberne, 1977; Keusch et al., 1983; Gershwin et al., 1984; Watson, 1984; Chandra, 1992, 1996, 1999; Woodward, 2001).

In PEM, most of the host defence mechanisms are breached (Fig. 3.1). Delayed cutaneous hypersensitivity responses to both recall and new antigens are markedly depressed. It is not uncommon to have complete anergy to a battery of different antigens (Chandra, 1972). These changes are observed in moderate nutrient deficiencies as well (Kielmann et al., 1976; McMurray et al., 1981). Findings in patients with kwashiorkor are more striking compared with those in marasmus. There is a significant correlation between the cumulative diameter of induration response to five common antigens and the serum concentration of albumin, an index of visceral protein synthesis. Similarly, there is a significant correlation between the size of the delayed-hypersensitivity skintest response and lean body mass (Fig. 3.2). The skin reactions are restored after appropriate nutritional therapy for several weeks or months.

The cellular and molecular reason for impaired skin responses lies in changes in the number and function of T lymphocyte subsets and macrophages

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).

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 fluorescent 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 lymphocytes. There is an increase in deoxynucleotidyl transferase activity in leucocytes (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 factors, 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, lymphocytes derived from mesenteric lymph nodes of immunized rodents normally revert back to the intestine in large numbers, whereas in malnutrition this homing 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.

Well-nourished Malnourished

CD8+

CD4+

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.

  1. 3.4. Number of immunoglobulin (IgG)-producing cells in co-cultures of T and B lymphocytes. T lymphocytes (T) and B lymphocytes (B) from children with PEM (p) or well-nourished controls (c) were co-cultured and stimulated with pokeweed mitogen. IgG-forming cells were identified by rosetting with sheep red blood cells. (Data are from Chandra, 1983b.)
  2. 3.4. Number of immunoglobulin (IgG)-producing cells in co-cultures of T and B lymphocytes. T lymphocytes (T) and B lymphocytes (B) from children with PEM (p) or well-nourished controls (c) were co-cultured and stimulated with pokeweed mitogen. IgG-forming cells were identified by rosetting with sheep red blood cells. (Data are from Chandra, 1983b.)

Serum antibody responses are generally intact in PEM, particularly when antigens are administered with an adjuvant or in the case of those materials that do not evoke a T-cell response. Rarely, the antibody response to organisms such as Salmonella typhi and influenza virus (Fig. 3.5) may be decreased. However, before an impaired antibody response can be attributed to nutritional deficiency, infection as a confounding factor must be ruled out. Antibody affinity is decreased in patients who are malnourished (Fig. 3.5; Chandra et al., 1984). This may provide an explanation for a higher frequency of antigen-antibody complexes found in such patients. As opposed to serum antibody responses, secretory IgA antibody levels after deliberate immunization with viral vaccines are decreased (Chandra, 1975a); there is a selective reduction in secretory IgA levels. This may have several clinical implications, including the increased frequency of septicaemia commonly observed in undernourished children.

The production of several cytokines, particularly interleukin-2 and interferon-7, is decreased in PEM (Chandra, 1992). Moreover, PEM alters the ability of T lymphocytes to respond appropriately to cytokines (Hoffman-Goetz et al., 1984).

Phagocytic function is deranged in PEM. Chemotactic migration of phagocytes is slower and less efficient (Chandra et al., 1976). In the presence of control serum that provides the normal concentrations and activity of various opsonins, phagocytes are able to ingest particles such as bacteria (Seth and Chandra, 1972). However, the next steps of metabolic activation - discharge of digestive enzymes into phagolysosomes, and microbial killing - are reduced (Seth and Chandra, 1972).

Many components of the complement system are reduced in concentration and activity in PEM (Chandra, 1975b; Haller et al., 1978). The most affected are complement C3, C5 and factor B. Total haemolytic activity is decreased. These changes affect the opsonic activity that facilitates phagocytosis.

Fig. 3.5. Antibody response to influenza virus vaccine in the elderly given a nutritional supplement and in controls on a placebo.

There is very little work on the effect of malnutrition on the integrity of physical barriers, quality of mucus or several other innate immune defences. However, lysozyme levels are decreased, largely as a result of reduced production 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 nutritional 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 retardation includes maternal malnutrition.

CD O

Weight-for-height (% standard)

Fig. 3.6. Correlation between the number of Klebsiella adhering to tracheal epithelial cells and nutritional status, assessed by weight-for-height.

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.

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.

Table 3.1. Low birth weight and risk of mortality.

