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Massachusetts Institute of Technology, Cambridge, MA and Food and Nutrition Programme, United Nations University, Tokyo, Japan
2To whom correspondence should be addressed. E-mail: nevin{at}cyberportal.net.
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ABSTRACT |
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 TOP ABSTRACT Effect of infections on...Effect of nutrition and...Evidence for the effect...Effect of infection on...The comprehensive review article...DiscussionLITERATURE CITED |
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KEY WORDS: • nutrition • nutrients • infection • immunity • morbidity • mortality • kwashiorkor
In the 1940s the leading textbook on clinical nutrition (1
) had only a short paragraph referring to nutrition and infection. It concluded that there was little evidence of a relationship, except possibly for tuberculosis, and this was not changed in the 1962 edition. During my internship in Gorgas Hospital, Panama Canal Zone in 1945–1946, I observed that tuberculosis, one of the leading causes of death, was a more virulent disease in the poorly nourished children and adults of Panama than in the relatively well-nourished patients in Rochester, NY. However, when I went to Guatemala in 1949 to establish the Institute of Nutrition of Central America and Panama (INCAP), I had no concept of the importance of infection in precipitating clinical malnutrition.
We soon observed that measles was more severe in poorly nourished Guatemalan children than those in Rochester and documented this (2
). We also noted the association between moderate to severe malnutrition in village children and a history of prior episodes of an infectious disease (3
). We particularly observed that kwashiorkor was almost always precipitated by one or more prior infections (4
). Diarrhea was so common that it was the most important factor (5
). However, measles, chicken pox, whooping cough, German measles and even skin infections were commonly implicated (6
).
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Effect of infections on growth |
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TOPABSTRACTEffect of infections on...Effect of nutrition and...Evidence for the effect...Effect of infection on...The comprehensive review article...DiscussionLITERATURE CITED |
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Figure 1
taken from Mata (7
) shows a surprising 39 wk for a child to regain the weight at the onset of whooping cough. Table 1
shows that long recovery times for this disease were so common in highland Guatemala that more than a quarter of cases observed required >25 wk to reach this end point. Even subclinical infections can affect growth, as illustrated in Figure 2
from the same source (7
). Daily rectal swabs were obtained from newborns for 1 y and examined for infectious agents. The very high frequency of enteroviruses and adenoviruses isolated was not usually associated with symptoms, but the tercile with the highest number of positive cultures gained less weight.
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). Figure 3
is characteristic of his observations. In all of our growth studies in this population in which all infants were breastfed, we observed a birth weight that was normal or low with catch-up or maintenance of a normal growth curve until 4 to 6 mo. Infections occurred in the early period but did not seem to affect growth. However, once breast milk was no longer adequate as a sole source of food and exposure to enteric infections more frequent, the growth curves continue to fall relative to standards for well-nourished children. Of course there are now hundreds of studies demonstrating this, but in the 1950s, poor diet alone was considered responsible.
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Effect of nutrition and infection on mortality |
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TOPABSTRACTEffect of infections on...Effect of nutrition and...Evidence for the effect...Effect of infection on...The comprehensive review article...DiscussionLITERATURE CITED |
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). In the civil register about one-third of the deaths were attributed to parasites because of local beliefs as to the cause of edema, but they were actually found to be associated entirely with the classical signs and symptoms of kwashiorkor (Table 2
). Nutritional, respiratory and enteric disease each accounted for nearly 30% of the postneonatal deaths for which a cause could be identified and the remainder were ascribed to systemic infections, mainly whooping cough. In addition, revealing the failure of official vital statistics to identify nutrition as a primary cause of child death, they also fail to identify malnutrition as an important contributory cause. Few of the cases of diarrheal and respiratory infections would have been fatal to well-nourished children. The same was true for the systemic infections. We concluded that after the neonatal period all of the deaths were attributable to the synergism between nutrition and infection.
