Rhoades Lecture Effect of Infection

on

Nutrient

Requirements*

NEVIN S. SCRIMSHAW PHD, MD, MPH From Massachusetts Institute

of Technology, Cambridge, and Food, Nutrition and Development Programme, United Nations University, Tokyo, Japan

ABSTRACT. All infections, no matter how mild, decrease nutrient intakes and increase nutrient losses even when subclinical. The losses include decreased intestinal absorption, direct loss of nutrients in the gut, 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. In industrialized countries particular attention must be paid to the nutrition of hospitalized patients inasmuch as they are frequently debilitated by their primary disease, morbidity, and nutritional status. Morbidity and mortality are increased by nosocomial infections to which the poorly nourished individual is more susceptible. ( Journal of Parenteral and Enteral Nutrition 15:589-600, 1991)

Infections, no matter how mild, affect both nutrient intakes and nutrient requirements through a number of mechanisms. In developing countries the presence of an infection is more likely to be responsible for clinically evident malnutrition than a lack of suitable available food. In a hospital situation in the United States, this is often also true. In both populations, the quantity and nutritional value of food available to the individual during the recovery period is likely to be the limiting factor. During the recovery period, there is a period of increased appetite, and recovery is rapid if the diet is adequate. The problem in generalizing about the magnitude of the adverse nutritional effect of infection on nutrient requirements is that it depends on the nature, duration, and severity of the infection for which the estimate is made/ Moreover, it is often not the effect of a single acute episode that is significant, but the presence of chronic infection or the pattern of frequent infections without time for full recovery in between. The issue is further complicated by the fact that a poorly nourished individual is likely to have reduced resistance and hence more frequent infections.’ Each new episode contributes cumulatively to further malnutrition if the infections are closely spaced and/or the diet is inadequate for full nutritional recovery before the next infectious episode. Well-nourished individuals recover quickly from most infections, but for already poorly nourished patients, nutritional status is worsened and resistance to infection further is reduced. For hospitalized patients the primary diseases for which they have been admitted often are ones that contribute to initial nutritional depletion and thereby decrease resistance to infection.

As Bistrian and collaborators showed more than a decade ago,2.3 malnutrition in hospital patients can be readily determined by the same measures used for studies in underprivileged populations, including serum albumin, anthropometric indices, and delayed cutaneous hypersensitivity. They found that, even in major Boston teaching hospitals, from lack of attention, the nutritional status of some surgical patients deteriorated during their hospital stay, even before surgery, and the situation was only slightly better on the medical services. Gorse et al4 as well as otherS5 have recently summarized similar findings from many other hospitals in North American.5 Interventions that improve the nutritional status of poorly nourished individuals at high risk can reduce both morbidity and mortality from infections. In the study of Gorse et al,4 nutritional status (using the criteria of serum albumin, total lymphocyte count, and unintentional body weight loss) was found, retrospectively, to be far more common in patients developing a nosocomial infection than in uninfected control patients. The data to make the diagnosis of malnutrition in these patients were available at the beginning of their hospital stay, but their use for this purpose is not yet part of usual hospital practice, even in most teaching hospitals. This neglect of the nutritional status of hospital patients can no longer be tolerated in the light of the conclusive evidence of its importance. This paper will review the specific nutritional consequences of infectious episodes. These are particularly significant for protein requirements, but infections also contribute to an increased need for energy and micro-

*

Rhoades Lecture

gress in San

presented

at

the A.S.P.E.N. 14th Clinical Con-

Antonio, TX, January 30. 1990.

nutrients. The

challenge

is to

move

bevond conceptual

and qualitative statements and give some idea of the magnitude of the effect of illness on nutritional requirements under various circumstances, including hospitalized patients. I will try to do this in terms of the range and relative magnitude of the effect of various kinds of 589

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590

infections and the evidence of their influence ual nutrients.

