Symposium: Nutrition and Infection, Prologue and Progress Since 1968

Diarrhea and Malnutrition1

Kenneth H. Brown 2
Program in International Nutrition and Department of Nutrition, University of California, Davis, CA
ABSTRACT Publication of the WHO monograph, Interactions of Nutrition and Infection, in 1968 by Scrimshaw, Taylor and Gordon stimulated many scientists to pursue further research on these issues. With regard to the relationships between diarrhea and malnutrition, the research conducted since 1968 can be categorized in one of three major areas: 1) the impact of diarrhea on nutritional status, particularly in young children; 2) nutritional risk factors for diarrhea; and 3) appropriate dietary therapy for patients during and after enteric infections. The results of these studies have prompted a number of changes in the clinical treatment of patients with diarrhea and in public health policies regarding its prevention. J. Nutr. 133: 328S332S, 2003.
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KEY WORDS:

diarrhea

malnutrition

infection

dietary intake

breastfeeding

It is personally very gratifying to be able to contribute to this symposium, which revisits the 1968 treatise by Scrimshaw, Taylor and Gordon entitled, Interactions of Nutrition and Infection (1), because this publication had a major impact on my own thinking and career development. For individuals like me who were U.S. university students at the time, the year 1968 was notable for the growing distrust of the military industrial complex, the widespread resistance to the war in Vietnam, and the reawakened social concern for disenfranchised peoples, both in the United States and elsewhere. At the same time, Timothy Leary was counseling students and other members of the love generation to turn on, tune in, and drop out (2); and the hippie movement was reaching its peak. As a graduating senior confronting these competing claims on my attention, and as the recipient of a lottery number from the U.S. Selective Service Board that all but ensured my inscription into the U.S. Army immediately after graduation unless other options were pursued, I chose instead to enroll in medical school until I could decide what I really wanted to do with my life. Because I had originally hoped to join the Peace Corps after nishing my undergraduate studies, once in medical school I began to explore opportunities for practicing medicine and/or conducting biomedical research in the developing world; and I soon discovered the series of publications by Scrimshaw, Gordon and colleagues on weanling diarrhea (3) and the interactions between infection and nutrition (4,5).
1 Presented as part of the symposium Nutrition and Infection, Prologue and Progress Since 1968 given at the 2002 Experimental Biology meeting on April 23, 2002, New Orleans, LA. The symposium was sponsored by The American Society for Nutritional Sciences. The proceedings are published as a supplement to The Journal of Nutrition. Guest editors were Nevin S. Scrimshaw, Massachusetts Institute of Technology, Cambridge, MA, and Food and Nutrition Programme, United Nations University, Tokyo, Japan, and William R. Beisel, Department of Microbiology and Immunology, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD. 2 To whom correspondence should be addressed. E-mail: khbrown@ucdavis.edu.

Thus began my personal and professional odyssey in quest of greater knowledge on these topics. The comprehensive monograph Interactions of Nutrition and Infection stimulated many scientists to pursue further research on these issues, and in this presentation I will highlight some of the resulting studies on diarrhea and nutrition. In general, the research conducted on this topic since 1968 can be categorized in one of three major areas: 1) the impact of diarrhea on nutritional status, particularly in young children; 2) nutritional risk factors for diarrhea; and 3) appropriate dietary therapy for patients during and after enteric infections. Notably, the results of these studies prompted a number of changes in the clinical management of patients with diarrhea and in public health policies regarding its prevention. For lack of time, and because of my own personal interests and experience, my comments will focus primarily on epidemiological and clinical studies that were conducted in humans. I will not attempt to provide a comprehensive treatment of the literature; rather, I will highlight those studies that I believe have exerted the greatest inuence on current thinking.

Overview of diarrhea and nutrition As articulated by Scrimshaw, Taylor and Gordon in their 1968 review, the relationship between infection and malnutrition is bidirectional (Fig. 1). Infection adversely affects nutritional status through reductions in dietary intake and intestinal absorption, increased catabolism and sequestration of nutrients that are required for tissue synthesis and growth. On the other hand, malnutrition can predispose to infection because of its negative impact on the barrier protection afforded by the skin and mucous membranes and by inducing alterations in host immune function.