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). They found that nutritional deficiency was either the primary or the associated cause of most child deaths in at least 57% of cases. In some areas two-thirds of children had evidence of increased nutritional vulnerability to disease and death. They concluded that the only way to measure the real magnitude of malnutrition as a health problem was the multiple causation approach. Pelletier et al. (11
) reviewed six more recent studies that support this conclusion. |
Evidence for the effect of improving nutrition on infection |
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TOPABSTRACTEffect of infections on...Effect of nutrition and...Evidence for the effect...Effect of infection on...The comprehensive review article...DiscussionLITERATURE CITED |
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). Table 3
shows the lower prevalence of illness of children in the supplementary feeding village as compared with those in the village that received medical treatment but no nutritional supplement.
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shows the striking decrease in infectious disease morbidity in preschool children in a Mexican village when they were given a daily snack that included milk (13
). After the early months of breastfeeding when the infant is protected, supplemented children had fewer days ill and less severe infections. The effect was equally evident with respiratory and diarrheal infection.
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) showed the effect of supplementation on the growth response to diarrhea in children in two lowland Guatemalan villages (Fig. 5
), in which children were given a nutritious high protein supplement. The best growth was in children with low diarrheal prevalence, but supplementation improved growth even when diarrheal prevalence was high. Similarly, Lutter et al. (15
) showed that in Colombian children diarrhea prevalence decreased growth but that the effect could be largely eliminated by supplementation.
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Effect of infection on nutritional status |
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TOPABSTRACTEffect of infections on...Effect of nutrition and...Evidence for the effect...Effect of infection on...The comprehensive review article...DiscussionLITERATURE CITED |
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that reveal a decrease in nitrogen retention of 21 to 45% over 1 to 2 wk with various infectious episodes (16
). Catch-up afterward depended on the quality of the diet and the interval between infections. We found that any infection in children, even immunization with a live attenuated virus, the 17-D strain of yellow fever vaccine, resulted in a negative nitrogen balance despite lack of symptoms or febrile response (17
).
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) and collaborators at Fort Detrick, MD, began to carry out similar studies in young adults. Beisel et al. (19
) described a volunteer who was one of group experimentally infected with Q-fever, but had no symptoms or signs other than rickettsia in the blood. He developed a negative nitrogen balance that lasted for 21 d.
In our studies all acute infections, including those that were subclinical, resulted in decreased food intake associated with decreased appetite and metabolic losses of nitrogen and other nutrients in the urine. Infections affecting the gastrointestinal tract decreased nutrient absorption, and metabolism was increased with fever. We assumed, but could not measure, an internal diversion of nutrients for immune responses. We also recognized that fever would increase nutrient requirements through increased metabolism. Thus the mechanisms for the effect of infection on nutritional status were fairly clear, although as described later in this symposium (20
), it was the studies at Fort Detrick that provided much additional quantitative data on the losses.
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The comprehensive review article and WHO monograph on interactions of nutrition and infection |
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TOPABSTRACTEffect of infections on...Effect of nutrition and...Evidence for the effect...Effect of infection on...The comprehensive review article...DiscussionLITERATURE CITED |
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). The review established the importance of the relationship for human health and led to an invitation to expand it into the WHO monograph published in 1968 (22
). This monograph summarized the conclusions from nearly 900 references. Most of these were experimental studies in animals. The 50 studies involving nutrients and pathogenic organisms in human subjects that provided evidence for the synergism of nutrition and infection are summarized in Table 5
.
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Discussion |
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TOPABSTRACTEffect of infections on...Effect of nutrition and...Evidence for the effect...Effect of infection on...The comprehensive review article...DiscussionLITERATURE CITED |
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It is now recognized that specific defense mechanisms influenced by nutritional status include interference not only with the production of humeral antibodies and the bacteriocidal capacity of phagocytes but also with mucosal secretory antibodies, cell-mediated immunity, complement formation, numbers of thymus-dependent T-lymphocytes and T-cell subsets (helper, suppressor-cytotoxic, natural killer cells, etc.), the complement system and more. The neutrophile is seen as a complex of antimicrobial systems, all of which are potentially affected by malnutrition. They include both oxygen-dependent systems, such as those responsible for the respiratory burst, and oxygen-independent systems such as cationic proteins, lactoferrin, lysozymes, hydrolases and proteases. Essentially all these forms of immunity have been shown to be affected by nutrient deficiencies and these immune responses are not specific to a single nutrient (23
).
