Despite numerous advances and improvements in child health globally, malnutrition remains a major problem, and in many parts of the world the situation seems to have worsened (1,2). In a recent estimation of approximately 10 million global under the age of 5 child deaths, malnutrition was estimated to underlie almost half of such deaths (3). A large proportion of cases of malnutrition occur in the south Asia region (3), which also harbours almost three fourths of the global burden of low birth weight (LBW) infants (4). In other parts of the world, high rates of HIV threaten to reverse all of the gains made by child survival programs, with malnutrition worsening (5). Such overt forms of malnutrition, however, do not reflect the true global burden of malnutrition because a large proportion of the hidden burden of malnutrition is represented by widespread single and multiple micronutrient deficiencies.
The relationship between micronutrient deficiencies such as vitamin A deficiency and increased risk of childhood infections and mortality is well established (6). Vitamin A supplementation is now recognized as an important public health intervention among young children in areas of endemic vitamin A deficiency. Other micronutrient deficiencies such as zinc and iron deficiency are also recognized as widespread in developing countries and associated with increased risk of morbidity (7) and mortality (8).
Although the effect of micronutrient deficiencies on immunity and burden of infections in developing countries is well documented, relatively little is known about the impact of infections on micronutrient status and their subsequent impact on health outcomes. This article focuses on the mechanisms and effect of infections on nutrition status and growth in children.
BIOLOGICAL PLAUSIBILITY OF THE EFFECT OF INFECTIONS ON GROWTH
The association of recurrent infections on nutrition and growth during childhood is well described. The classic studies in rural Guatemala by Scrimshaw et al. (9–15) established the important relationship among infections, nutrition and growth. This relationship was also vividly described by Mata et al. (16,17) in follow-up studies that demonstrated the relationship of recurrent infections with growth failure. The recognition of the synergistic relationship between nutrition and infection influences most public health interventions to prevent malnutrition.
All infections, irrespective of the degree of severity, decrease nutrient intakes and increase nutrient losses. The nutrient losses include decreased intestinal absorption, direct loss of nutrients in the gut through increased secretion, internal diversion for metabolic responses to infection and increased basal metabolic rate when fever is present. In this way, infection influences not only protein and energy status but also that of most other nutrients. The clinical importance of these consequences of infection depends on the prior state of the individual, the nature and duration of the infection and the diet of the individual during the infection, particularly dietary intake during the convalescent period and whether full recovery takes place before another infection occurs. The principal mechanisms of effect of infections on growth include anorexia and poor intake, protein and energy losses (eg, in diarrhoea and fever), impact on micronutrient status, and effects of catabolism during infection and protein diversion on growth.
Anorexia and Poor Intake
Many infections are associated with increased production of inflammatory cytokines that may directly affect appetite (18,19). In a study of malnourished children in Goncalves Dias, Brazil, Schorling et al. (20) observed an ablation of catch-up growth with progressively increasing diarrhoeal burdens. In addition, many parents themselves reduce dietary intake during or after infections such as diarrhoea, thereby compounding the impact on nutrient intakes (21).
Protein and Energy Losses
Even subclinical gastrointestinal infections and increased secretion are associated with direct nutrient losses from the body. These losses may include both protein (22) and substantial losses of micronutrients such as zinc and vitamin A from the intestine or urinary tract (23). Faecal nitrogen losses may contribute significantly to the negative nitrogen balance in children with acute diarrhoea. Nitrogen malabsorption may be substantial during acute diarrhoea, ranging from 40% to 75% of intake (24). Rotavirus diarrhoea appears to be associated with more marked and prolonged nitrogen losses than shigella or Escherichia coli infections (24). The energy cost of nitrogen losses during acute illness has been estimated at 5 to 7 energy units/kg/d (25).
Chronic diarrhoea, intestinal parasitism, and protein-losing enteropathy are associated with sustained loss of protein through the gastrointestinal tract. It has been estimated that a moderate degree of intestinal hookworm parasitation may cause an average loss of 100 energy units/d (26). In particular, protein losses and impaired absorption may be both marked and sustained in persistent diarrhoea (27), and the effect on protein metabolism can be compounded by coexisting malnutrition and micronutrient deficiency.
