Effect of infection on nutrient requirements1 Nevin
S.
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ABSTRACT
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Am.
J. Clin.
Nutr.
nutrition 30:
Each dilemma: 1536
of
of the
The
recommended
following
American
Journal
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ofClinical
Nutrition
in iron
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30:
infection for
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1977.
1) Granted that an acute infectious episode depletes the body of a nutrient, to what extent, in normal individuals, will increased absorption and efficiency of utilization duning the recovery phase obviate the need for an actual increase in dietary allowance for that nutrient? 2) Granted that a significant number of individuals in a population experience nutnitionally debilitating acute infections, does the decreased intake of nutrients by the ill compensate for increased food consumption by those convalescing from an infectious episode so that the overall nutrient and food needs of the population are unaffected? 3) How much less is the nutrient loss with infection in a malnourished individual than observed in the usual studies with well-nounished subjects? 4) What allowance is appropriate for damage from chronic infections that result in continuing malabsonption or nutrient losses? 5) If there is an increased requirement for a nutrient as the result of acute and chronic infections, when is it appropriate to recommend an increased dietary allowance for the nutrient instead of relying on measI
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1536-1544,
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Infections have profound effects on the intake, metabolism, and excretion of most nutrients and, hence, on nutritional status (1). These effects have been further descnibed and discussed in the presentations at this Workshop. Nearly all expert groups who have examined the problem of nutrient requirements have recognized such effects, and most suggest that “they be taken into account” in applying recommended allowances to populations in whom infectious diseases are prevalent. Because they lack specific instructions on how to do so, such admonitions are of little value and have generally been ignored. In fairness, the issues are so complex and the data so limited that it is not yet clear what recommendations should be made. In addition to lack of sufficient quantitative information on the effects of various infections on the status of specific essential nutrients in the body, there is great uncertainty as to how requirements are affected. Even when individual needs are clearly increased, the influence of disease prevalence on nutrient requirements for populations is less apparent. Principles ances
effects
have specific
as to how
nutrient
,
and
nutrients.
but
allowances
of anorexia
absorption,
requirements
account,
uncertainty
alter
dietary
constitute
tion.
into
might
because
sequestration.
purposes
nutrient
is great
establishing
intestinal
on
to be taken
prevalence for
infections
impaired
through
expert
formulated.
principles
of treatment, or
been
or how
traditional
all
of infection
not
affected
of acute
M.D.
Nearly
nutritional do this
,
D.
.
From
the
Department
of Nutrition
ence, bridge,
Massachusetts Institute of Massachusetts 02139. 2 Institute Professor and Head. for reprints should he addressed
SEPTEMBER
1977,
pp.
15361544.
and
Technology, To
whom
Printed
Food
SciCam-
requests
in U.S.A.
INFECTION
ON
NUTRIENT
ures to eliminate the infections from the population? There is now sufficient evidence to confirm the qualitative effects of infection on the requirements for some essential nutrients, but it is still difficult to make reliable quantitative recommendations. This will be clearer from a review of the following mechanisms by which infection affects nutritional status: Anorexia Even with mild and subclinical infections, the loss of appetite is sufficient to make it difficult or impossible to maintain a constant food intake during the acute phase of illness. Withdrawal
ofsolid
food
Especially when fever, diarrhea, or malaise is present, i.e., when an individual is recognized to be sick, there is a strong cultural tendency to withdraw solid food and substitute watery infusions, gruels, and the like for more nourishing solid food. This is often reinforced by physicians who advise a liquid diet for the sick child without emphasizing that solid foods must be given as soon as the child can tolerate them. Other tion
adverse
effects
of
treatment
on
nutri-
There is a common tendency to give strong purgatives to children who have diarrhea or pass worms in their feces. The resulting diarrhea further reduces intestinal absorption. Also, prolonged sulfonamide or other antibiotic therapy can interfere with the intestinal flora that synthesize some of the B vitamins and vitamin K. Impaired
absorption
Acute conditions. Those that affect the gastrointestinal tract, such as diarnheab disease, interfere with the absorption of protein, fat, and most of the other essential nutrients. Some systemic diseases, such as measles, tuberculosis, or bacterial sepsis, also impair absorption through their direct effects on the gastrointestinal epithebium. Other acute infections, for example, otitis media, affect absorption indirectly by producing diarrhea. Malaria in monkeys has
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REQUIREMENTS
1537
been shown to decrease absorption. The suggested mechanism is interference with capillary circulation in the mesentary(2). Repeated exposure to enteric infection. This is apparently capable of causing damage to the intestinal mucosa to the point where the villi and microvilli are reduced in height and absorption of xybose is impaired (3). Absorption of lactose, other disaccharides, and even simple sugars may also be affected. There is less quantitative information on the effect of entenic infection on fat absorption because it is harder to measure, but reduced absorption of sugars and fat would lessen the amount of dietary energy available from the diet. There are too few data to know the extent to which absorption of other essential nutrients, including protein, is affected. Heavy concentrations of intestinal parasites. Parasites such as hookworm, Ascaris, Giardia, and coccidia have been shown to reduce absorption of protein and vitamin A, and this is probably true for some of the other nutrients (1). Mild and moderate infestations apparently do not have a detectable effect. Specific effect offish tapeworm on vitamin B12. The fish tapeworm, Diphyllobothrium latum , acquired from eating raw fresh water fish in northern Europe, the U.S.S.R., and sometimes in the northern United States, has an avidity for vitamin B12. Megaloblastic anemia due to vitamin B12 deficiency has been demonstrated repeatedly in persons harboring this worm (1). All of the above contribute to nutrient depletion during infection by reducing either the intake of essential nutrients or their absorption. Equally important in infection is the increased loss of an essential nutrient from the body or a decrease in its availability within the body for normal metabolism. increased
urinary
loss
Increased urinary excretion of nitrogen and other essential nutrients occurs as a consequence of the stress response with almost any degree of infection. Urinary boss of vitamin A (1), ascorbic acid (1), iron, and zinc have also been described (4) . The quantitative aspects of urinary nitrogen boss
1538
SCRIMSHAW
will be discussed later. (Fe and protein) occurs matobium infection.