0022-3166/03 $3.00 2003 American Society for Nutritional Sciences.

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The most recent phase of research on this theme has begun to examine the effect of diarrhea on micronutrient balance and assessment of micronutrient status. For example, CastilloDuran et al. (15) assessed trace element balance during and after acute diarrhea, noting a negative balance of zinc during the early phase of illness. Nutritional risk factors for diarrhea Nutritional risk factors for diarrhea can be grouped as anthropometric risk factors, infant and child feeding practices and micronutrient status. Measures of resulting morbidity from diarrhea include both incidence rates and the duration and severity of illness. Research on these issues is summarized in the time line presented in Figure 4. Studies by James et al. in 1972 (16) and Sepulveda et al. in 1988 (17) span the period when investigators conrmed a relationship between preexisting anthropometric status and diarrheal incidence. Although most investigators accept the conclusion that malnutrition increases the risk of diarrhea, it must be recognized that the design of these descriptive epidemiological studies does not permit elimination of the possibility that confounding factors may explain as least some of the observed results. For example, researchers have noted the possibility that children with some underlying predisposition to enteric infection, such as environmental exposures or immunodysfunction, may have become undernourished because of earlier illnesses. Thus, baseline malnutrition, as dened by anthropometric indicators, may have been a result of these prior illnesses rather than a cause of subsequent ones. Disentanglement of the causal sequence of these events has remained problematic. During this same period of time, investigators also described associations between anthropometric indicators of nutritional status and the duration of illness (18), the severity of fecal purging (19) and, most important, the case-fatality rates (20). In each case, preexisting malnutrition was associated with an increased severity of diarrheal disease. Infant feeding practices is another nutrition-related risk factor that received heightened attention during the period after 1968. Two important studies published from Latin America and Asia at the end of the 1980s found that exclusively breastfed infants had considerably reduced risks of diarrhea

FIGURE 1

Relationship between nutrition and infection.

Nutritional impact of diarrhea A time line showing each of the major lines of research concerning the nutritional impact of diarrhea is provided in Figure 2. As indicated, a number of eld studies conducted during the 1970s and 1980s attempted to quantify the nutritional impact of diarrhea on childrens growth. Leonardo Mata and colleagues at the Institute of Nutrition of Central America and Panama produced a series of graphic presentations illustrating the temporal relationships between individual episodes of infection and periods of growth faltering (6), an example of which is presented in Figure 3. Subsequently, Martorell et al. in Guatemala (7), Rowland et al. in West Africa (8) and Black et al. in Bangladesh (9) developed statistical models to estimate the proportion of the total growth decit that could be attributed to diarrhea, and they concluded that an important component of the observed growth failureperhaps as much as one-fourth to one-thirdwas attributable to enteric infections. The groups in Guatemala and Bangladesh proceeded to explore the mechanisms whereby diarrhea causes growth failure, focusing on dietary intake and intestinal malabsorption. Martorell et al. (10) reported that fully weaned Guatemalan children reduced their energy intake by 30% during acute infections, whereas Brown et al. (11) found that Bangladeshi children who were still breastfeeding reduced their intakes by only about 7%, suggesting that breastfeeding may protect against diarrhea-induced reductions in intake. During a subsequent study in Peru (12), intakes of breast milk energy and nonbreast milk food sources were examined separately; and this analysis of disaggregated data conrmed the foregoing hypothesis. Whereas intake of nonbreast milk energy declined by about 30% during illness, there were no changes in breast milk consumption. Thus, the overall impact of illness on energy intake was partially mitigated by breastfeeding. Beginning in the 1980s, researchers started to explore factors that might modify the nutritional impact of diarrhea. Rowland et al. (13) discovered that the previously observed diarrhea-induced growth decit was absent in fully breastfed infants in an urban eld site in West Africa, and they concluded that exclusive breastfeeding prevents the adverse nutritional consequences of diarrhea. Lutter et al. (14) found that the usual diet also inuenced the growth response to diarrhea in older children. Whereas the Colombian children in these studies who lived in control villages displayed the expected negative relationship between diarrheal prevalence and height at 3 y of age, there was no effect of diarrhea on the height of those children who lived in villages where food supplements were being distributed.

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FIGURE 2 Summary of research on the nutritional impact of diarrhea.

