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5. protein needs associated with infection

5.1. Basis of recommendations in the 1985 report

The 1985 report pointed out that young children in disadvantaged populations experience frequent infections, which can have a significant impact on protein requirements. However, because there were few quantitative estimates of the increased need for protein during infection, this section of the 1985 report was brief. Information from one long-term nitrogen balance study of six children 8-12 months of age in Thailand (Tontisirin et al, 1984) was used to estimate the order of magnitude of increases that might be needed. In that study, measurements were made under relatively controlled conditions, but the children were exposed to some degree of infection and parasitism. The average intake of 1.35 g/kg/d was considered to meet their protein requirements, but was not sufficient to be considered a 'safe level'. It was suggested that if 1.35 g/kg/d could be considered the requirement level under those conditions, the safe level would be 1.69 g/kg/d (1.35 × 1.25), which was 14% higher than the requirement calculated by the factorial method for children of that age. In a later section, a 20% increment in protein intake for children 12-18 months exposed to infection was suggested as an approximation. It was pointed out that children younger than this would need a larger increase and older children less of an increase. The conclusion was that until more information was available, more detailed calculations were unwarranted. It was recommended that field studies be conducted to test assumptions about protein requirements under actual environmental conditions.

5.2. Metabolic changes accompanying infection: implications regarding protein and amino acid requirements

Ideally, the calculation of the likely impact of infection on nutrient requirements should take into account the metabolic changes that occur during and after an illness. Severe infection obviously requires immediate clinical intervention and while febrile illness has a major metabolic impact, supporting the infected individual's nutritional needs is not a substitute for the appropriate therapeutic measures. Of greater concern at the population level are the circumstances of infants and children in environments in which persistent immune activation, not necessarily manifested as overt infection, may be prevalent. Solomons et al (1993) have suggested that such continuous 'low level' activation of the host defense mechanisms diverts nutrients away from growth and towards the needs of the immune system. They cite studies showing that chickens raised in sanitary environments grow more rapidly and utilize their diet more efficiently than those housed under less advantageous conditions even though these animals do not display any clinically identifiable infections (Libby and Schaible, 1955; Hill et al, 1952; Lillie et al, 1952).

Although the nutrient requirements of severely infected individuals should not, perhaps, be the model when we seek to define estimates of nutrient requirements for populations, the changes that accompany more severe illness can provide insights into the ways in which less severe, but continuous, immune activation might impact nutrient requirements. With regard to protein and amino acid nutrition, the key factors are (1) synthesis of new proteins associated with host defense, (2) muscle protein loss, (3) metabolic diversion of nutrients during the active infection and (4) impaired intestinal absorption with some infections. All these responses occur in concert, largely initiated by the increase in cytokine levels consequent upon immune activation and the increased secretion of the so-called stress hormones: cortisol, epinephrine and glucagon.

5.2.1. Synthesis of immune-response proteins. Host defense depends on the ability to support the proliferation of the cells of the immune system, the synthesis of the positive acute-phase proteins and factors involved in the complement system, and the maintenance of peroxidative defenses by increased synthesis of glutathione and other free radical scavenging molecules (such as nitric oxide) derived from amino acids. It is important to bear in mind that the new protein synthesis associated with the activation of the body's defense mechanisms is highly specific and therefore may demand specific nutrients. Little quantitative information on the scale of these 'anabolic' responses is available. Waterlow (1991) has calculated that at the height of a 'typical' infection the circulating positive acute-phase reactant proteins may rise by a total of 1.2 g/kg. This is a substantial proportion of whole body protein synthesis. In well-nourished individuals it seems reasonable that the substrates available for these changes are adequate, but the inability of undernourished individuals to mount an adequate response is well established. The suppression of immune activity by undernutrition may persist even when immediate nutritional deficits have been replenished. For example, Doherty et al (1993) have shown that in infants the response of C-reactive protein and serum amyloid A to vaccination with diphtheria-pertussis-tetanus vaccine was impaired for some time after an episode of severe protein energy malnutrition, despite nutritional rehabilitation. In this case a specific role of protein deficiency cannot be established because of the likelihood of multiple micronutrient deficiencies accompanying an episode of severe protein energy malnutrition.