The WHO monograph on nutrition and infection cited many individuals whose work had shown an adverse effect of malnutrition on the response to infections. However, most of their studies were in experimental animals. There were very few studies describing the effect of infection on nutrition in either animals or humans. The most notable of these was Williams’ 1934 recognition of the role of infection as well as protein malnutrition in kwashiorkor in what is now Ghana (24
). Even though her paper was published in The Lancet, it was not until the 1949 FAO/WHO survey of kwashiorkor in Africa by Brock and Autret (25
) that this disorder was rediscovered and found to be a continent-wide problem. Soon afterward, the FAO/WHO-sponsored survey in Central America confirmed it as a problem in the Americas (26
). While INCAP was working intensively on this protein deficiency disease and its relation to infection, recognition spread rapidly that it was a serious global problem at the time. It is hard to believe now the extent to which kwashiorkor, like scurvy, beri beri and pellagra, has largely disappeared as a public health problem except in some refugee groups.
In reviewing its publication list, I was surprised to find that in its first 30 y, INCAP had 190 publications relating directly to nutrition and infection. Since the publication of the WHO monograph in 1968 there has been a rapid growth in the world literature relevant to nutrition and infection that is increasingly focused on the role of immunity. In the early part of the 20th century, there were a number of outstanding individuals who published books and articles suggesting an important relationship between some aspect of nutrition and infection. By and large, their voices were not heard. It was only in the 1950s and 1960s that concurrent work, not only in Guatemala but also in Chile, Gambia, Jamaica, Mexico, South Africa, Uganda, the United Kingdom, the United States and elsewhere, supported the conclusions of the WHO monograph. Today, recognition of the synergistic relationship between nutrition and infection is a strong force in most public health interventions to prevent infection and correct malnutrition. With the increasing resistance of important pathogens to available antibiotics and other medications, the relationship is likely to receive renewed attention.
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FOOTNOTES |
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LITERATURE CITED |
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TOPABSTRACTEffect of infections on...Effect of nutrition and...Evidence for the effect...Effect of infection on...The comprehensive review article...DiscussionLITERATURE CITED |
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1. Jeliffe, N. (1950) Textbook of Clinical Nutrition 1950 Harper & Brothers New York, NY.
2. Gordon, J. E., Jansen, A.A.J. & Ascoli, W. (1965) Measles in rural Guatemala. J. Pediatr. 66:779-786.[Medline]
3. Scrimshaw, N. S. & Behar, M. (1961) Protein malnutrition in young children. Science 133:2039-2047.
4. Scrimshaw, N. S., Béhar, M., Viteri, F., Arroyave, G. & Tejada, C. (1957) Epidemiology and prevention of severe protein malnutrition (kwashiorkor) in Central America. Am. J. Public Health 47:53-62.
5. Salomon, J. B., Gordon, J. E. & Scrimshaw, N. S. (1966) Studies of diarrheal disease in Central America: X. Associated chickenpox, diarrhea and kwashiorkor in a highland Guatemalan village. Am. J. Trop. Med. Hyg. 15:997-1002.
6. Salomon, J. B., Mata, L. J. & Gordon, J. E. (1968) Malnutrition and the common communicable diseases of childhood in rural Guatemala. Am. J. Public Health 58:505-516.
7. Mata, L. J. (1978) The Children of Santa Maria Cauqué: A Prospective Field Study of Health and Growth 1978 MIT Press Cambridge, MA.