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FIGURE 3 Example of the temporal relationship between infection and growth of an individual child. [Data from Mata et al. 1976 (6).]

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(and other infections) compared with infants who either received other foods or liquids along with breast milk or were fully weaned from the breast (21,22); and similar results have been published more recently from more industrialized settings (23). During the 1980s and 1990s researchers began to question whether deciencies of specic micronutrients might also affect the risk of diarrhea. Studies were beginning to emerge that indicated that the risk of mortality was reduced in children who had received large doses of vitamin A (24). Because most childhood deaths in low income settings are attributable to infection, it was reasonable to assume that this effect of vitamin A might be attributable to a reduced incidence of infections. Despite the apparent logic of this assumption, most studies of this relationship found no effect of vitamin A supplementation on the incidence of diarrhea (25,26). However, researchers in Ghana claried this issue when they dis-

covered that clinic visits and hospital admissions for diarrhea were decreased in vitamin Asupplemented children, even though diarrheal incidence rates remained unchanged (27). Thus, it appeared that vitamin A reduced the severity of illness without affecting the overall attack rate. More recently, several groups of investigators have pursued studies of the effect of zinc supplementation on the risk of diarrhea (28,29). These and other studies, which have been summarized in a recently published pooled analysis (30), demonstrate an impressive reduction in diarrheal incidence of nearly 20% among zinc-supplemented children. Dietary management of patients with diarrhea In response to the growing recognition that diarrhea undermines nutritional status, a number of investigators began to reexamine the prevailing approaches to the dietary management of these patients, as summarized in Figure 5. As early as 1924, Parks stated that, The habit of starving an infant just because he has frequent stools is fallacious and gives rise to disastrous results. In 1948 Chung and Viscorova found that children who were fed continuously during diarrhea gained weight more rapidly and did not differ with regard to diarrheal duration or treatment failure rates compared with those who were starved during the rst 24 48 h of hospital-based treatment (31). Despite these observations, pediatrics textbooks published during the 1960s and 1970s continued to advise bowel rest for 12 48 h followed by several days of gradual refeeding (32,33), and in 1979 the 3rd edition of the Pediatric Nutrition Handbook of the American Academy of Pediatrics remained silent on the issue of appropriate dietary therapy during acute diarrhea (34). In 1988 researchers from Peru published the results of a randomized, clinical trial to assess the optimal approach for the initial dietary management of children with acute diarrhea and dehydration (35). Immediately after several hours of rehydration therapy, the patients were assigned to receive one of four different dietary regimens for 48 h: 1) a nutritionally

FIGURE 4 diarrhea.

Summary of the research on nutritional risk factors for

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complete, lactose-free formula, which provided 110 kcal/kg body weight d1; 2) the same formula diluted with water to provide half the amount of daily energy; 3) oral glucoseelectrolyte solution (GES); or 4) intravenous GES. The levels of intake were progressively advanced during ensuing 48-h periods, so that all children were receiving the complete diet by d 5 of hospitalization. There were no differences in treatment failure rates or fecal purging (except for the intravenous group during the rst 2 d), and the children gained weight in direct relation to the amount of energy received. Even after 2 wk of therapy, children in the group that was fed continuously with the full-strength formula weighed signicantly more than those who initially received only GES. The advantage of continuous feeding was later conrmed during a multicenter study in Europe (36), and the most recent version of the Pediatric Nutrition Handbook concludes that, It has now been convincingly and repeatedly demonstrated that children of all ages who return to normal feedings as soon as appetite allows after completion of rehydration (4 to 6 hours) fare much better in the duration and severity of illness (37). A number of studies were carried out during the period from 1968 to 1993 to determine whether substitution of lactosefree, milk-based diets for ones that contained lactose would modify the outcome of treatment of acute diarrhea. The results of these trials were inconsistent, although a meta-analysis that was conducted to reexamine them indicated that the rates of treatment failure were nearly twofold greater (22 vs. 12%) in the groups that received lactose-containing milk feeding (36). However, the excess rate of treatment failure was conned to those studies that enrolled children with initial severe dehydration. Among the studies that enrolled children with mild or no dehydration, there was no difference in the treatment failure rates. The authors concluded that it is safe to manage the vast majority of children by using lactose-containing milk, especially if they have no clinical evidence of dehydration. Nevertheless, dehydrated children may benet from reduced lactose intake and close supervision during the early phase of therapy. As reviewed previously (41), a number of studies completed during the 1980s and 1990s examined the use of mixed diets based on staple foods, and others assessed the effects of individual food components, such as dietary ber and micronutrients, on the outcome of diarrhea. In general, children fared at