5.2.2. Catabolism of skeletal muscle. A uniform finding in a wide variety of traumatic conditions, including injury, is a loss of muscle protein. This may be particularly marked in undernourished individuals (Nessan et al, 1974). The muscle protein mobilization is greater (Garlick et al, 1980) than would be expected from the reduction in intake that almost invariably accompanies infection, and it appears to be actively regulated by the combination of catabolic cytokines and hormones that also initiate a number of the other metabolic responses to infection (Beisel, 1975). It is presumed that muscle protein mobilization is directed towards supplying amino acids for other processes. These could include the provision of glutamine, glycine and cysteine for glutathione synthesis, the provision of essential amino acids for cellular proliferation and new secretory protein synthesis and the possibility that amino acids assume a greater importance as energy sources during active infection. A recent study of the amino acid composition of the major acute phase proteins (Reeds et al, 1994) has revealed that, as a group, they have unusually high concentrations of phenylalanine and tryptophan. It has been hypothesized that this necessitates excessive muscle protein mobilization. The mobilization of muscle protein is not, in and of itself, a contributor to increased amino acid requirements, but depletion of muscle protein is an indication that these requirements have increased beyond those being supplied by the diet of the infected individual. The replenishment of the depleted muscle mass is an important factor in the nutritional requirements for the recovery period.

5.2.3. Metabolic diversion of nutrients - specific effects on amino acid needs. Overt infection is characteristically associated with substantial changes in circulating and tissue amino acid concentrations. The large majority of the amino acids show an early and rapid decline in concentration (Beisel, 1975; Wannemacher, 1977). The decline in plasma amino acid concentrations occurs early in the illness. In a number of studies of experimental infection (Feigen and Dangerfield, 1967; Feigen et al, 1967, 1968; Wannemacher et al, 1972), the decline in circulating amino acids preceded the onset of fever. In general it is believed that these changes are a reflection of increased hepatic utilization which, in this context, includes both acute-phase protein synthesis and gluco-neogenesis (Beisel, 1975).

The general decline in amino acid concentrations is not uniform. Research in the 1970s with Diplococcus pneumoniae infection (Wannemacher et al, 1971; Wannemacher, 1977) showed early reductions in the branched chain amino acids, threonine, tyrosine, proline and arginine. Subsequent studies (Souba et al, 1990) have also established consistent reductions in circulating glutamine concentrations in a variety of traumatic circumstances. These changes persist as long as the infection persists. It has generally been presumed that the particularly marked changes in the branched chain amino acids and glutamine are related to their metabolic interrelationships, their involvement in muscle energy metabolism and interorgan nitrogen transport and hence that the alterations are primarily associated with derangements in energy metabolism. By contrast, the concentrations of phenylalanine, tryptophan and glycine increase during infection (Wannemacher, 1977). The underlying reason for these changes remains obscure, as the release of these amino acids from skeletal muscle is not excessive (Bostian et al, 1976) and infection is associated with accelerated hepatic uptake, at least of phenylalanine. The changes are particularly paradoxical given that a case can be made for a specific increase in phenylalanine and tryptophan requirements during infection (Reeds et al, 1994).

Recent work has also suggested an increase in proline requirements under traumatic conditions. Jaksic et al (1987) have shown that the ability of humans to synthesize this 'non-essential' amino acid is limited; in burn injury, humans move into a profound negative proline balance (Jaksic et al, 1991).

5.2.4. Implications regarding protein and amino acid requirements. The above sections illustrate that overt infection not only alters protein requirements in general but probably has effects on the needs for some specific amino acids, notably the aromatic amino acids as well as cysteine, glutamine, arginine and proline However, the quantitative impact of infection still requires investigation, particularly with regard to persistent subclinical infections.

For children, one approach that has been taken is to estimate the amount of protein needed to restore the growth deficit caused by infections. However, this ignores the unique alterations of amino acid metabolism that accompany infection.

Another approach is to estimate nutrient losses during infection and calculate the amount needed from the diet to recover those losses during convalescence. Scrimshaw (1992) has utilized this approach in a recent review of the effect of infection on nutritional status. He cites data from Powanda (1977) as indicating that the average additional loss of protein during infection in adults is about 0.6 g/kg/d; losses are higher (0.9 g/kg/d) for diseases associated with diarrhea or dysentery. Some infections, such as typhoid fever, are associated with even higher losses, up to 1.2 g/kg/d. Scrimshaw estimated that it generally takes two to three times longer to replete than to deplete an individual. Thus, the amount of extra protein required to recover losses due to infection would be one-half to one-third of the daily loss during infection, provided that this augmentation was available for the total duration of the convalescent period. Taking the mean daily loss of 0.6 g/kg/d, and assuming that this estimate also applies to children, the protein increment during convalescence would be 0.2-0.3 g/kg/d (0.3-0.5 g/kg/d for diarrhea). This represents about 20-30% of the normal protein requirement (3050% in the case of diarrhea), depending on the age of the child.