8. Mata, L. J., Urrutia, J. J., Albertazzi, C., Pellecer, O. & Arellani, B. (1972) Influence of recurrent infections on nutrition and growth of children in Guatemala. Am. J. Clin. Nutr. 25:1267-1275.[Medline]
9. Béhar, M., Ascoli, W. & Scrimshaw, N. S. (1958) An investigation into the causes of death in children in four rural communities in Guatemala. Bull. World Health Organ. 19:1093-1102.
10. Puffer, R. & Serrano, P. (1975) Patterns of Mortality in Latin American Children 1975 Pan American Health Organization Washington, D.C.
11. Pelletier, D. L., Frongillo, E. A. & Habicht, J. P. (1993) Epidemiologic evidence for a potentiating effect of malnutrition on child mortality. Am. J. Public Health 83:1130-1133.
12. Scrimshaw, N. S. & Guzman, M. A. (1995) A comparison of supplementary feeding and medical care of preschool children in Guatemala, 1959–1964. Scrimshaw, N. S. eds. Community-Based Longitudinal Nutrition and Health Studies: Classical Examples from Guatemala, Haiti and Mexico 1995:1-28 International Nutrition Foundation for Developing Countries (INFDC) Boston, MA. .
13. Chávez, A., Martínez, C. & Soberanes, B. (1995) The effect of malnutrition on human development: a 24-year study of well-nourished and malnourished children living in a poor Mexican village. Scrimshaw, N. S. eds. Community-Based Longitudinal Nutrition and Health Studies: Classical Examples from Guatemala, Haiti and Mexico 1995:79-124 International Nutrition Foundation for Developing Countries Boston, MA. .
14. Martorell, R. (1995) The INCAP longitudinal study (1969–1977) and its follow-up (1988–1989); an overview of results. Scrimshaw, N. S. eds. Community-Based Longitudinal Nutrition and Health Studies: Classical Examples from Guatemala, Haiti and Mexico 1995:124-142 International Nutrition Foundation for Developing Countries Boston, MA. .
15. Lutter, C. K., Moral, J. O., Habicht, J. P., Rasmussen, K. M., Robson, D. S., Sellers, C. M., Super, C. M. & Herrera, M. G. (1989) Nutritional supplementation: effects on child stunting because of diarrhea. Am. J. Clin. Nutr. 50:1-8.
16. Scrimshaw, N. S., Wilson, D. & Bressani, R. (1960) Infection and kwashiorkor. J. Trop. Pediatr. African Child Health 6:37-43.
17. Gandra, Y. R. & Scrimshaw, N. S. (1961) 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. 9:159-163.
18. Beisel, W. R. (1972) Interrelated changes in host metabolism during generalized infectious illness. Am. J. Clin. Nutr. 25:1254-1260.[Abstract]
19. Beisel, W. R., Sawyer, W. D., Ryll, E. D. & Crozier, D. (1967) Metabolic effects of intracellular infections in man. Ann. Intern. Med. 67:744-779.
20. Powanda, M. & Beisel, W. R. (2002) Metabolic effects of infection on protein and energy metabolism. J. Nutr. 133:322S-327S.
21. Scrimshaw, N. S., Taylor, C. E. & Gordon, J. E. (1959) Interactions of nutrition and infection Am. J. Med. Sci. 237:367-403.
22. Scrimshaw, N. S., Taylor, C. E. & Gordon, J. E. (1968) Interactions of Nutrition and Infection 1968 World Health Organization Geneva, Switzerland.
23. Scrimshaw, N. S. & SanGiovanni, J. P. (1977) Synergism of nutrition, infection and immunity: an overview. Am. J. Clin. Nutr. 66:464S-477S.
24. Williams, C. D. (1934) Kwashiorkor, a nutritional disease associated with a maize diet. Lancet 2:1151-1152.
25. Brock, J. F. & Autret, M. (1952) Kwashiorkor in Africa. WHO monograph series no. 8 1952 World Health Organization Geneva, Switzerland.
26. Autret, M. & Behar, M. (1954) Sindrome pluricarencial infantile (kwashiokor) and its prevention in Central America. FAO Nutritional Studies no. 13 1954 Food and Agriculture Organization Rome, Italy .
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