FIGURE 6 Overall summary of research on diarrhea and nutrition. Downloaded from jn.nutrition.org by guest on January 30, 2013

least as well with mixed diets as they did with more highly processed formulas, and dietary ber was found to reduce the duration of the period of liquid stool excretion (42). With regard to micronutrients, studies were conducted to determine the impact of vitamin A and zinc. Little benet of vitamin A was detected, except in nonbreastfed infants, in whom vitamin A reduced slightly the number of bowel movements and the duration of illness (43). By contrast with this limited impact of vitamin A, all of the published studies of zinc supplementation during both acute and persistent diarrhea found signicant reductions of about 20% in diarrheal duration (44). More studies are currently under way to assess different combinations and dosages of multiple micronutrients on outcomes of diarrhea. In summary, applied research published since 1968 has conrmed the deleterious effect of diarrhea on childrens nutritional status and has produced new evidence in support of revised approaches to prevent and treat these illnesses (Fig. 6). In particular, promotion of breastfeeding to prevent diarrhea and reduce its nutritional complications, continued feeding during illness and supplementation with selected micronutrients, both to prevent enteric infections and to reduce their severity, are all important nutritional aspects in the control of diarrheal diseases and their associated nutritional complications. LITERATURE CITED
1. Scrimshaw, N. S., Taylor, C. E. & Gordon, A.J.E. (1968) Interactions of Nutrition and Infection. WHO monograph series no. 57. World Health Organization, Geneva, Switzerland. 2. Leary, T. (1965) The Politics of Ecstasy. Putnam, New York, NY. 3. Gordon, J. E., Chitkara, I. D. & Wyon, J. B. (1963) Weanling diarrhea. Am. J. Med. Sci. 245: 129 160. 4. Scrimshaw, N. S., Guzman, M. A. & Gordon, J. E. (1967) Nutrition and infection eld study in Guatemalan villages, 1959 1964. I. Study plan and experimental design. Arch. Environ. Health 14: 657 662. 5. Gordon, J. E., Ascoli, W., Mata, L. J., Guzman, M. A. & Scrimshaw, N. S. (1968) Nutrition and infection eld study in Guatemalan villages, 1959 1964. VI. Acute diarrheal disease and nutritional disorders in general disease incidence. Arch. Environ. Health 16: 424 437. 6. Mata, L. J., Kronmal, R. A., Garcia, B., Butler, W., Urrutia, J. J. & Murillo, S. (1976) Breast-feeding, weaning and the diarrhoeal syndrome in a Guatemalan Indian village. Acute diarrhoea in childhood. Ciba Found. Symp. 42: 311 338. 7. Martorell, R., Habicht, J.-P., Yarbrough, C., Lechtig, A., Klein, R. E. & Western, K. A. (1975) Acute morbidity and physical growth in rural Guatemala children. Am. J. Dis. Child. 129: 1296 1301. 8. Rowland, M.G.M., Cole, T. J. & Whitehead, R. G. (1977) A quantitative

FIGURE 5 rhea.