Urinary loss of blood in Schistosoma hae-
increased
losses
integumental
Increased nitrogen and mineral boss occur in sweat in association with fever but there are no quantitative data. There is also some loss of nitrogen with the peeling of skin following exanthematous diseases. increased
fecal
losses
Hookworm infection affects the duodenum, so there is an opportunity for reabsorption of the nitrogen present in the blood boss caused by the worms, but there is a marked added loss of iron. This also tends to be true in the intestinal bleeding associated with Schistosoma mansoni , but in amebiasis the blood is lost in the colon, so there is no chance for either the protein or the iron in this blood to be reabsorbed (5). internal
sequestering
of nutrients
Beisel et al. (4) described in detail the incorporation of amino acids into a- and glyco-proteins and C-reactive proteins during the early stress response to infection. Plasma iron and zinc levels were lowered at the same time. These factors are responsible for the adverse effects of acute, and of some types of chronic, infections on nutritional status. If nutrient intakes are marginal in an individual before the infection is acquired, the depletion of that nutrient during the period of infection may be significant. Moreover, a simple return to the previous marginal diet during convalescence will be inadequate for rapid repletion unless a sufficient increase in efficiency of absorption and retention occurs. At best, repletion can be expected to be slower if intake is limited to normal maintenance requirements. For a population group in whom acute infections are highly prevalent, for example, preschool children in developing countries, slow recovery is highly dangerous because the next disease episode may come along to deplete the child further before he has recovered from the preceding illness. Eventually, an infection that is seemingly no more severe than a long series of preceding
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ones “suddenly” precipitates kwashiorkor, or xerophthalmia and keratomalacia, or scurvy, or beriberi, depending on the preceding dietary deficiency. The problem is to: I ) Estimate the quantitative effects of infections on individuals; 2) determine the extent to which these are compensated for by increased efficiency of utilization during recovery; and 3) estimate the overall quantitative effects of infections in a population. If individual requirements were known, it would be possible to apply the same procedure as that for estimating the normal vaniation in requirements for a nutrient among a population of presumably healthy persons, taking into account such population differences as body size and environmental temperatures. It is manifestly more difficult in practice, because the data cannot be generalized from one population to another. The second can be estimated to some degree by analysis of existing information, but will require considerably more research on the metabolism of nutrients in affected human subjects before we can hope to arrive at any definitive recommendations. It can be clearly stated, however, that whenever chronic infectious disease causes an additional loss of nutrients from the body or impaired absorption of dietary nutrients, increased nutrients are required and must be supplied by the diet if nutritional deficiency is to be avoided. It has been suggested that in such cases the effort should be to eliminate the infection, not to provide additional nutrients. However, this is impractical in many instances. The required prevention may be beyond the human or financial resources available, or may take a number of years. Even when prevention is possible increased nutrient intake may be a less cost-effective interim solution in an economically deprived population. I will try to examine these various issues as specifically as possible. Effect needs
of
infections
on
protein
and
energy
Other papers in this Conference have brought out clearly that individuals are usuably in negative protein and energy balance during acute infectious episodes. In the case
INFECTION
ON
NUTRIENT
of protein, amino acids are withdrawn from skeletal muscle and other peripheral tissues. In diseases as severe as typhoid fever, this boss may be equivalent to 2.5 to 3.5 g/kg of muscle (6). Kocher (7), in 1914, reported that 2 .5 to 3 .5 g/kg of protein were required daily for nitrogen equilibrium in patients with enysipelas. Patients with rheumatoid arthritis or enysipebas have been reported to lose about 1 5 g of urinary nitrogen daily (8). In this case 94 g of protein would be required to replace this loss alone, or 1 .5 g/kg for a 60-kg individual. At this Conference, Powanda reviewed various patients with acute infections who had a cumulative negative N balance of 971 g of nitrogen over 162 days of illness (9). This is equal to 37 g of protein daily, or approximately 0.6 g protein/kg. The diseases included typhoid fever, meningitis, and scarlet fever. Diarrhea of infectious ongin induced an average daily negative halance of 0.9 g/kg per day. Even with subclinical infections, the penod of negative nitrogen balance may last for days or weeks, and the recovery or anabolic phase may take from two to four times longer, as judged by return to nitrogen balance or, in children, growth. Unfortunately, it is impossible to be more precise. After even a single day of diarrhea it may be 3 to 5 days before children who have been receiving adequate protein for several weeks return to the same percentage of nitrogen retention as before the episode (1 0) , but for longer periods of infection rebevant data are not available. A published INCAP study of children with chicken pox demonstrated increased urinary nitrogen excretion during the acute period (1 1), but the children were not followed through the recovery phase In a later unpublished INCAP study, nitrogen retention was still elevated 3 weeks after the rash. Beiseb et al. (4) described a young adult exposed to Q fever who developed nickettsemia and progressive, cumulative nitrogen loss over a period of 21 days, despite the absence of fever or other symptoms. We have observed similar negative nitrogen halance in children (12) and adults (unpublished MIT data) following immunization with the 1 7-D strain of yellow fever vaccine even though they did not develop fever on .
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REQUIREMENTS
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other symptoms, and also in subjects immunized against smallpox, and in those with minor infections such as small staphybococcab abscesses and mild bronchitis. Because of the significance of infection for nitrogen balance we have assembled information documenting the high prevalence of diarrheab, respiratory, and other infections among lower socioeconomic groups in many developing countries. The most complete information has come from studies in preschool children. The highest rates of disease prevalence are among children 6 to 24 months of age, where point prevalence may be as high as 40% if one includes upper respiratory infections and pyoderma as well as lower respiratory infections, diarrhea, dysentery, and the common communicable diseases of childhood. Thus, no time is permitted for growth in a child who is almost constantly in the catabolic or anabobic phase of response to frequent episodes of disease. In a Guatemalan highland village, the incidence of infections during pregnancy was 12%, and for 653 persons of all ages exammed on a coastal sugar cane-coffee plantation, 138 had skin infections, 43, conjunctivitis, 39, upper or lower respiratory disease, and 35, diarrhea. Among anemic male plantation workers in Indonesia, the 2month period prevalence for disease was 7.5% for upper respiratory infections and influenza, 2.5% for bronchitis, 1 .7% for tuberculosis, and 3.3% for entenitis. Nonanemic males had a disease prevalence rate of 4.8% for upper respiratory infections, 0.8%, for bronchitis, 0%, for tuberculosis, and 2.4%, for entenitis. Most infections were not associated with fever (13). Because fever elevates basal metabolic rate, it is the principal mechanism influencing energy expenditures during infection. Some protein depletion occurs with infection whether on not fever is present. Reductions in intake of the usual diet because of anorexia would affect the intake of both calories and protein, but because the tendency is to substitute starchy gruebs of bower protein-to-calorie ratios for solid diets, this factor would also tend to exaggerate protein needs more than those for calories. There are three further points in considering the effect of infection on dietary energy needs: 1) Illness is usually associated with