The duration of the period needed to recover nitrogen losses will depend on the severity and duration of the illness. In the 1985 report it was recommended that children be fed according to their appetite, which seems the only practical way to proceed. However, if appetite is impaired by illness (even after the acute phase) the time needed for repleting nutrient losses will be longer. It should also be emphasized that for many children in disadvantaged populations, the needs for catch-up growth may be superimposed on the extra needs during the period of recovery from infection. The total need will obviously depend on the desired rate of catch-up growth, as explained in the previous section.

While calculation of nitrogen losses during infection can provide an overall estimate of total protein needs, this approach does not stipulate the optimal amino acid balance that would restore those losses most efficiently. Given the disproportionate needs for certain amino acids during infection, merely providing more of the same mix of amino acids as consumed when healthy may be less effective than a mixture specifically designed for the recovery period. One approach to this is to measure flux rates, rates of efflux from skeletal muscle, and rates of influx into acute-phase proteins of amino acids in response to specific infections and in varying states of initial nutritional status. This kind of investigation can be done in children using stable isotopes; a multi-site study of this nature is currently underway as part of a Coordinated Research Programme by the Section of Nutritional and Health-Related Environmental Studies, International Atomic Energy Agency and several co-funders. When the results are available, it may be possible to make more precise estimates of amino acid requirements associated with infection.

Whatever the approach taken, it is important to note that, just as for catch-up growth, the extra nutrient needs associated with infections include not just protein and amino acids but energy and other nutrients as well.

5.3. Recommendations for revision of the 1985 report

Until further data are available, a reasonable estimate of protein needs following infection is a 20-30% increase in total protein (30-50% in the case of diarrhea) during a recovery period that is two to three times longer than the duration of the illness. In the case of persistent diarrhea with accompanying anorexia, the desired increase may be very difficult to achieve. When children have diarrhea for 20-30% of the time, following the above recommendation will essentially result in a permanent increase in the protein level of the diet provided (until they reach an age when diarrhea is less prevalent).

6. Assessment of protein quality of weaning diets

The procedures for making adjustments for protein digestibility and quality were described thoroughly in the 1985 report and in a subsequent Joint FAO/WHO expert report (Joint FAO/WHO Expert Consultation on Protein Quality Evaluation, 1991) and do not need to be reiterated here. Use of the protein digestibility corrected amino acid score is considered the most appropriate method for evaluating protein quality. This method obviously depends heavily on the estimated amino acid requirements at each age. For infants, both the 1985 report and the 1991 Consultation recommended that the amino acid composition of human milk be accepted as the suggested pattern of requirement. However, as the discussion in section 2.5 indicates, the essential amino acid content of human milk is generally above 'requirements' based on calculated needs for growth and maintenance. Thus, using the human milk amino acid pattern (mg/g protein) as the basis for evaluating weaning foods may underestimate their protein quality (depending on which amino acids are potentially limiting in the food being evaluated).

For children, the 1991 Consultation (FAO/WHO Expert Consultation, 1991) recommended that the amino acid scoring pattern for preschool children (see section 3.4) be used for all age groups (except infants). Until more information is available on amino acid requirements, this recommendation appears to be justified. However, because that scoring pattern was based on only one set of studies in a small sample of children, replication of the findings is essential. The lack of information on sulfur amino acid needs is particularly unfortunate as these amino acids, together with lysine, may be marginal in vegetable protein sources if Rose's (1957) 'safe' rather than 'minimal' level is closer to true needs (see section 2.5). Even so, data from Guatemala (Scrimshaw et al, 1961; Torun and Viteri, 1981b; Torun et al, 1984) suggest that predominantly vegetable multi mixes can provide an adequate source of amino acids for children beyond the age of one year.

Aside from protein quality, any evaluation of weaning foods must also consider the content and bioavailability of other nutrients, particularly trace elements, and the potential presence of 'antinutritional' factors such as plant lectins.

7. Future research needs

To better understand protein requirements of infants and children, more information is needed on a variety of topics. The following is a partial list of research priorities:

(1) There is a need for studies of protein requirements that include functional outcome measures (both short term and long-term), not just growth rate or nitrogen balance. The question 'protein requirements for what?' has not been adequately addressed. Such studies should include not only the potential consequences of marginal intakes, but also the long-term impact of moderately high protein intakes (such as later kidney function in formula-fed infants).