individ-

onset of the disease for the child’s weight to return to what it was at the time the infection began, thus, leaving the child further retarded in weight for age. As summarized in Table III, of the 44 cases of whooping cough MORBIDITY FROM INFECTIOUS DISEASE observed in this village, 25% required more than 25 weeks It is an epidemiological truism that disease morbidity to regain initial weight, and only one third recovered in varies with time, place, and person. This means that in 8 weeks or less. Under some circumstances, nutritional some places infections may be highly prevalent and in can completely offset the negative efothers less prevalent. Even within the same place, overall supplementation fect of diarrheal disease on growth. morbidity and the burden of infections responsible Although infectious disease prevalence is high under change over time. Finally, there is great individual vari- village conditions, it is even higher when children are ability, even at the same time and place. The first step in institutions. Table IV lists 108 infecin estimating the effect of infection under any given brought together tious episodes in 90 days among 32 children in a model circumstance is to identify the representative burdens of convalescent home in Guatemala City. This model conmorbidity. valescent home had good sanitation, ample room, and In developing countries, the incidence of infections is between beds, as well as a large protected high. Figure 1 from Guatemala,6 Table I from the Gam- partitionsfor play (INCAP, unpublished data, 1972). garden bia,’ and Figure 2 from Mexico’ illustrate the high fre60 children in a 6-month feeding study in an Among of infections in children under young village quency conditions in these countries and a reduction in the orphanage in Vellore, India, 136 infectious episodes were burden of infection with supplementary feeding. Every observed (Pereira, unpublished data, 1974) (Table V). These two reports are only examples of a universal and one of these episodes of infections is associated with adverse nutritional consequences ranging from mild to inadequately studied phenomenon. The nutritional significance of the infections frequently acquired in US severe. For example, Table II shows that children who have hospitals, nursing homes, and other institutions is largely had measles in preceding weeks in a Guatemalan village neglected. A hospitalized patient with a nosocomial inhave a marked loss of lean body mass, as judged by fection needs special attention paid to the adverse nutricreatinine excretion, compared with children in the same tional effects of the infection and to the additional nuvillage who did not experience this disease. Figure 3 tritional needs during the recovery period. illustrates the devastating effect of whooping cough on Figure 4 shows the negative nitrogen balance of an the growth of a poorly nourished Guatemalan child from individual with a viral infection while on a low-protein the same village.6 In this case it required 26 weeks after diet and his subsequent lack of recovery on this diet.9 on

Weight, infections, and infectious a boy. Top, solid line represents weight of child; broken line shows median of the INCAP standard (1956). Length of horizontal FiG. 1.

diseases in

lines indicates duration of infectious disease. Each mark shows 1-week positive for a particular infectious agent. Bottom, observed weight increments (vertical bars) and expected median increments (dots) of the standard.’