1540
SCRIMSHAW
decreased physical activity, which would reduce caloric needs, while the stress response would increase urinary nitrogen losses. 2) When the diet is deficient, energy deficits are met from both body fat stores and tissue proteins, while the amino acids for protein synthesis can come only from the breakdown of tissue proteins. During the recovery period the amino acids drawn from the lean body mass, mainly skeletal muscle, must be promptly replaced for both new protein synthesis and body energy, or the degree of depletion of reserves may still be significant when the next infectious disease episode occurs. In the case of depletion of fat stores for energy, replacement is not urgent unless there is almost complete loss of subcutaneous fat, as observed only in infants with advanced marasmus and adults with severe cachexia. Such extreme states of inanition are much less common than the protein depletion resulting from the stress of infectious illness. 3) A third factor has the opposite effect. Excess dietary calories spare dietary protein, and when calories are deficient the utilization of protein is decreased. Thus, a deficient caloric intake during infection exacerbates the nitrogen loss and a liberal caboric intake during recovery favors protein retention. Using the data I have cited and those presented by Powanda (9) at this workshop, the calculation for the net loss of nitrogen during infections varies from a protein equivalent of 0.6 to 1 .2 g/kg per day, depending on the nature and severity of the infection. If one assumes that the anabolic phase of recovery will last three times longer than the catabolic period, then the effect of each day of the catabolic phase means an average extra daily allowance during recovery of 0.2 to 0.4 g protein/kg to replace that lost during the acute infectious episode. If one takes the intermediate value of 0.9 g of protein/kg per day additional loss seen in children with scarlet fever, 0.3 g/kg per day would be required during the recovery penod. At the start of recovery, absorption might be 30% more efficient, but this would decrease gradually with repletion. This figure
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is suggested by INCAP observations in young children of the greater absorption of milk following a period of inadequate protein intake than when the preceding protein intake was adequate (14, 15). However, a mean figure of 15% for the increase in utibization would not appreciably affect the final figure for additional nitrogen during recoveny, and it does not seem worth including on such flimsy evidence. For the calculation of possible additional dietary energy needs for a whole population the problem is more complex, because even if infection does increase average need, we must not propose a dietary energy intake that would make most people obese. Individuals during and after acute infections may require 10 to 30% more calories, but this cannot be recommended for an entire population. Moreover, the extent to which increased metabolic needs are compensated for by decreased activity has never been firmly established. The best solution is to stress that present estimated caloric requirements do not cover needs resulting from infection and do not provide for catch-up growth in children. The diet during the recovery period fobbowing an infection clearly should provide sufficient additional calories and protein for as rapid repletion as possible and maximize catch-up growth in the case of children. Unfortunately, we cannot specify how much of either calories or protein at the present time because this varies widely with the circumstances and there have been too few studies to have reliable guidelines. We would note, however, that the long time lag generally observed in both resumption of growth on restoration of nitrogen balance may result from lack of optimum calories as well as protein for recovery. iron Several common infections lead to increased iron losses from the body, most notabby hookworm and schistosomiasis. The effects of acute infection on iron metabolism in man are well-documented, although some of the mechanisms are only partly understood. These effects have considerable clinical and public health importance. Infections influence iron metabolism most
INFECTION
ON
NUTRIENT
directly through boss of blood and resulting anemia. The figure of 0.67 ml of blood lost per day pen hookworm, frequently cited in the older literature (16), is now known to be an overestimate. By measuring the excnetion of 51Cr-labeled hemoglobin, Roche and co-workers (17, 18) showed that each Necator americanus causes daily losses of 0.031 ± 0.017 ml blood, or 2.74 ± 1.50 ml per million eggs. Gibles and associates (19) obtamed a figure of 0.05 ml of blood lost per worm per day for this species. Using the same techniques, Fanid and co-workers (20) found that the blood loss for Ancylostoma duodenale was five to 10 times greater than that cited for Necator They reported a loss pen worm per day of 0.26 ± 0.045 ml. In heavily infected patients, the loss ranged from 14 to 45 ml of blood per day, with a daily iron loss of 3.56 to 9.94 mg. Mean values were 26 .4 ml of blood and 6 .06 mg of iron. These investigators concluded that the mean blood loss per 1 000 ova per gram of feces was 4.47 ± 1 .6 ml. The data of Lee are similar (21). Picou, at this workshop, mentioned evidence that acute infections interfere with iron absorption There is also indication that iron-deficient individuals and populations in developing countries are more susceptible to many types of infections. Studies from Alaska document meningitis deaths in children (22) and diarrheal morbidity (23) to be increased in children with hemoglobin levels between 7.1 and 10.0 g/100 ml. Among the Indonesian rubber plantation workers referred to earlier (13), anemic rubber tappers given 100 mg of iron daily for 60 days showed significant improvement in Harvard Step Test performance and work output, while the nonanemic showed no change in these characteristics. However, nearby similar improvement was observed for the placebo group. This was ultimately explained by the fact that all workers received a cash incentive equivalent to U.S. 3 per day, which was used mainly to purchase additional food, mostly green leaves (papaya, cassava, and spinach). This resulted in increased intakes of about 200 g of leaves per worker. Indonesian food composition tables show an iron content of these leaves varying from 3 to 10 mg/100 g, depending .
.
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REQUIREMENTS
1541
on variety, and providing an average of 12 mg of iron per portion, with an absorption rate of 25%. On this basis, a net intake of elemental iron of 3 to 5 mg extra per day from leaves was calculated to be sufficient to overcome dietary iron deficiency in the presence of hookworm . This can be taken as a rough estimate of the increase in iron requirement due to hookworm in this population. Thus, the effect of infection on iron nutnitune is paradoxical. Infections, depending on type, variously reduce intake, absorption, retention, and storage of iron, and, hence, deplete the individuals whose dietary iron intake is borderline or deficient, but the depleted individual absorbs iron more efficiently than one whose stores are not deficient. As in the case of protein, the only appropriate course is to base recommendations on absorption and retention at requirement bevels. The fact that individuals do attempt metabolicabby to compensate for deficient intakes of both iron and protein is not a valid basis for reducing estimated intakes for maintenance, although this can legitimately be taken into account in estimates of the amounts needed for recovery from infection. Moreover, depletion occurs because there are sharp limits to the amount of adaptation that can occur to bow nutrient intakes. Other
nutrients
During infections the metabolism of many of the vitamins is affected ( 1 , 24) The suggested mechanisms include interference with their absorption in the gastrointestinal tract, changes in the rates of urinary excretion of some vitamins, and liver cell damage. For example, Beisel and co-workers (25), in an experimental study of sandfly fever in male volunteers, found an increased riboflavin excretion . These effects are additive to those of reduced intake. It is also well-recognized that infections are capable of precipitating xerophthalmia and keratomalacia, scurvy, beriberi, megaboblastic anemia, and other acute nutritional disease states in individuals whose nutritionab status is borderline with respect to the corresponding vitamins . Clearly , infections also influence requirements for vitamins, .