Summary of research on dietary management of diar-

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study into the role of infection in determining nutritional status in Gambian village children. Br. J. Nutr. 37: 441 450. 9. Black, R. E., Brown, K. H. & Becker, S. (1984) Effects of diarrhea associated with specic enteropathogens on the growth of children in rural Bangladesh. Pediatrics 73: 799 805. 10. Martorell, R., Yarbrough, C. & Klein, R. E. (1980) The impact of ordinary illnesses on the dietray intakes of malnourished children. Am. J. Clin. Nutr. 33: 345350. 11. Brown, K. H., Black, R. E., Robertson, A. D. & Becker, S. (1985) Effects of season and illness on the dietary intake of weanlings during longitudinal studies in rural Bangladesh. Am. J. Clin. Nutr. 41: 343355. 12. Brown, K. H., Stallings, R. Y., Creed de Kanashiro, H., Lopez de Roman a, G. & Black, R. E. (1990) Effects of common illnesses on infants energy intakes from breast milk and other foods during longitudinal community-based studies in Huascar (Lima), Peru. Am. J. Clin. Nutr. 52: 10051013. 13. Rowland, M.G.M., Rowland, S.G.J.G. & Cole, T. J. (1988) Impact of infection on the growth of children from 0 to 2 years in an urban West African community. Am. J. Clin. Nutr. 47: 134 138. 14. Lutter, C. K., Mora, J. O., Habicht, J.-P., Rasmussen, K. M., Robson, D. S. & Sellers, S. G. (1989) Nutritional supplementation: effects on child stunting associated with diarrhea. Am. J. Clin. Nutr. 50: 1 8. 15. Castillo-Duran, C., Vial, P. & Uauy, R. (1988) Trace mineral balance during acute diarrhea in infants. J. Pediatr. 113: 452 457. 16. James, J. W. (1972) Longitudinal study of the morbidity of diarrheal and respiratory infections in malnourished children. Am. J. Clin. Nutr. 25: 690 694. 17. Sepulveda, J., Willett, W. & Munoz, A. (1988) Malnutrition and diarrhea: a longitudinal study among urban Mexican children. Am. J. Epidemiol. 127: 365376. 18. Black, R. E., Brown, K. H. & Becker, S. (1984) Malnutrition is a determining factor in diarrheal duration, but not incidence, among young children in a longitudinal study in rural Bangladesh. Am. J. Clin. Nutr. 39: 8794. 19. Palmer, D. L., Koster, F. T., Alam, A.K.M.J. & Islam, M. R. (1976) Nutritional status: a determinant of severity of diarrhea in patients with cholera. J. Infect. Dis. 134: 8 14. 20. Samadi, A., Chowdhury, A. I., Huq, M. I. & Shahid, N. S. (1985) Risk factors for death in complicated diarrhoea of children. Br. Med. J. 290: 1615 1617. 21. Brown, K. H., Black, R. E., Lopez de Roman a, G. & Kanashiro, H. C. (1989) Infant-feeding practices and their relationship with diarrheal and other diseases in Huascar (Lima), Peru. Pediatrics 83: 31 40. 22. Popkin, B. M., Adair, L., Akin, J. S., Black, R., Briscoe, J. & Flieger, W. (1990) Breast-feeding and diarrheal morbidity. Pediatrics 86: 874 882. 23. Kramer, M. S., Chalmers, B., Hodnett, E. D., Sevkovskaya, Z., Dzikovich, I., Shapiro, S., Collet, J. P., Vanilovich, I., Mezen, I., Ducruet, T., Shishko, G., Zubovich, V., Mknuik, D., Gluchanina, E., Dombrovskiy, V., Ustinovitch, A., Kot, T., Bogdanovich, N., Ovchinikova, L., Helsing, E. & PROBIT Study Group (Promotion of Breastfeeding Intervention Trial). (2001) Promotion of Breastfeeding Intervention Trial (PROBIT): a randomized trial in the Republic of Belarus. J. Am. Med. Assoc. 285: 413 412. 24. Sommer, A., Tarwotjo, I., Djunaedi, E., West, K. P., Jr., Loeden, A. A., Tilden, R., Mele, L. & Aceh Study Group. (1986) Impact of vitamin A supplementation on childhood mortality. A randomised controlled community trial. Lancet 1: 1169 1173. 25. Rahmathullah, L., Underwood, B. A., Thulasiraj, R. D. & Milton, R. C. (1991) Diarrhea, respiratory infections, and growth are not affected by a weekly low-dose vitamin A supplement: a masked, controlled eld trial in children in southern India. Am. J. Clin. Nutr. 54: 568 577. 26. Dibley, M. J., Sadjimin, T., Kjolhede, C. L. & Moulton, L. H. (1996) Vitamin A supplementation fails to reduce incidence of acute respiratory illness and diarrhea in preschool-age Indonesian children. J. Nutr. 126: 434 442. 27. Ghana VAST Study Team. (1993) Vitamin A supplementation in north-

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