The effects of subclinical gastrointestinal infections may be manifest by an increase in intestinal permeability, which may reflect subclinical intestinal inflammation and alteration in barrier function. This increase in intestinal permeability has been shown to be associated with growth faltering in Gambian children (28,29). Although such growth failure may be a result of overt gastrointestinal infections, in recent years there has been much interest in subclinical infections, especially those occurring in early infancy. Helicobacter pylori infections are ubiquitous and have been shown to affect young infants and children in diverse settings in Africa (30) and Asia (31). Altered intestinal permeability and gut barrier function may lead to subclinical bacterial translocation and bacteremia, causing increased mortality in malnourished children (32), and these have also been associated with cytokine release from other intestinal bacterial infections (33–36). In other instances chronic viral infection such as with HIV may be associated with systemic immune activation and wasting (37), as well as increased losses from the gastrointestinal tract.
Impact on Micronutrient Status
A number of factors may influence micronutrient deficiencies in developing countries, including poor body stores at birth as a consequence of maternal intrauterine malnutrition, dietary deficiencies and high intake of inhibitors of absorption such as phytates and increased losses from the body. To illustrate, in the case of iron deficiency, in addition to poor dietary intake and inhibitors of absorption (38), increased intestinal losses following parasitic infestation may also be an important cause of iron deficiency anaemia (39). Overall, although the effects of poor intake and increased micronutrient demands are well described, the potential effects of acute and chronic infections on the body's micronutrient status is less well appreciated. Even more obscure is the potential effect of immunostimulation and intercurrent infections on the micronutrient distribution and homeostasis. There is little information on the short-term compartment changes of micronutrients such as iron, zinc and vitamin A. However, other mechanisms underlying net body losses and homeostasis are well described. It is possible to elucidate the mechanism of alteration in micronutrient status and consequent deficiency from other direct studies and observations.
The gut plays a special role in the pathogenesis and severity of micronutrient deficiencies. The association of helminthic infections, especially hookworms, with iron deficiency in young children is well established and largely relates to direct intestinal losses (40). Although the association between diarrhoeal disease control programs and malnutrition or growth rates has been questioned, in many parts of the world there is a close relationship between the two. In particular, prolonged and recurrent episodes of diarrhoea, frequently in association with HIV infection, are a frequent cause of morbidity and micronutrient deficiency. In recent years the association of increased micronutrient losses such as those of zinc and copper with acute diarrhoea has been well recognized (41). These findings may explain the high rates of subclinical zinc deficiency among children with frequent and recurrent bouts of diarrhoea, and may be particularly marked among children with persistent diarrhoea.
It is also recognized that children with shigellosis can lose a significant amount of vitamin A in the urine, thus further aggravating preexisting subclinical vitamin A deficiency (42). As already illustrated, the risk of micronutrient deficiency in infancy and early childhood can be compounded severalfold by the presence of low body stores from birth as in low birth weight infants, and further aggravated by poor breast feeding and complementary feeding practices (43).
Effects of Catabolism during Infection and Protein Diversion on Growth
This is one of the most important mechanisms that may underlie the growth failure seen in children with infections. Subclinical infection with possible immunostimulation has been hypothesized as a possible mechanism for growth failure and stunting in children from developing countries, where poor environmental hygiene and exposure to a high burden of infections are ubiquitous (44). It has long been recognized that accidental injury, surgical trauma and infection lead to a significant loss of body nitrogen (45). Although the anorexia that often accompanies these insults will in itself lead to negative nitrogen balance, the nitrogen loss (≈220 mg/kg/d) (45,46) exceeds even that which is expected under fasting conditions. Given the dominating influence of muscle mass protein pool on whole-body protein, it is expected that much of the nitrogen mobilized during acute need derives from the skeletal muscle protein mass. However, following infection or injury, mechanisms are activated that lead to depletion of muscle protein. These changes are presumably induced by the combined actions of the cytokines (eg, interleukin-1, tumour necrosis factor-α) and stress hormones (eg, the glucocorticoids, glucagons, epinephrine).
Recent advances in stable isotope techniques have allowed measurements of protein synthesis and losses in a variety of physiological states (47–49). These studies indicate that subclinical and acute infections accelerate protein catabolism and diversion to the production of acute phase proteins. Reeds et al. (50,51) have estimated the approximate amino acid composition of various acute-phase proteins and the protein or amino acid “cost” of a typical acute-phase response (Table 1). In a study of children (ages 6–24 months) with persistent diarrhoea we estimated whole-body protein kinetics using 15N-glycine and indicated that despite adequate nutrient intake, most children with subclinical infections were in negative protein balance (Fig. 1). In a subsequent phase following nutritional rehabilitation and treatment of infection, these children were exposed to a vaccine challenge. Evaluation of protein kinetics indicated that the immunostimulation was associated with a phase of negative protein balance (Fig. 2). These studies indicate that in many children with subclinical infections and immunostimulation, a limiting factor may be amino acid and protein intakes during rehabilitation.