I 542
SCRIMSHAW
but there is even less quantitative information on which to base recommendations than exists for protein, calories, and iron. Discussion The foregoing considerations of available data on the effects of acute and chronic infections on the intake, absorption, retention, and loss of selected nutrients makes it possible to provide some qualitative answers to questions raised in the introduction. The data are not sufficient, however, to provide the quantitative answers really needed in the formulation of recommended dietary ablowances for individuals or populations. Among the unanswered questions is the extent to which increased efficiency of utilization of a nutrient assures adequate intake for optimum recovery if the recommended dietary allowance for healthy individuals is supplied. There is not enough information available for nutrients other than iron and protein to make any useful statement about increased utilization after acute periods of depletion . Moreover, reliance upon increased utilization during recovery from illness to make up for the nutritional deficits brought on by chronic disease requires specific determination of nutrient requirements for persons subjected to such diseases, not just general assertions of increased efficiency of utilization. In evaluating data, there are some basic statistical considerations. If the recommended allowances for healthy individuals have been arrived at correctly, they will provide more than most individuals require because the allowances are intended to represent the mean plus two standard deviations of the distribution of actual requirements. Therefore , many individuals will receive enough more than their requirements to meet the needs imposed by infection and other types of stress. If the intent is to cover nearby all of the individuals in a population, however, then the higher requirements imposed by a high prevalence of infection will be significant. If one is concerned principally with food supplies and not individual requirements, the argument is quite different. If at any given time a certain proportion of individuals is eating less because of acute infectious
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disease while others require more because they are recovering from these diseases, then perhaps no adjustment need be made in total food supplies. The trouble is that if no emphasis is placed on increased food during convalescence, the individual is not likely to receive the foods needed, for social, economic, or political reasons. Where some degree of malabsorption affects nearly all of the population of lower socioeconomic groups, as appears to be the case in many developing countries, two courses of action would appear urgent and obvious. One is a determination of the quantitative significance of this condition for absorption so that any necessary provision can be made in current allowances for essential nutrients; the other is a massive governmental effort to improve the poor e nvinonmental sanitation a nd inadequate personal hygiene largely responsible for the frequent occurrence of infectious disease in these populations. It is often suggested that one should not recommend increased provision of nutrients where the incidence of infectious diseases increases requirements because measures should be taken instead to eliminate these diseases. I believe this to be a highly specious and theoretical argument. Under the most favorable circumstances, i.e., enlightened and determined political leadenship and allocation of substantial resources, it will take many years to achieve the desired reduction in the high prevalence of enteric and systemic infectious diseases in the populations of most developing countries. In the meantime, physical growth and mental performance will be impaired, the frequency and severity of infectious diseases will be enhanced, and mortality increased in individuals who fail to receive the diets they require. Condusions
1 ) It would
and
recommendations
seem appropriate to follow the present procedure of first calculating estimates of requirements and recommended allowances for essential nutrients based on the needs of healthy individuals. However, these should be based on studies at requirement levels, not under conditions of adaptation to low protein and high calorie intakes.
INFECTION
ON
NUTRIENT
2) Given the high prevalence of acute and chronic infections among some populations, especially vulnerable age groups in the developing countries of the tropics, it would also seem appropriate to suggest that in recommendations intended to cover the needs of nearby all individuals for purposes of nutrition education, dietary evaluation, or nutritional rehabilitation, a specific additional allowance for infection should be made. 3) While the data are admittedly deficient, a figure of 0.3 g/kg per day of high quality protein for adults would appear reasonable to allow for recovery from acute episodes of infectious diseases. This is in the range of 50% more than that calculated for healthy populations. 4) For caloric requirements, which must be expressed on the basis of average needs, increasing the recommended dietary allowance is not appropriate. Instead, there should be an allowance for recovery from infection analogous to that for different levels of activity. 5) Even under circumstances in which moderate to heavy hookworm infections are associated with iron deficiency anemia, 3 to 5 mg of available iron appears sufficient to correct this condition even with continued hookworm infection. 6) More information will be required before appropriate recommendations can be made for the effects of infection on requirements for other essential nutrients. El References 1.
2.
N. S., C. E. TAYLOR Interactions of Nutrition Monograph Series No. 57. Organization, 1968.
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P., AND B. G. MAEGRAITH. Intestinal in malaria. I. The absorption of an (AIB-1-’4C) across the gut membrane and Plasmodium knowlesi-infected Ann. Trop. Med. Panasitol. 63: 439,
monkeys. 1969. 3 . ROSENBERG, I. H . , AND N . S. SCRIMSHAW. Workshop on malabsorption and nutrition, pants I and II. Am. J. Clin. Nutr. 25: 1046, 1226, 1972. 4. BEISEL, W. R., W. D. SAWYER, E. D. RYLL AND D. CROZIER. Metabolic effects of intracellular infections in man. Ann. Internal Med. 67: 744, 1967. 5. FARID, Z., AND A. MIALE, JR. Treatment of hookworm infection in Egypt with bephenium hydnoxynaphthoate and the relationship between iron defi-
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anemia and intensity of infection. Am. J. Med. Hyg. 11: 497, 1962. MACCALLUM, W. G. Fever. In: Harvey Lectures, 3rd Series, Vol. 4. Philadelphia: J. B. Lippincott, 1910. KOCHER, R. A. Uber die Grosse des Eiweisszerfalls bei Fieber und bei Arbeitsleistung. Untersuchungen mittels des Stickstoffminimums . Dtsch. Arch. KIm. Med. 115: 82, 1914. COLEMAN, W., D. P. BARR AND E. F. DUBOIS. Clinical calorimetry. XXX. Metabolism in erysipelas. Arch. Internal. Med. 29: 567, 1922. POWANDA, M. C. Changes in body balances of nitrogen and other key nutrients. Am. J. Clin. Nutr. 30: 1254, 1977. MATA,
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Influence of recurrent infections on nutrition and growth of children in Guatemala. Am. J. Clin. Nutr. 25: 1267, 1972. WILSON, D., R. BRESSANI AND N. S. SCRIMSHAW. Infection and nutritional status. I. The effect of chicken pox on nitrogen metabolism in children. Am. J. Clin. Nutr. 9: 154, 1961. GANDRA, Y. R., AND N. S. SCRIMSHAW. Infection and nutritional status. II. Effect of mild virus infection induced by 17-D yellow fever vaccine on nitrogen metabolism in children. Am. J. Clin. Nutr. 9: 159, 1961. BASTA, S. Iron deficiency anemia in adult males and work capacity. Sc.D. Thesis. Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Mass., 1974. SCRIMSHAW, N. S., R. BRESSANI, M. BEHAR AND F. VITERI. Supplementation of cereal proteins with amino acids. I. Effect of amino acid supplementation of corn-masa at high levels of protein intake on the nitrogen retention of young children. J. Nutn. 66: 485, 1958. BRESSANI, R.. N. S. SCRIMSHAW, M. BEHAR AND F. VITERI. Supplementation of cereal proteins with amino acids. II . Effect of amino acid supplementation of corn-masa at intermediate levels of protein intake on the nitrogen retention of young children. J. Nutr. 66: 501, 1958. FAUST, E. C., AND P. F. RUSSELL. Craig and Faust’s Clinical Parasitology, 6th ed. Philadelphia: Lea and Febiger, 1957, p. 386. ROCHE, M., M. E. PEREZ-GIMENEZ, M. LAYRISSE AND E. D. Di PRISCO. Study of urinary and fecal excretion of radioactive chromium Cr’ in man . Its use in the measurement of intestinal blood loss associated with hookworm infection. J. Clin. Invest. 36: 1183, 1957. ROCHE, M., M. E. PEREZ-GIMENEZ, M. LAYRISSE AND E. D. DI PRISCO. Gastrointestinal bleeding in hookworm infection . Studies with radioactive chromium (Cr). Report of 5 cases. Am. J. Digest. Diseases 2: 265, 1957. GILLES, H. M., E. J. WATSON WILLIAMS AND P. A. J. BALL. Hookworm infection and anaemia. An epidemiobogical, clinical and laboratory study. Quart. J. Med. 33: 1, 1964. FARID, Z., J. H. NICHOLS, S. BASSILY AND A. R. SCHULERT. Blood loss in pure Ancylostoma duodenale infection in Egyptian farmers. Am. J. Trop. Med. Hyg. 14: 375, 1965. PELLECER
16.