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591 TABLE I

Parameters

having significant effect

NUTRITIONAL upon SNIR and

RQ

CONSEQUENCES OF SYSTEMIC

AND

LOCAL INFECTIONS

Figure 6’ is a schematic representation of the onset of various metabolic, endocrine, biochemical, and immunological responses of the host during the sequential phases of an acute self-limited generalized model of an infectious illness. The first stage is a phagocytic response with the release of endogenous mediators, identified as Interleukins 1 and 2. Interleukin 1 has been found to mediate multiple aspects of the &dquo;acute-phase reaction&dquo; during infection caused by many types of infectious agents. It stimulates proteolysis, neutrophilia, decreased serum iron and ironbinding capacity, increased serum copper, production of SMR, sleeping metabolic rate; RQ, respiratory quotient; ALL, well and serum amyloid A protein, and production of haptoglobin ill values; Well, well values only in Gambia. and C-reactive proteins. Interleukin 2 acts on the hypoMultiple regression analysis of the effect of different variables inserted thalamus to cause fever and to stimulate the increased in the order shown. production of adrenocorticotrophic hormone (ACTH) by *p < 0.05, **p < 0.01, ***p < 0.001. the anterior pituitary. ACTH enhances the production of cortisone by the However, in Figure 5 a similar individual receiving adeadrenal cortex. The interaction of cortisone with glucaquate protein showed no significant nitrogen loss during hormone, insulin, and catecholamines leads gon, growth an acute episode of otitis media. Both of these subjects to the release of gluconeogenic amino acids, primarily were obese and on 1000-calorie diets. Wiafe et all° studied patients with protein depletion from skeletal muscle, into the blood stream and their use for gluconeogenesis by the liver. The excess nitrogen and a complicating infection in Baltimore. Six patients released is excreted as urea. Excess iron and zinc are also in addition to given relatively large protein supplements, removed from plasma by the liver and by the reticuloan already adequate diet, at first retained the extra endothelial system. nitrogen in proportion to the amount supplied by the Anorexia is induced and hepatic synthesis of glycoprosupplement. One patient who did not receive a supple- tein and ceruloplasm is increased. In addition to vitamin ment required 50 days to achieve a near-nitrogen balance. utilization increasing, the excretion of riboflavin and The improved appetite of the individual during recovascorbic acid increases. As the infection becomes acute, ery will help to ensure an adequate intake during conthe catabolic response becomes more pronounced with valescence if an appropriate diet is offered. For the negative balances of nitrogen, potassium, and zinc, and individual dependent on parenteral feeding during and loss of muscle mass and overall weight. During the conafter an infection, specific attention is required to insure valescent period, if the diet permits, nutrient balances that the food supplied meets the added requirements become positive and the cumulative metabolic deficits associated with an infection. are made up.

2. The nonsupplefrom the third to the fifth semester, have some illness for as much as half the time. Teozonteopan, Mexico.&dquo;

FIG.

mented,

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592

Effect of measles on compared with children

TABLE II chi index in children in Guatemalan village with kwashiorkor from the region (unpublished I1~TCAP data)

TABLE IV Acute infections among 32 children age 2-9 y observed in a &dquo;model&dquo; convalescent home in Guatemala City for 90 days (INCAP unpublished

data)

TABLE V Illnesses among 60 children 2-5 years old in a 6-month orphanage feeding study in Vellore, South India (Pereira SM, unpublished data)

FIG. 3. Deterioration of the nutritional status of a girl after an attack of whooping cough. Broken top line corresponds to the INCAP standard; solid line shows the mean weight curve for Cauque children; bottom broken line is observed weights of the child. 0, onset of disease; A, weight loss, B, weight gain expected in period equivalent to the length of recuperation if not attacked by the disease. To estimate this amount, the mean weight curve for Cauqué children was used; the curve of the child was assimilated to such a curve at the time of onset.’ Time

required

to recover

TABLE III the weight lost from

a

single episode of

whooping cough’

As mentioned earlier, these metabolic responses occur whether or not the infection is sufficient to produce a febrile response. These consequences can be minimized by effective control of the illness and by assuring an optimal diet during convalescence. If an adequate diet for recovery is not provided, patients may emerge from episodes of infections at a more depressed and chronically wasted level. The possible effects of infections on nutritional status are summarized in Table VII. These will be reviewed before attempting to quantify the overall effect of infections on individual nutrients.

FIG. 4. Mean N balance and total body K before, infection in one patient.’

during,

and after

unknown, presumed viral

FIG. 5. Mean N balance and total otitis media in one patient.’

body

K

before, during, and

after

acute

Anorexia Infection constantly results in a loss of appetite that leads to a spontaneous decrease in dietary intake. Figure

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593

FIG. 6. Schematic representation of the sequence of nutritional responses that evolve during the course of a ‘‘typical&dquo; generalized febrile infectious illness.&dquo;

712 shows that

TABLE VI Potential effects of infection on nutritional status

more than one third of the negative nitrogen balance associated with an episode of tularemia in a young boy was due to a spontaneously reduced food

intake and the catabolic response. INCAP studies of the effect of yellow fever vaccine on young children showed no febrile response, but all efforts to coax the children to eat as much of the formula diet in the days immediately after immunization as they had eaten before were