(2) Information on the efficiency of utilization of dietary protein at various ages and in children with different growth rates is needed. In particular, the efficiency of protein utilization in formula-fed vs breastfed infants should be studied to determine whether protein requirements differ by feeding mode in early infancy. Additional data on the utilization of non-protein nitrogen in human milk and infant formulas would also be useful.

(3) It is essential to determine the degree of intra-individual day-to-day variation in growth at various ages, and the nutrient needs (not just protein) required to permit the child to deposit new tissue rapidly during growth 'spurts'. Limited information (Lampl et al, 1992) suggests that spurts in linear growth may be of short duration (24-48 h), but it is not known whether the magnitude of growth during such episodes or the frequency of episodes can be affected by protein intake. Both animal models and human studies would be useful in answering these questions.

(4) Updated information on body composition during infancy and childhood, particularly the percentage of weight gain that is fat-free body mass, is important for accurate estimates of protein requirements using the factorial method.

(5) Better data on maintenance nitrogen requirements of infants, children and adolescents are needed, although ethical issues may limit the types of studies that can be carried out. Studies in children who were not previously malnourished, and data on the protein needs of female adolescents should be a high priority. In addition, long-term balance studies at protein intakes close to estimated requirements would provide key evidence to support or reject the adequacy of the estimates based on short-term balance studies.

(6) Amino acid requirements require further study at all ages, including children. Such research should consider not only amino acid needs for protein metabolism, but the other functions of amino acids as well. Requirements for the sulfur amino acids in particular require investigation. These, ironically are the amino acids for which calculated 'needs' are lower in the MIT pattern (see section 2.5) than in Rose's estimates. Yet data from rats, pigs and chicks suggest a high requirement for cysteine (as a proportion of total amino acid needs) at protein intakes close to maintenance levels, and recent data from the Rowett Research Institute (Fuller, personal communication) suggest that a significant proportion of this need appears to be devoted to the synthesis of taurine.

(7) To determine protein and amino acid needs for catch-up growth, data are needed on the maximal rate of growth that can be achieved without compromising body composition or function. The rates of catch-up growth achievable in non-hospital settings should be documented.

(8) In disadvantaged populations, community studies evaluating the impact of nutrition interventions that provide extra protein, controlling for the intakes of energy and other nutrients, would be particularly useful in determining whether protein is a key limiting nutrient for such children.

(9) The impact of infection on amino acid and protein needs requires further investigation. The impact of acute-phase protein synthesis on whole body protein economy and requirements is of particular interest. Data are needed to determine whether chronic stimulation of the immune system diverts essential nutrients from whole body growth in undernourished children, and, secondly, the dietary needs to prevent or compensate for this outcome. Several outcome variables would be useful: (a) the ratio of protein synthesis to protein breakdown under conditions of immunostimulation and refeeding; (b) the rate of oxidative loss of dietarily indispensable amino acids and (c) the rates of acute-phase protein synthesis, of transport protein synthesis, and the interactions between these and whole body protein metabolism. In studies of amino acid requirements in infected children, identification of the infective agent(s) should be attempted and concentrations of hormones known to mediate amino acid/protein metabolism during infection should be determined because these indices may facilitate predictions of the impact of infection in other populations.

Acknowledgements - Data for the pooled analysis of growth of breastfed infants came from seven studies conducted by the following investigators: KG Dewey, MJ Heinig, LA Nommsen and B Lonnerdal (USA); NF Krebs, CJ Reidinger and KM Hambidge (USA); KF Michaelsen and G Samuelson (Denmark); LA Persson and G Samuelson (Sweden); L Salmenpera, J Perheentupa and MA Siimes (Finland); AA Paul, TJ Cole, EA Ahmed and RG Whitehead (UK); and D Yeung (Canada). The analysis was funded by a grant from Wellstart International through the US Agency for International Development (AID), Bureau for Research and Development, Office of Health (Cooperative Agreement No. DPE-5966-A-00 1045-00) to the University of California, Davis. The contribution of Peter Reeds to this paper has been funded in part with federal funds from the US Department of Agriculture, Agricultural Research Service under Cooperative Agreement number 58-6250-1-003. The contents of this publication do not necessarily reflect the views or policies of the US Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement from the US Government. We gratefully acknowledge comments on the initial draft from JC Waterlow and SJ Fomon.

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