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.
SCRIMSHAW LEE,
M.
Ferrokinetic
In: Malnutrition Proc.
Panels ence
1972,
study
and
of hookworm anemia. of Blood Cells.
Symposium sponsored by the of the U.S-Japan Cooperative Program,
edited
Tokyo:
The
Kyoto,
by N. National
Japan,
Shimazono Institute
Malnutrition Medical
Sci28-29, and T. Arakawa. of Nutrition, 1973,
FORTUINE,
natives: Canad.
R. Acute epidemiology Med. Assoc.
purulent
meningitis
diagnosis, and J. 94: 19, 1966. ,
24.
November
p. 295. 22.
23.
Functions
in Alaska
prognosis.
Downloaded from https://academic.oup.com/ajcn/article-abstract/30/9/1536/4650615 by Washington University, Law School Library user on 09 April 2018
25.
C. V., G. W. BROWN AND B. BONEHILL. Relationship of anemia to infectious illnesses on Kodiak Island. Alaska Med. (Sept.) 1967, p. 93. FEIGIN, R. D. Interaction of nutrition and infection: plans for future research. Am. J. Clin. Nutr. 30: 1553, 1977. BEISEL, W. R., Y. F. HERMAN, H. E. SAUBERLICH, R. H. HERMAN, P. J. BARTELLONI AND J. E. CANHAM. Experimentally induced sandfly fever and vitamin metabolism in man. Am. J. Clin. Nutr. 25: 1165, 1972. BROWN,
S.
m2
Ph
ABSTRACT
are The
effects have
or chronic
disease
groups
need
There
internal
The
do the
major
problems
as
Despite
these
complexities
the
estimated
for
of
education,
Am.
J. Clin.
Nutr.
nutrition 30:
Each dilemma: 1536
of
of the
The
recommended
following
American
Journal
dietary
allow-
questions
presents
ofClinical
Nutrition
in iron
Downloaded from https://academic.oup.com/ajcn/article-abstract/30/9/1536/4650615 by Washington University, Law School Library user on 09 April 2018
30:
infection for
for food
on
large
and
or
effects
skin,
(eces,
energy
of
calories,
presence
adverse
urine,
those
to
populations.
in the
via
the
requirements
fever,
protein and
protein,
evaluation,
.
losses
metabolism
needs dietary
needs
other and
essential iron
nutritional
be
can
rehabilita-
1977.
1) Granted that an acute infectious episode depletes the body of a nutrient, to what extent, in normal individuals, will increased absorption and efficiency of utilization duning the recovery phase obviate the need for an actual increase in dietary allowance for that nutrient? 2) Granted that a significant number of individuals in a population experience nutnitionally debilitating acute infections, does the decreased intake of nutrients by the ill compensate for increased food consumption by those convalescing from an infectious episode so that the overall nutrient and food needs of the population are unaffected? 3) How much less is the nutrient loss with infection in a malnourished individual than observed in the usual studies with well-nounished subjects? 4) What allowance is appropriate for damage from chronic infections that result in continuing malabsonption or nutrient losses? 5) If there is an increased requirement for a nutrient as the result of acute and chronic infections, when is it appropriate to recommend an increased dietary allowance for the nutrient instead of relying on measI
a
an
nutrient
that on how
individual
be reevaluated
of solid
increased
increased
1536-1544,
must
suggested
instructions
requirements
withdrawal
of
changes
Infections have profound effects on the intake, metabolism, and excretion of most nutrients and, hence, on nutritional status (1). These effects have been further descnibed and discussed in the presentations at this Workshop. Nearly all expert groups who have examined the problem of nutrient requirements have recognized such effects, and most suggest that “they be taken into account” in applying recommended allowances to populations in whom infectious diseases are prevalent. Because they lack specific instructions on how to do so, such admonitions are of little value and have generally been ignored. In fairness, the issues are so complex and the data so limited that it is not yet clear what recommendations should be made. In addition to lack of sufficient quantitative information on the effects of various infections on the status of specific essential nutrients in the body, there is great uncertainty as to how requirements are affected. Even when individual needs are clearly increased, the influence of disease prevalence on nutrient requirements for populations is less apparent. Principles ances
effects
have specific
as to how
nutrient
,
and
nutrients.
but
allowances
of anorexia
absorption,
requirements
account,
uncertainty
alter
dietary
constitute
tion.
into
might
because
sequestration.
purposes
nutrient
is great
establishing
intestinal
on
to be taken
prevalence for
infections
impaired
through
expert
formulated.
principles
of treatment, or
been
or how
traditional
all
of infection
not
affected
of acute
M.D.
Nearly
nutritional do this
,
D.
.
From
the
Department
of Nutrition
ence, bridge,
Massachusetts Institute of Massachusetts 02139. 2 Institute Professor and Head. for reprints should he addressed
SEPTEMBER
1977,
pp.
15361544.
and
Technology, To
whom
Printed
Food
SciCam-
requests
in U.S.A.
INFECTION
ON
NUTRIENT
ures to eliminate the infections from the population? There is now sufficient evidence to confirm the qualitative effects of infection on the requirements for some essential nutrients, but it is still difficult to make reliable quantitative recommendations. This will be clearer from a review of the following mechanisms by which infection affects nutritional status: Anorexia Even with mild and subclinical infections, the loss of appetite is sufficient to make it difficult or impossible to maintain a constant food intake during the acute phase of illness. Withdrawal
ofsolid
food
Especially when fever, diarrhea, or malaise is present, i.e., when an individual is recognized to be sick, there is a strong cultural tendency to withdraw solid food and substitute watery infusions, gruels, and the like for more nourishing solid food. This is often reinforced by physicians who advise a liquid diet for the sick child without emphasizing that solid foods must be given as soon as the child can tolerate them. Other tion
adverse
effects
of
treatment
on
nutri-
There is a common tendency to give strong purgatives to children who have diarrhea or pass worms in their feces. The resulting diarrhea further reduces intestinal absorption. Also, prolonged sulfonamide or other antibiotic therapy can interfere with the intestinal flora that synthesize some of the B vitamins and vitamin K. Impaired
absorption
Acute conditions. Those that affect the gastrointestinal tract, such as diarnheab disease, interfere with the absorption of protein, fat, and most of the other essential nutrients. Some systemic diseases, such as measles, tuberculosis, or bacterial sepsis, also impair absorption through their direct effects on the gastrointestinal epithebium. Other acute infections, for example, otitis media, affect absorption indirectly by producing diarrhea. Malaria in monkeys has
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REQUIREMENTS
1537
been shown to decrease absorption. The suggested mechanism is interference with capillary circulation in the mesentary(2). Repeated exposure to enteric infection. This is apparently capable of causing damage to the intestinal mucosa to the point where the villi and microvilli are reduced in height and absorption of xybose is impaired (3). Absorption of lactose, other disaccharides, and even simple sugars may also be affected. There is less quantitative information on the effect of entenic infection on fat absorption because it is harder to measure, but reduced absorption of sugars and fat would lessen the amount of dietary energy available from the diet. There are too few data to know the extent to which absorption of other essential nutrients, including protein, is affected. Heavy concentrations of intestinal parasites. Parasites such as hookworm, Ascaris, Giardia, and coccidia have been shown to reduce absorption of protein and vitamin A, and this is probably true for some of the other nutrients (1). Mild and moderate infestations apparently do not have a detectable effect. Specific effect offish tapeworm on vitamin B12. The fish tapeworm, Diphyllobothrium latum , acquired from eating raw fresh water fish in northern Europe, the U.S.S.R., and sometimes in the northern United States, has an avidity for vitamin B12. Megaloblastic anemia due to vitamin B12 deficiency has been demonstrated repeatedly in persons harboring this worm (1). All of the above contribute to nutrient depletion during infection by reducing either the intake of essential nutrients or their absorption. Equally important in infection is the increased loss of an essential nutrient from the body or a decrease in its availability within the body for normal metabolism. increased
urinary
loss
Increased urinary excretion of nitrogen and other essential nutrients occurs as a consequence of the stress response with almost any degree of infection. Urinary boss of vitamin A (1), ascorbic acid (1), iron, and zinc have also been described (4) . The quantitative aspects of urinary nitrogen boss
1538
SCRIMSHAW
will be discussed later. (Fe and protein) occurs matobium infection.