unsuccessful. 13 The negative correlations of infections with food intake in a study in Guatemala&dquo; are given Table VII. Martorell et al15, 16 have described the lower home dietary energy intake of children with selected common infections compared with that of healthy children (Fig. 8). In studies in Bangladesh (Table VIII), caloric intakes of infants with diarrhea were more than 40% lower than in those without it. 17 The cause of the diarrhea strongly influenced the magnitude of the drop in intake. As shown in Table IX, rotavirus and enteropathogenic Escherichia coli (ETEC) infections produced the greatest effect on dietary intake, both in the acute stage of the illness and

during recovery. 18 Cultural and

Therapeutic Practices Withdrawing solid food from individuals with fever, diarrhea, or other symptoms of infection is a universal practice. Although the consumption of food is reduced TABLE VII Correlations of calorie intake and morbidity in 30 weaned children in Santa Maria, Guatemala!4

FIG. 7. Cumulative loss of N in

change alone.&dquo;

acute

tularemia in

excess

of

dietary All other comparisons

negative,

Downloaded from pen.sagepub.com at FLORIDA INTERNATIONAL UNIV on June 26, 2015

not

statistically significant.

594

tern, followed by carbohydrates and the lowest values

are

associated with fat. A decrease in food intake would obviously result in lower dietary thermogenesis.

Malabsorption In the studies by Chung and Viscorova2l over 30 years absorption of nitrogen in four children with diarrhea varied from 40% to 74% and fat absorption ranged from 39% to 67% when caloric intake was moderate to high. Data from Bangladesh on patients with diarrhea caused by rotavirus indicate an average 42% nitrogen and fat absorption, 48% carbohydrate absorption, and 55% intestinal absorption of total energy. The corresponding figures for absorption by patients with diarrhea due to enterotoxigenic E coli and Shigella were slightly lower.23 Many other studies confirm that sufficient intestinal absorption remains in diarrhea to make normal feeding highly desirable. A wide range of infections are associated with malabsorption. These include the bacterial, viral, and protozoan enteritides; intestinal parasites such as hookworm, fish tapeworm, Ascaris, and Strongyloides; and systemic diseases such as measles, tuberculosis, malaria, and streptococcal infections. These infections reduce absorption by shortening intestinal transit time, by physical blocking of the mucosal surfaces, by damaging intestinal epithelium, or by reducing mesenteric blood flow. A certain proportion of individuals with acute diarrheal disease of nonspecific origin have persistent carbohydrate intolerance and undergo a much more severe and prolonged nutritional deficit. In children recovering from severe malnutrition precipitated by infection, malabsorption of fat and carbohydrate persisted for 4 to 6 months after apparent complete recovery from malnuago,

or

FIG. 8. Comparison of home dietary energy intake for children with without selected common symptoms.15 TABLE VIII Total calorie intake (kcal/kg/24 h) from breast milk, oral fluids, and weaning foods among children with diarrhea and healthy controls

(mean ± SEM) in

*

Figures

Intake

in

Bangladesh!?

parentheses indicate the number

of subjects studied.

TABLE IX in acute stage (A), 2 weeks (RJ and 8 weeks (RJ recovery (mean ± SD) in Bangladesh&dquo;

of calories

after

trition.24, 25

addition, between 30% and 50% of individuals living unsanitary environment experience so-called tropical jejunitis or enteritis that causes chronic changes in the intestinal epithelium, including flattening of the villi and loss of microvilli, with reduced absorption of xylose, fat, and nitrogen, and sometimes vitamin B12.26 With prolonged intestinal infections, bacterial overgrowth in the small intestine contributes further to malabsorpIn

in *

ETE, enterotoxigenic E coli.

by anorexia, the purposeful withholding of food has significant negative impact. In the case of young children with diarrhea, fever, or other signs or symptoms of infection, there is a strong tendency for the parent to withdraw solid food and

also a

substitute a watery gruel.19,

20 Under these circumstances,

protein intake is usually reduced

more

than that of

energy, but both are affected. Since this practice is highly variable, it is a confounding factor that affects any estimate of the nutritional effects of infection. Many years ago Chung and Viš~orová21 showed that the common practice of withholding food from children with diarrhea adversely affected their recovery. Many similar studies have followed, and it is now strongly recommended that food not be withdrawn during diarrhea and other infections. 22