Amino Acid Supply, Growth and Implications for Therapy
The role of dietary protein as a determinant of growth is well recognized. Millward (52) proposed a protein-driven regulatory mechanism, centered on the control of bone elongation by protein availability. Other studies (53) showed that bone growth continued at reduced but substantial rates even when dietary energy intake was reduced by 50%, as long as protein intake remained constant. The ability of dietary protein to increase growth, particularly during periods of catch-up growth after illness is well recognized (54,55). The amino acid composition of dietary proteins has a direct effect on growth by determining the supply of essential amino acids at the cellular level. Protein synthesis requires the presence of each component amino acid at the time of chain elongation. Thus, a dietary protein intake deficient in ≥1 essential amino acids will not be able to sustain protein synthesis. Many vegetable proteins have ≥1 limiting amino acids (eg, with levels below those in high-quality reference proteins such as egg or milk).
Among the adaptive changes in plasma amino acid concentrations with malnutrition are a temporary increase in the levels of branched-chain amino acids, an increase in glycine levels, and a fall in alanine concentration (56). This specific and early effect on branched-chain amino acids is an indication that these are among the first to become limiting for protein synthesis in malnourished children. The presence of intermediary metabolites of histidine and tyrosine in the urine of malnourished children (57) suggests a widespread impairment of enzyme activity. It must be emphasized that the plasma amino acid profile in most malnourished children also reflects the superimposed effects of infection and anorexia. In the well-nourished host, infection episodes trigger a cascade of adaptive responses, aimed at enhancing immune competence and preserving vital cellular activities and preventing colonization of the infective agent. The role of cytokines as mediators of systemic responses to infection has become clearer during the past decade (58). Although the precise molecular mechanisms are unclear, the cellular biology of tumour necrosis factor suggests a role in promoting the transfer of amino acids from peripheral tissues to liver for use in acute-phase protein synthesis and gluconeogenesis (59). It is important to emphasize that this cytokine-induced catabolic state cannot be overcome merely by enhancing substrate availability.
As indicated above, acute infection has a major negative impact on nitrogen balance. Studies by Biesel (60) showed that the infection process was responsible for higher nitrogen losses than could be accounted for by a decreased protein intake. This specific effect of infection varied depending on the etiological agent and on the initial nutritional status of the host. In the relatively well-nourished host, mild infection was associated with an increased protein turnover (61), although the modest rise in protein synthesis could be negated by the associated marked increase in the rate of protein breakdown (62,63). The host response to infection requires the rapid synthesis of immune proteins. The catabolic response to infection leading to breakdown of skeletal muscle protein and release of free amino acids into the bloodstream provides most of the extra amino acids needed to mount that response. Although the impact of protein deficiency on altering the acute-phase response is well recognized (64), the precise amino acid requirements to mount this immune response have been the subject of speculation. The issue is particularly important for developing countries, where childhood infections are common and the cumulative burden that these episodes can have on amino acids requirements of the small child is substantial (65).
Table 2 indicates the alterations in plasma amino acid profiles in response to short-term dietary alterations, malnutrition or infection (66,67). These complex changes do not provide much help in understanding the dynamics of protein metabolism in malnourished infected individuals. Preliminary animal data suggest that it is possible to modulate the endogenous production (68) as well as the metabolic response to tumour necrosis factor-α (69) by modifying the amino acid composition of the diet.
Intervention Strategies to Reduce the Nutritional Impact of Infections
Given the above findings, it is important to ensure that a wide variety of intervention strategies are employed to ameliorate the nutritional penalty of infections. These can be broadly classified as follows.
The major environmental penalty of poverty is increased burden of infections, and clearly this must be a long-term goal for most developing countries. The reality of global inequity and poverty, however, is totally different in many parts of the world, especially sub-Saharan Africa, which has slid down the poverty ladder. Thus, there is continued interest in intervention strategies to accelerate the reduction in childhood diarrhoea and acute respiratory infections.
It has been shown that targeted education strategies do have an impact on reducing diarrhoea burdens and improving breast-feeding practices (70,71). In addition, interventions focused on improving the supply of safe water through filters (72,73), chlorination (74) or other strategies (75) have been shown to have a significant impact on diarrhoea rates. Community education and hand washing strategies through promotion of the use of soap have been shown to reduce rates of diarrhoea and acute respiratory infections in community-cluster randomized trials (76–78), indicating the benefit of incremental strategies for community behaviour change.