Urinary loss of blood in Schistosoma hae-
increased
losses
integumental
Increased nitrogen and mineral boss occur in sweat in association with fever but there are no quantitative data. There is also some loss of nitrogen with the peeling of skin following exanthematous diseases. increased
fecal
losses
Hookworm infection affects the duodenum, so there is an opportunity for reabsorption of the nitrogen present in the blood boss caused by the worms, but there is a marked added loss of iron. This also tends to be true in the intestinal bleeding associated with Schistosoma mansoni , but in amebiasis the blood is lost in the colon, so there is no chance for either the protein or the iron in this blood to be reabsorbed (5). internal
sequestering
of nutrients
Beisel et al. (4) described in detail the incorporation of amino acids into a- and glyco-proteins and C-reactive proteins during the early stress response to infection. Plasma iron and zinc levels were lowered at the same time. These factors are responsible for the adverse effects of acute, and of some types of chronic, infections on nutritional status. If nutrient intakes are marginal in an individual before the infection is acquired, the depletion of that nutrient during the period of infection may be significant. Moreover, a simple return to the previous marginal diet during convalescence will be inadequate for rapid repletion unless a sufficient increase in efficiency of absorption and retention occurs. At best, repletion can be expected to be slower if intake is limited to normal maintenance requirements. For a population group in whom acute infections are highly prevalent, for example, preschool children in developing countries, slow recovery is highly dangerous because the next disease episode may come along to deplete the child further before he has recovered from the preceding illness. Eventually, an infection that is seemingly no more severe than a long series of preceding
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ones “suddenly” precipitates kwashiorkor, or xerophthalmia and keratomalacia, or scurvy, or beriberi, depending on the preceding dietary deficiency. The problem is to: I ) Estimate the quantitative effects of infections on individuals; 2) determine the extent to which these are compensated for by increased efficiency of utilization during recovery; and 3) estimate the overall quantitative effects of infections in a population. If individual requirements were known, it would be possible to apply the same procedure as that for estimating the normal vaniation in requirements for a nutrient among a population of presumably healthy persons, taking into account such population differences as body size and environmental temperatures. It is manifestly more difficult in practice, because the data cannot be generalized from one population to another. The second can be estimated to some degree by analysis of existing information, but will require considerably more research on the metabolism of nutrients in affected human subjects before we can hope to arrive at any definitive recommendations. It can be clearly stated, however, that whenever chronic infectious disease causes an additional loss of nutrients from the body or impaired absorption of dietary nutrients, increased nutrients are required and must be supplied by the diet if nutritional deficiency is to be avoided. It has been suggested that in such cases the effort should be to eliminate the infection, not to provide additional nutrients. However, this is impractical in many instances. The required prevention may be beyond the human or financial resources available, or may take a number of years. Even when prevention is possible increased nutrient intake may be a less cost-effective interim solution in an economically deprived population. I will try to examine these various issues as specifically as possible. Effect needs
of
infections
on
protein
and
energy
Other papers in this Conference have brought out clearly that individuals are usuably in negative protein and energy balance during acute infectious episodes. In the case
INFECTION
ON
NUTRIENT
of protein, amino acids are withdrawn from skeletal muscle and other peripheral tissues. In diseases as severe as typhoid fever, this boss may be equivalent to 2.5 to 3.5 g/kg of muscle (6). Kocher (7), in 1914, reported that 2 .5 to 3 .5 g/kg of protein were required daily for nitrogen equilibrium in patients with enysipelas. Patients with rheumatoid arthritis or enysipebas have been reported to lose about 1 5 g of urinary nitrogen daily (8). In this case 94 g of protein would be required to replace this loss alone, or 1 .5 g/kg for a 60-kg individual. At this Conference, Powanda reviewed various patients with acute infections who had a cumulative negative N balance of 971 g of nitrogen over 162 days of illness (9). This is equal to 37 g of protein daily, or approximately 0.6 g protein/kg. The diseases included typhoid fever, meningitis, and scarlet fever. Diarrhea of infectious ongin induced an average daily negative halance of 0.9 g/kg per day. Even with subclinical infections, the penod of negative nitrogen balance may last for days or weeks, and the recovery or anabolic phase may take from two to four times longer, as judged by return to nitrogen balance or, in children, growth. Unfortunately, it is impossible to be more precise. After even a single day of diarrhea it may be 3 to 5 days before children who have been receiving adequate protein for several weeks return to the same percentage of nitrogen retention as before the episode (1 0) , but for longer periods of infection rebevant data are not available. A published INCAP study of children with chicken pox demonstrated increased urinary nitrogen excretion during the acute period (1 1), but the children were not followed through the recovery phase In a later unpublished INCAP study, nitrogen retention was still elevated 3 weeks after the rash. Beiseb et al. (4) described a young adult exposed to Q fever who developed nickettsemia and progressive, cumulative nitrogen loss over a period of 21 days, despite the absence of fever or other symptoms. We have observed similar negative nitrogen halance in children (12) and adults (unpublished MIT data) following immunization with the 1 7-D strain of yellow fever vaccine even though they did not develop fever on .