an

tion. 27-29 The

malabsorption resulting from tropical enteritis

attracted considerable attention when it was identified in returning US Peace Corps volunteers who had lived in unsanitary environments. Many required up to a year for full recovery of epithelial integrity and normal function of the gastrointestinal tract .30 Tropical sprue, as classically defined, cannot be differentiated from tropical enteritis.3~, 32 In some enteric infections, it is not just absorption of dietary protein that is affected, but also there is an additional loss of serum protein into the intestinal tract-the so called protein-losing enteropa-

thy. 33 Decreased

Dietary Thermogenesis

The thermal effect of various foods on metabolism is well established and depends on the composition of the diet. The highest values are associated with dietary pro-

Catabolic Responses A catabolic response occurs with all infections even when they are subclinical and not accompanied by symp-

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595

toms.34 Figure 9 shows the metabolic

response of

an

individual with completely asymptomatic Q fever, whose cumulative nitrogen balance nevertheless became increasingly negative over a period of 21 days before daily balances became positive once again.3~ In INCAP metabolic studies in children, infections, with the exception of uncomplicated upper respiratory infections, were always associated with a period of negative nitrogen bal-

and duration of the fever. As I have empharesponse to infection is a reaction to stress and occurs with infections even in the absence of fever or symptoms. It also occurs in response to trauma.

the

degree

sized, the catabolic

Internal Diversion

of Nutrients

In the

early metabolic studies at INCAP in children during episodes of infection, we were surprised by the much greater retention of nitrogen during the recovery ance. This was true not only for the common communicable diseases of childhood, lower respiratory infections, period than could be accounted for by the cumulative diarrhea, and dysenteries, but also for pyogenic skin negative balance that we measured during the catabolic Although some of this may have been recovery infections, otitis media, and illness after measles vacci- period. the underlying malnutrition on which the infection nations. A catabolic response has even been observed from was superimposed, it was observed in children who had with yellow fever immunization despite a lack of fever or apparently recovered from malnutrition. other symptoms. Figure 10 shows the marked increase in nitrogen retention in 15 children consuming approximately 2 g of Fever protein and 100 to 200 kcal/kg per day after an acute of measles (INCAP, unpublished data, 1972). Fever, no matter what its contribution to the resistance episode Similar results have been obtained with chickenpox.4° to infection might be, has a metabolic cost. The reguladifficult to measure, I believe the internal tion of normal body temperature within the narrow range Although diversion of nutrients for the synthesis of compounds of 38.5°C to 39°C, is a complex phenomenon that is involved in the response to infection contributes imporaltered by the endogenous pyrogenic activity of Interleuto the depletion of body stores. These include the kin 1. Fever increases basal metabolic rate to 12% to tantly of new cells for phagocytosis, cell-mediated production 13% for each 1°C rise.36 This means an increase of 30% immunity, antibody synthesis, and repair of structural to 60% for a 3°C rise in temperature from 37°C to 40°C. tissue damage. Additional intracellular components reBarr and Dubois3’ found that the metabolic rate was quired to combat infection include the nucleic acids, increased 216% during a violent malarial chill. ribosomes, enzymes, etc, and finally, endogenous producAnother source of energy is required because carbo- tion of immunoglobulins and interferon, complement hydrate stores are inadequate to meet the increased fractions, hormones, acute-phase glycoproteins, and enenergy requirement induced both by fever and the catadogenous mediators.41 bolic response to infection 3’ and because lipid stores are EFFECTS OF SPECIFIC BACTERIAL AND VIRAL not effectively used by the infected patient .3’ This source DISEASES ON NUTRIENT REQUIREMENTS of energy is protein from skeletal muscle transported as Intracellular infections of any kind set off the train of gluconeogenic amino acids for the synthesis of glucose in the liver. The energy deficit is increased in proportion to metabolic responses outlined earlier. Figure 9 illustrates

FIG. 9. Nitrogen balance data in a subject who remained asymptomatic despite subclinical Q fever. This individual showed neither an elevation of rectal temperature above 100°F nor diminution of dietary intake despite the presence of Coxiella burnetii in the blood over an 8-day period. 15

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596 associated with toxoplasmosis, onchocerciasis, Leishmaniasis, and trypanosomiasis. However, there

episodes

may be additional localized effects.