Although these studies are important and systematic reviews (79) support the benefit of hand washing and soap, the reality is that this is an expensive intervention that is difficult to roll out and sustain. As a recent analysis (80) of the global costs for child survival interventions indicates, we are currently spending almost $2 billion on safe water and sanitation in developing countries, yet the intervention does not reach those in greatest need. There is thus the continued need for additional preventive strategies. Given the close relationship between malnutrition and infections, nutrition interventions are widely regarded as critical to public health programs.
Although the role of balanced energy-protein supplementation for nutritional rehabilitation is well described, the critical role of adequate protein intake in malnutrition is also widely recognized (81,82). Although some regard the absolute intake of protein as a more important factor (83), others have evaluated specific amino acids in malnourished children with infections (84,85) and found them to be equally beneficial. Some of this uncertainty stems from observations that during acute stress if infections some amino acids become conditionally essential and that replenishing the need acute phase proteins would result in breakdown of muscle protein (51). Manary et al (86,87) specifically demonstrated the benefits of using an egg whites–based tryptophan source in infected severely malnourished children.
In addition to the role of protein and amino acid intakes, a number of epidemiological studies support the close association of infections with micronutrient deficiencies. These include findings of lower serum concentrations of zinc with increasing burden and duration of diarrhoea (88), as well as lower serum concentrations in patients with HIV infection (89). Although children with hypovitaminosis A and low serum concentrations of vitamin A have higher rates of associated infections, the specific contribution of infection to vitamin A deficiency cannot be discounted. The relationship between low serum vitamin A and severity of disease has been observed with increasing severity of HIV infection (90). Several infections are, however, directly associated with an increased risk of micronutrient deficiency. These include diseases such as measles, which have been directly implicated in unmasking as well as triggering vitamin A deficiency (91). The association of relatively higher rates of micronutrient deficiencies with infectious diseases may be reflective of both increased predisposition to infections in deficient populations as well as a direct effect of the infection itself on the micronutrient status indicators (92). Low serum concentrations of micronutrients have been frequently described in subclinical infections. These levels also appear to be lowest at the highest levels of inflammatory proteins. High serum concentration of C-reactive protein and haptoglobin are known to relate to the density of malarial parasites, with correspondingly lower concentrations of plasma retinol, in Tanzanian children (93). The levels of plasma retinol among apparently healthy children in Ghana were also found to be lowest in those with raised markers of acute inflammation (94). The effects of infection on blood indicators of micronutrient status may be more marked in areas with widespread malnutrition. To illustrate, in an evaluation of the comparative effects of malnutrition and coexisting malaria on serum antioxidant levels in Nigeria, the reduction in plasma β-carotene concentrations was significant with malaria rather than with malnutrition (95).
CONCLUSIONS AND IMPLICATIONS
The present review illustrates the close interaction between infections, especially those prevalent in poor, deprived populations and malnutrition. Although this relationship is bidirectional, with malnutrition predisposing to infections, the role of recurrent infections in inducing and worsening malnutrition must be equally emphasized. A number of intervention strategies target reducing the burden of infections directly through nutrition education (eg, promotion of exclusive breast-feeding and appropriate complementary feeding and water/sanitation and hygiene interventions). It is anticipated that the reduction of the burden of infections would lead to substantial benefits in growth, and this has been demonstrated in several intervention studies (96,97).
The important contribution of some infections to aggravation of micronutrient deficiencies in at-risk populations cannot be ignored. Increased losses of micronutrients such as vitamin A and zinc during infectious illnesses such as diarrhoea are important contributors to micronutrient deficiencies. This may be particularly marked with prolonged diarrhoea and dysentery and may lead to clinically significant deficits and overt micronutrient deficiency.
Given that the epidemiological association between micronutrient deficiencies, such as zinc and diarrhoea, is well established, supplementation strategies are logical in endemic areas. The growing body of evidence on the key role of zinc supplementation in accelerating recovery from diarrhoeal illnesses in developing countries supports its use in public health strategies in endemic areas (98–100). The association of measles with overt and subclinical vitamin A deficiency also recognized that the administration of vitamin A to all such malnourished and at-risk children forms a cornerstone of such management strategies. Population-based micronutrient interventions and targeted replenishing of critical nutrients that may become deficient during infective stress may have significant public health benefits in developing countries.
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