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REQUIREMENTS
1539
other symptoms, and also in subjects immunized against smallpox, and in those with minor infections such as small staphybococcab abscesses and mild bronchitis. Because of the significance of infection for nitrogen balance we have assembled information documenting the high prevalence of diarrheab, respiratory, and other infections among lower socioeconomic groups in many developing countries. The most complete information has come from studies in preschool children. The highest rates of disease prevalence are among children 6 to 24 months of age, where point prevalence may be as high as 40% if one includes upper respiratory infections and pyoderma as well as lower respiratory infections, diarrhea, dysentery, and the common communicable diseases of childhood. Thus, no time is permitted for growth in a child who is almost constantly in the catabolic or anabobic phase of response to frequent episodes of disease. In a Guatemalan highland village, the incidence of infections during pregnancy was 12%, and for 653 persons of all ages exammed on a coastal sugar cane-coffee plantation, 138 had skin infections, 43, conjunctivitis, 39, upper or lower respiratory disease, and 35, diarrhea. Among anemic male plantation workers in Indonesia, the 2month period prevalence for disease was 7.5% for upper respiratory infections and influenza, 2.5% for bronchitis, 1 .7% for tuberculosis, and 3.3% for entenitis. Nonanemic males had a disease prevalence rate of 4.8% for upper respiratory infections, 0.8%, for bronchitis, 0%, for tuberculosis, and 2.4%, for entenitis. Most infections were not associated with fever (13). Because fever elevates basal metabolic rate, it is the principal mechanism influencing energy expenditures during infection. Some protein depletion occurs with infection whether on not fever is present. Reductions in intake of the usual diet because of anorexia would affect the intake of both calories and protein, but because the tendency is to substitute starchy gruebs of bower protein-to-calorie ratios for solid diets, this factor would also tend to exaggerate protein needs more than those for calories. There are three further points in considering the effect of infection on dietary energy needs: 1) Illness is usually associated with
1540
SCRIMSHAW
decreased physical activity, which would reduce caloric needs, while the stress response would increase urinary nitrogen losses. 2) When the diet is deficient, energy deficits are met from both body fat stores and tissue proteins, while the amino acids for protein synthesis can come only from the breakdown of tissue proteins. During the recovery period the amino acids drawn from the lean body mass, mainly skeletal muscle, must be promptly replaced for both new protein synthesis and body energy, or the degree of depletion of reserves may still be significant when the next infectious disease episode occurs. In the case of depletion of fat stores for energy, replacement is not urgent unless there is almost complete loss of subcutaneous fat, as observed only in infants with advanced marasmus and adults with severe cachexia. Such extreme states of inanition are much less common than the protein depletion resulting from the stress of infectious illness. 3) A third factor has the opposite effect. Excess dietary calories spare dietary protein, and when calories are deficient the utilization of protein is decreased. Thus, a deficient caloric intake during infection exacerbates the nitrogen loss and a liberal caboric intake during recovery favors protein retention. Using the data I have cited and those presented by Powanda (9) at this workshop, the calculation for the net loss of nitrogen during infections varies from a protein equivalent of 0.6 to 1 .2 g/kg per day, depending on the nature and severity of the infection. If one assumes that the anabolic phase of recovery will last three times longer than the catabolic period, then the effect of each day of the catabolic phase means an average extra daily allowance during recovery of 0.2 to 0.4 g protein/kg to replace that lost during the acute infectious episode. If one takes the intermediate value of 0.9 g of protein/kg per day additional loss seen in children with scarlet fever, 0.3 g/kg per day would be required during the recovery penod. At the start of recovery, absorption might be 30% more efficient, but this would decrease gradually with repletion. This figure
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is suggested by INCAP observations in young children of the greater absorption of milk following a period of inadequate protein intake than when the preceding protein intake was adequate (14, 15). However, a mean figure of 15% for the increase in utibization would not appreciably affect the final figure for additional nitrogen during recoveny, and it does not seem worth including on such flimsy evidence. For the calculation of possible additional dietary energy needs for a whole population the problem is more complex, because even if infection does increase average need, we must not propose a dietary energy intake that would make most people obese. Individuals during and after acute infections may require 10 to 30% more calories, but this cannot be recommended for an entire population. Moreover, the extent to which increased metabolic needs are compensated for by decreased activity has never been firmly established. The best solution is to stress that present estimated caloric requirements do not cover needs resulting from infection and do not provide for catch-up growth in children. The diet during the recovery period fobbowing an infection clearly should provide sufficient additional calories and protein for as rapid repletion as possible and maximize catch-up growth in the case of children. Unfortunately, we cannot specify how much of either calories or protein at the present time because this varies widely with the circumstances and there have been too few studies to have reliable guidelines. We would note, however, that the long time lag generally observed in both resumption of growth on restoration of nitrogen balance may result from lack of optimum calories as well as protein for recovery. iron Several common infections lead to increased iron losses from the body, most notabby hookworm and schistosomiasis. The effects of acute infection on iron metabolism in man are well-documented, although some of the mechanisms are only partly understood. These effects have considerable clinical and public health importance. Infections influence iron metabolism most
INFECTION
ON
NUTRIENT
directly through boss of blood and resulting anemia. The figure of 0.67 ml of blood lost per day pen hookworm, frequently cited in the older literature (16), is now known to be an overestimate. By measuring the excnetion of 51Cr-labeled hemoglobin, Roche and co-workers (17, 18) showed that each Necator americanus causes daily losses of 0.031 ± 0.017 ml blood, or 2.74 ± 1.50 ml per million eggs. Gibles and associates (19) obtamed a figure of 0.05 ml of blood lost per worm per day for this species. Using the same techniques, Fanid and co-workers (20) found that the blood loss for Ancylostoma duodenale was five to 10 times greater than that cited for Necator They reported a loss pen worm per day of 0.26 ± 0.045 ml. In heavily infected patients, the loss ranged from 14 to 45 ml of blood per day, with a daily iron loss of 3.56 to 9.94 mg. Mean values were 26 .4 ml of blood and 6 .06 mg of iron. These investigators concluded that the mean blood loss per 1 000 ova per gram of feces was 4.47 ± 1 .6 ml. The data of Lee are similar (21). Picou, at this workshop, mentioned evidence that acute infections interfere with iron absorption There is also indication that iron-deficient individuals and populations in developing countries are more susceptible to many types of infections. Studies from Alaska document meningitis deaths in children (22) and diarrheal morbidity (23) to be increased in children with hemoglobin levels between 7.1 and 10.0 g/100 ml. Among the Indonesian rubber plantation workers referred to earlier (13), anemic rubber tappers given 100 mg of iron daily for 60 days showed significant improvement in Harvard Step Test performance and work output, while the nonanemic showed no change in these characteristics. However, nearby similar improvement was observed for the placebo group. This was ultimately explained by the fact that all workers received a cash incentive equivalent to U.S. 3 per day, which was used mainly to purchase additional food, mostly green leaves (papaya, cassava, and spinach). This resulted in increased intakes of about 200 g of leaves per worker. Indonesian food composition tables show an iron content of these leaves varying from 3 to 10 mg/100 g, depending .
.