Reduced intestinal absorption of nutrients can occur in malaria as a consequence of reduced mesenteric blood flow. In endemic areas there is an association between malaria and low birth weight. Anemia is a common sequel to Plasmodaum falciparum infection, and to a lesser extent in the other types of malaria. This is due in part to increased iron loss caused by hemolysis, but immunological destruction of unparasitized erythrocytes may also occur.

FIG. 10.

INCAP, unpublished data.

the impact of a rickettsial infection (Q fever). Figure 11 shows the impact on nitrogen balance of sandfly fever (viral infection), tularemia (a Bedsonian infection), and malaria (a protozoan infection).42 The most dramatic example of the effect of a specific infection is the cachexia associated with AIDS,43,44 although a recent publication indicates that even this can be minimized by appropriate diet therapy. Intracellular Parasitic

Infections

Malaria, an acute intracellular febrile illness, has the systemic consequences as acute infections of bacterial, viral, or rickettsial origin. This is true for febrile same

The protozoan, Giardia lamblia, is a common cause of chronic malabsorption, including wasting, hypoalbuminemia, diarrhea, and steatorrhea.45 Specific malabsorption of fat and carbohydrate has been well documented. Poor absorption of vitamin A in Giardia infections of young children was first described in 193446 and since then has been repeatedly found to be clinically significant. In addition, a number of investigators have reported evidence of malabsorption of vitamin B12 and low serum folate in patients with giardial infections. Intestinal helminths, such as Ascaris, hookworm, Strongyloides, Trichuris, and Trichocephalus, may also reduce intestinal absorption of protein and other nutrients, but the worm burdens must be sufficiently great to cause significant mechanical interference.34 Coccidioides may also be caused by malabsorption. 41 Careful metabolic balance studies generally fail to detect a significant effect of mild to moderate worm burdens on intestinal absorption, although the appetite may be re-

FIG. 11. Nitrogen balance data plotted in relationship to the fever curve in representative bacterial, viral, and parasitic illnesses. A cumulative plot of nitrogen balance is also shown for nonexposed controls who were pair-fed to match the tularemia group.42

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597

duced. Ascaris and Clonorchis

can

also

cause

biliarv and -

pancreatic obstruction. -18 The hookworm .vector americanus

causes an

average

daily loss of 0.0~ mL of blood per worm per day and Ancylostoma duodenale results in a loss per worm 10 times higher. Most of the protein is reabsorbed, but in heavily infected patients, increased fecal protein loss may occur49 and daily iron loss can average 6 mg per day. Surprisingly, even with severe hookworm anemia, adequate dietary iron can fully compensate for these losses without removal of the worms. 50, 51 Individuals with Schistosoma hematobium are also at an increased risk of iron deficiency because they lose blood in the urine. The massive bleeding from the intestinal tract sometimes seen in Schistosoma mansoni may require surgical intervention. This parasite can also obstruct lymphatic return and thereby interfere with fat absorption. Other reported nutritional consequences of heavy S mansoni infections in human clinical studies include loss of albumin, zinc, and vitamin A as well as elevated fecal fat content, glucose intolerance, and subnormal levels of serum

carotene.52

Because of their bulk, some parasites require sizeable quantities of nutrients that must be obtained from the same sources available to the host’s cells. For physicians practicing in northern Michigan, Wisconsin, and Minnesota, where the Scandinavian custom of consuming marinated raw fresh-water fish persists, massive infection with the fish tapeworm, Diphyllobothrium latum, is associated with megaloblastic anemia because of competition for vitamin B12.53 Some of this effect and that of G lamblia may be also due to hypochlorhydria or achlorhydria in the stomach, which interferes with vitamin B12

absorption. EFFECTS ON SPECIFIC NUTRIENTS

Physicians called upon to determine an appropriate nutritional regimen for patients with acute or chronic infection should be aware that any past dietary deficiencies have been worsened and that current intake and absorption of essential nutrients is likely to be impaired. Because of anorexia and reduced absorption, correction of these deficiencies by diet alone while the infection persists is likely to be difficult. Therefore, special attention must be given during the convalescence to the use of enriched diets or oral formulas. If parenteral alimentation is judged necessary, nutritional status should be appraised and the formula adjusted for optimal recovery. Some of the specific nutritional requirements to be taken into consideration under these circumstances are included. Protein