Age

Sample size

Birth weight

Risk ratio

Country

Design

Gestation

(months)

(deaths)

(g)

(95% CI)

Outcome

Brazil

Cohort

Term

0-6

393

(12)

3000-3499

1.0

1500-2499

10.2 6.6a

(2.2-46.7) (1.4-31.2)

All causes

India

Cohort

Term

0-11

4,590

(213)

^ 2500

1.0

2000-2499

2.6

All causes

India

Cohort

Term

0-11

4,220

(362)

^ 2500 < 2500

1.0 1.7

All causes

Guatemala

Cohort

Term

0-11

385

(24)

^ 2500

1.0

< 2500

1.7

All causes

12-47

(39)

1.8

Indonesia

Cohort

Term + preterm

0-11

687

(83)

^ 2500 < 2500

1.0 3.4

All causes

Nigeria

Cohort

Term + preterm

0-11

4,334

(133)

> 2500 « 2500

1.0 5.8

All causes

Brazil

Cohort

Term + preterm

0-11

5,914

(215)

^ 2500 < 2500

1.0 11.0 6.7

(8.7-14.4) (3.0-14.9)

All causes ARI

2.5 (0.9-6.7)

Diarrhoea

2.9

(1.0-8.3)

Other infections

12-59

(29)

3.3

All causes

Brazil

Case-control

Term + preterm

0.25-11

1,070

(357)

^ 2500

1.0

1500-2499

1.9a 2.0a 5.0a

(1.1-3.6)b (1.1-3.6)b (1.3-18.6)b

Diarrhoea Other infections

2.3a

(1.6-3.4)b

All infections

India

Cohort

Term + preterm

0-11

659

(19)

^ 2500 < 2500

1.0 8.0

ARI

UK

Cohort

Term + preterm

1-50

5,522

(40)

^ 2500 < 2500

1.0 3.6

Bronchitis + pneumonia

USA

Cohort

Term + preterm

1-11 12-84

51,931

(371) (258)

^ 2500 1500-2499

2.5

(1.4-4.0) (1.3-4.5)

Infectious disease

USA

Cohort

Term + preterm

1-11

193,733

(93)

^ 2500

1.0

Diarrhoea

< 2500

7.1

aAdjusted for confounders. b90% confidence intervals.

CI, confidence interval; ARI, acute respiratory infections. See Ashworth (2001) for references.

aAdjusted for confounders. b90% confidence intervals.

CI, confidence interval; ARI, acute respiratory infections. See Ashworth (2001) for references.

Ol o

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

3-40

201

2500

1.0

<

2500

1.5 (1.1-2.1)

All infections

Brazil

Cohort

Term

0-6

393

3000-3499

1.0

1500-2499

1.3a

(1.1-1.6)

Diarrhoea

India

Cohort

Term

0-3

152

2500

1.0

1500-2499

2.4

Diarrhoea

3.6

ALRI

Guatemala

Cohort

Term

2 days-

267

2500

1.0

Mostly sepsis

3 months

<

2500

3.0

and ALRI

Papua New Guinea

Cohort

Term + preterm

400

2500

1.0

0-17

<

2500

1.7a

(1.4-2.1)

Diarrhoea

18-35

1.4a

(1.0-1.9)

36-59

1.2a

(0.5-1.8)

Brazil

Case-control

Term + preterm

0-23

1300

2500

1.0

2000-2499

1.4

Pneumonia

<

2000

3.2a

(1.1 to 8.9)

India

Cohort

Term + preterm

0-11

659

2500

1.0

ARI

<

2500

1.2

Uruguay

Cohort

Term + preterm

0-35

166

2500

1.0

ARI

<

2500

0.9 (0.7-1.2)

UK

Cohort

Term + preterm

0-23

690

2500

1.0

ALRI

2300-2499

1.2

2000-2299

1.6

<

2000

3.5

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 illness 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 a¡., 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 2-3 months of age, SGA infants continue to exhibit impaired cell-mediated immune responses for several months or even years (Chandra et a¡., 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 subclasses of IgG are detected in fetal sera as early as 16 weeks of gestation, the bulk being IgGx (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 IgGx but not for IgG2. 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 IgG2 levels and often show infections with organisms that have a polysaccharide capsule.

In preterm infants with a birth weight between 1800 and 2200 g, moderate oral zinc supplementation accelerates immunological recovery (Chandra, 1991a). In SGA infants, zinc supplements given from birth to 6 months of age improve immune responses and reduce mortality from diarrhoea and respiratory illness. A micronutrient supplement is more beneficial (Chandra, 2001).

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