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REQUIREMENTS
1541
on variety, and providing an average of 12 mg of iron per portion, with an absorption rate of 25%. On this basis, a net intake of elemental iron of 3 to 5 mg extra per day from leaves was calculated to be sufficient to overcome dietary iron deficiency in the presence of hookworm . This can be taken as a rough estimate of the increase in iron requirement due to hookworm in this population. Thus, the effect of infection on iron nutnitune is paradoxical. Infections, depending on type, variously reduce intake, absorption, retention, and storage of iron, and, hence, deplete the individuals whose dietary iron intake is borderline or deficient, but the depleted individual absorbs iron more efficiently than one whose stores are not deficient. As in the case of protein, the only appropriate course is to base recommendations on absorption and retention at requirement bevels. The fact that individuals do attempt metabolicabby to compensate for deficient intakes of both iron and protein is not a valid basis for reducing estimated intakes for maintenance, although this can legitimately be taken into account in estimates of the amounts needed for recovery from infection. Moreover, depletion occurs because there are sharp limits to the amount of adaptation that can occur to bow nutrient intakes. Other
nutrients
During infections the metabolism of many of the vitamins is affected ( 1 , 24) The suggested mechanisms include interference with their absorption in the gastrointestinal tract, changes in the rates of urinary excretion of some vitamins, and liver cell damage. For example, Beisel and co-workers (25), in an experimental study of sandfly fever in male volunteers, found an increased riboflavin excretion . These effects are additive to those of reduced intake. It is also well-recognized that infections are capable of precipitating xerophthalmia and keratomalacia, scurvy, beriberi, megaboblastic anemia, and other acute nutritional disease states in individuals whose nutritionab status is borderline with respect to the corresponding vitamins . Clearly , infections also influence requirements for vitamins, .
I 542
SCRIMSHAW
but there is even less quantitative information on which to base recommendations than exists for protein, calories, and iron. Discussion The foregoing considerations of available data on the effects of acute and chronic infections on the intake, absorption, retention, and loss of selected nutrients makes it possible to provide some qualitative answers to questions raised in the introduction. The data are not sufficient, however, to provide the quantitative answers really needed in the formulation of recommended dietary ablowances for individuals or populations. Among the unanswered questions is the extent to which increased efficiency of utilization of a nutrient assures adequate intake for optimum recovery if the recommended dietary allowance for healthy individuals is supplied. There is not enough information available for nutrients other than iron and protein to make any useful statement about increased utilization after acute periods of depletion . Moreover, reliance upon increased utilization during recovery from illness to make up for the nutritional deficits brought on by chronic disease requires specific determination of nutrient requirements for persons subjected to such diseases, not just general assertions of increased efficiency of utilization. In evaluating data, there are some basic statistical considerations. If the recommended allowances for healthy individuals have been arrived at correctly, they will provide more than most individuals require because the allowances are intended to represent the mean plus two standard deviations of the distribution of actual requirements. Therefore , many individuals will receive enough more than their requirements to meet the needs imposed by infection and other types of stress. If the intent is to cover nearby all of the individuals in a population, however, then the higher requirements imposed by a high prevalence of infection will be significant. If one is concerned principally with food supplies and not individual requirements, the argument is quite different. If at any given time a certain proportion of individuals is eating less because of acute infectious
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disease while others require more because they are recovering from these diseases, then perhaps no adjustment need be made in total food supplies. The trouble is that if no emphasis is placed on increased food during convalescence, the individual is not likely to receive the foods needed, for social, economic, or political reasons. Where some degree of malabsorption affects nearly all of the population of lower socioeconomic groups, as appears to be the case in many developing countries, two courses of action would appear urgent and obvious. One is a determination of the quantitative significance of this condition for absorption so that any necessary provision can be made in current allowances for essential nutrients; the other is a massive governmental effort to improve the poor e nvinonmental sanitation a nd inadequate personal hygiene largely responsible for the frequent occurrence of infectious disease in these populations. It is often suggested that one should not recommend increased provision of nutrients where the incidence of infectious diseases increases requirements because measures should be taken instead to eliminate these diseases. I believe this to be a highly specious and theoretical argument. Under the most favorable circumstances, i.e., enlightened and determined political leadenship and allocation of substantial resources, it will take many years to achieve the desired reduction in the high prevalence of enteric and systemic infectious diseases in the populations of most developing countries. In the meantime, physical growth and mental performance will be impaired, the frequency and severity of infectious diseases will be enhanced, and mortality increased in individuals who fail to receive the diets they require. Condusions
1 ) It would
and
recommendations
seem appropriate to follow the present procedure of first calculating estimates of requirements and recommended allowances for essential nutrients based on the needs of healthy individuals. However, these should be based on studies at requirement levels, not under conditions of adaptation to low protein and high calorie intakes.
INFECTION
ON
NUTRIENT
2) Given the high prevalence of acute and chronic infections among some populations, especially vulnerable age groups in the developing countries of the tropics, it would also seem appropriate to suggest that in recommendations intended to cover the needs of nearby all individuals for purposes of nutrition education, dietary evaluation, or nutritional rehabilitation, a specific additional allowance for infection should be made. 3) While the data are admittedly deficient, a figure of 0.3 g/kg per day of high quality protein for adults would appear reasonable to allow for recovery from acute episodes of infectious diseases. This is in the range of 50% more than that calculated for healthy populations. 4) For caloric requirements, which must be expressed on the basis of average needs, increasing the recommended dietary allowance is not appropriate. Instead, there should be an allowance for recovery from infection analogous to that for different levels of activity. 5) Even under circumstances in which moderate to heavy hookworm infections are associated with iron deficiency anemia, 3 to 5 mg of available iron appears sufficient to correct this condition even with continued hookworm infection. 6) More information will be required before appropriate recommendations can be made for the effects of infection on requirements for other essential nutrients. El References 1.
2.
N. S., C. E. TAYLOR Interactions of Nutrition Monograph Series No. 57. Organization, 1968.
J. E.
AND
DON.
and Infection. Geneva: World
WHO Health MIGASENA,
absorption amino acid in
ciency Trop. 6.
7.
8.
9.
10.
I 1.
12.
13.
14.
15.
normal
G0R-
P., AND B. G. MAEGRAITH. Intestinal in malaria. I. The absorption of an (AIB-1-’4C) across the gut membrane and Plasmodium knowlesi-infected Ann. Trop. Med. Panasitol. 63: 439,
monkeys. 1969. 3 . ROSENBERG, I. H . , AND N . S. SCRIMSHAW. Workshop on malabsorption and nutrition, pants I and II. Am. J. Clin. Nutr. 25: 1046, 1226, 1972. 4. BEISEL, W. R., W. D. SAWYER, E. D. RYLL AND D. CROZIER. Metabolic effects of intracellular infections in man. Ann. Internal Med. 67: 744, 1967. 5. FARID, Z., AND A. MIALE, JR. Treatment of hookworm infection in Egypt with bephenium hydnoxynaphthoate and the relationship between iron defi-
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anemia and intensity of infection. Am. J. Med. Hyg. 11: 497, 1962. MACCALLUM, W. G. Fever. In: Harvey Lectures, 3rd Series, Vol. 4. Philadelphia: J. B. Lippincott, 1910. KOCHER, R. A. Uber die Grosse des Eiweisszerfalls bei Fieber und bei Arbeitsleistung. Untersuchungen mittels des Stickstoffminimums . Dtsch. Arch. KIm. Med. 115: 82, 1914. COLEMAN, W., D. P. BARR AND E. F. DUBOIS. Clinical calorimetry. XXX. Metabolism in erysipelas. Arch. Internal. Med. 29: 567, 1922. POWANDA, M. C. Changes in body balances of nitrogen and other key nutrients. Am. J. Clin. Nutr. 30: 1254, 1977. MATA,
17.
18.
19.
20.
L. J., J. J. URRUTIA, AND E. ARELLANO.
C.
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