During infection, protein catabolism in skeletal muscle is increased and amino acids such as those of the branched-chain group are utilized as energy sources for the synthesis of alanine or glutamine that are rapidly taken up by the liver as substrates for gluconeogenesis. Those amino acids, such as phenylalanine and tryptophan, that cannot be metabolized in skeletal muscle are

released in elevated amounts. Pocv anda’~ has summarized data available in the literature for a wide variety of acute infectious diseases by adding the total nitrogen losses and dividing them by the number of davs over which these losses occurred. For all infections, the average loss of 0.6 g of protein per kg per day, is greater than the estimated protein allowance for adults of 0.57 g/kg per day . Diseases associated with diarrhea of dysentery produced an average loss of 0.9 g of protein/kg per day. Even higher losses are observed with typhoid fever, pneumonia, and other severe infections, reaching 1.2 g of protein/kg per day. Moreover, such calculations do not even include nutrients expended for the multiple anabolic responses caused by the infection. Balance studies during recovery indicate these to be substantial. Although there are &dquo;savings&dquo; of dietary energy because of anorexia during the acute phase of an infection, this loss must be made up during the recovery period, just as the losses because of malabsorption and infection-stimulated catabolism must also be made up. Both metabolic and field observations suggest that, even with an optimum diet, it may take two to three times longer to replete than to deplete an individual. In this case, any figure for daily increment of additional protein or energy during recovery only needs, in theory, to be from one half to one third of the daily loss during the acute phase of an infection. If the diet is not sufficient for optimum catch-up, the time required for complete recovery greatly increases. Under developing country conditions there is a high risk that another episode of infection will occur before recovery from the first one has taken place. This is also true for nosocomial infections in hospitals and other institutions, particularly among poorly nourished individuals.

Energy The energy cost of depositing a gram of protein is estimated to be 24 kcal, or about 6 kcal per gram of total weight gain.55 If this figure is applied to the observed protein losses, average caloric losses from this source alone are between 4 and 5 calories per kg per day. When protein loss during infection is estimated from urinary 3-methylhistidine as a measure of muscle protein catab01ism,56 losses are calculated to be the equivalent of 0.14

protein per kg/day or about 7 kcal/kg per day. The energy costs represented by the loss of protein must be added to the energy costs of the protein diverted for internal synthesis of protein compounds in response to infection. Even in the aggregate, these losses are relatively small compared with the protein losses and are usually at least partially compensated for by the reduced physical activity associated with illness. In any case the energy content of the diet during convalescence should always be sufficient for prompt recovery from any undesirable weight loss. A fixed stress factor of 1.75 basal metabolic rate has been proposed for the treatment of traumatized patients on the basis of experimental evidence.; Similar studies are required to establish an appropriate factor for optimal recovery from infections.

g of

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598

Vitamin A The capacity of infections to precipitate xerophthalmia and keratomalacia in individuals already marginally deficient in vitamin A is well established .5’ The mechanisms include the loss of vitamin A in the urine. Ascorbic Acid

Historically, infections are associated with the precipitation of florid scurvy in individuals already on a diet borderline in vitamin C.:3-! As already noted, ascorbic acid levels decrease in plasma and increase in the urine in infected individuals compared to those in non-infected persons living under comparable conditions. This is even seen with immunization against smallpox and measles (INCAP, unpublished data, 1958). Thiamine and Niacin The classic nutritional diseases of beriberi and pellagra known to be precipitated in vulnerable individuals by a variety of infections.34 This is of more than historical interest since alcoholics frequently consume diets deficient in thiamine and niacin, and infections increase the likelihood of clinically significant deficiencies in such individuals. Given the frequency with which infections occur in indigent alcoholics, physicians treating them should be alert to this. were

Riboflauin

duction of ceruloplasm.60 Conversely, plasma zinc levels often decline during acute infections because of an internal redistribution of this metal to the liver. The reduced retention of zinc during diarrhea interacts with the redistributional influence of the infection. On the basis of these findings, it is reasonable to suggest that treatment regimens for diarrhea should contain supplemental amounts of both copper and zinc, but whether this would make any detectable difference in therapeutic results remains to be demonstrated. Iron One metabolic consequence of infection is a decrease serum iron because of its sequestering in the reticuloendothelial system. In addition lactoferrin, with a higher iron-binding capacity than bacterial siderophores, is released by phagocytes. The net effect is to deprive the infectious agent of iron for its replication and thereby to inhibit the spread of the infection. The total iron-binding capacity to iron ratio in plasma has been proposed as a criterion for distinguishing between true iron deficiency and that caused by acute inflammation. If iron deficiency anemia, or even moderate iron deficiency without anemia, is present at the time of the infection, a number of normal resistance mechanisms are compromised. These include impaired phagocytic killing power, delayed cutaneous hypersensitivity, T-cell proliferation and T-killer cell activity, and if sufficiently in

severe,

The diets of indigent alcoholics are also likely to be low in riboflavin. It should be recognized that the effects of infection in depressing plasma riboflavin levels, even in previously well-nourished individuals, can be quite

dramatic.&dquo; Vitamin B12

Tropical enteritis or tropical sprue has already been described as a result of chronic intestinal infections because of a variety of causes. Vitamin Bis malabsorption and megaloblastic anemia are sometimes a consequence. Copper and Zinc Careful metabolic studies by Castillo-Duran et a159 have documented the impact of diarrhea on zinc and copper status. Both were strongly negative during the period of acute diarrhea in infants compared with strongly positive balances in the control subjects. During the recovery period zinc balances became positive (49.6 ± 20.4), but the copper balance remained negative, although less so (-21.5 ~ 46.7). Because the normal state for the growing infant is net retention of these minerals, the true magnitude of these losses is somewhat greater than indicated by balance studies. The mechanism for the adverse impact on copper and zinc status is a combination of intestinal malabsorption and increased endogenous losses from the gastrointestinal tract. The magnitude of these losses cannot be predicted from serum levels. Copper levels often increase during infections as a result of stimulation of the hepatic pro-

impaired antibody formation.61

When individuals compromised in this way are given parenteral iron or large doses of oral iron, a disastrous exacerbation of the infection and death may occur.62° 63 This happens because the infectious agent is supplied with iron for replication before the host immune system has had time to recover. Inasmuch as the biological withholding of iron is part of normal resistance mechanisms, large doses of iron should never be administered to a patient whose immune status is compromised. However, in field studies of poorly nourished populations, supplementation with up to 100 mg of iron daily for adults and proportionately less for children consistently results in decreased morbidity from infectious disease.64 It is desirable, therefore, to include iron in conservative amounts in the dietary treatment of the malnourished in order to allow for gradual restoration of normal host resistance without oversaturating the plasma with iron or lactoferrin iron-binding capacities. SUMMARY

All infections, no matter how mild, with the possible exception of the common cold, worsen nutritional status through a variety of mechanisms. These include reduced appetite, withdrawal of solid food, reduced absorption, fever, increased catabolic losses, and internal diversion or sequestering of nutrients. Whether these effects are of clinical significance depends on the nature of the infectious stress, the prior nutritional status of the individual, the nutrient intake during the infection, and particularly the diet during the recovery period. Accordingly, patients with a chronic infectious disease or who

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have had recent or current acute infections, require careful evaluation of their nutritional status and adequate provision of nutrients for optimal recovery, whether the regimen is enteral or parenteral.

of Macronutrients During Acute Stage and After Recovery. International Centre for Diarrheal Disease Research, Dacca. Bangladesh. 1981

Absorption

25.

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