Susceptibility to infectious disease is mult ifactorial and impinges on native and acquired immunity influenced by the host's genetic constitution, sex, age, and nutritional status.
The worldwide prevalence of malnutrition is difficult to ascertain; however, it is generally accepted that the coexistence of nutritional deficiency states and infection represents the leading cause of morbidity and mortality in p re -industrialized countries and among the poorer populations of affluent countries. The report of the InterAmerican Investigation of Mortality in Childhood provides the first in-depth series of data on deceased children, and documents causes.1 The results of this and similar clinical, dietary, and environmental surveys indicate that for many countries in the Western Hemisphere infectious diseases represent the leading cause of childhood mortality and that malnutrition continues to be the most serious health problem.2-4
Clinical, metabolic and biochemical evidence, largely derived from these and similar human epidemiologie surveys as well as laboratory animal experiments, provides substantial support for the concept that malnutrition may affect host susceptibility to infection and the latter (once established) can result in further deterioration of the host's nutritional status.
Although patients with clinically apparent signs of malnutrition other than obesity are not commonly seen in health care facilities in the United States, physicians are becoming increasingly aware of the association of malnutrition with other disease states such as cancer, renal failure, liver disease, cystic fibrosis, and prematurity. It is also recognized that these patients, already debilitated by underlying acute or chronic illness, are further compromised by associated nutritional deficiencies and are at increased risk for severe, often fatal opportunistic infections. These observations have resulted in an increased interest in the interaction between nutrition and disease and more specifically in the role of nutritional support to improve the host defenses of seriously ill patients. I ndeed, one of the most notable advances in medicine during this past decade has been the development and utilization of specialized diets and feeding techniques for patients who can not digest, absorb or take in adequate nutrition orally. While there is no doubt that we must refrain from unwarranted enthusiasm in prescribing nutritional support as a therapeutic adjunct, it is clear that the under* standing of the interrelationships between nutrition, infection, and immune function is more than just another intellectual exercise. Information which has been gathered from epidemiologie surveys in developing countries should provide us with a better understanding of disease and a more rational approach in the treatment of nutritionally compromised infants and children with infections.
INTERACTION OF NUTRITION AND INFECTION
Malnutrition represents a state in which there exists a deficiency and /or excess of one or more essential nutrients which may or may not be accompanied by overt clinical signs and/or loss of specific function. A malnourished individual would be, in the modern langa uge, a nutritionally comprised host. While it has proved easier to define the effects of infection on nutritional status, it has been more difficult to determine the role of nutrition or specific nutrient deficiencies isolated from other environmental factors, on host susceptibility to infection. Further, the nutritional status of the host may have a profound effect on the outcome of specific infectious diseases. For example, the walling-off process initiated by an infecting agent requires the synthesis of fibrin polysacca rides and collagen. This process would be retarded with lack of essential precursors such as protein. In this situation, in which there is no walling-off, the infection may be expected to spread, increasing both the severity of the disease and the utilization of additional nutrients.
Some purpose may be served to illustrate this synergistic relationship between nutrition and infection, a combination which accounts for most of the morbidity in the world. Table 1 lists mortality figures for children under five years of age in 13 Latin American cities. The relationship of nutritional deficiency as associated cause of death to three broad grouping of underlying causes is clearly illustrated by these figures. Nutritional deficiency was associated cause in 47.1% of all deaths. A higher association, 60.9% is observed when the underlying cause of death to three broad groupings of underlying causes is accord with previous studies which indicate the synergistic action of infectious diseases and malnutrition.4
Diarrhea, measles and respiratory infections are of minor consequence in the well-nourished child but obviously deadly in the malnourished host, and the host attempting to meet the challenge imposed by the offending organism finds himself nutritionally bankrupt and unable to draw further from his depleted reserves of proteins, minerals and other essential nutrients; necessary components for a competent host response.
IMMUNOCOMPETENCE IN THE MALNOURISHED HOST
Having touched on the interactions between undernutrition and infection, let us examine briefly the manner by which malnutrition favors increased susceptibility to infection. It is well accepted that the malnourished host is more susceptible to infection. However, since studies of malnourished subjects have generally dealt with generalized malnutrition involving multiple deficiency states, it is difficult to attribute changes in the immune status to any specific nutrient deficiency. The most one is able to do is document the changes in the immune response and determine whether these changes are reversible with improved nutrient intake.
Several immunologie functions have been studied in children with varying degrees of malnutrition who are generally grouped in the literature into the category of protein-energy malnutrition or protein-calorie malnutrition.
Protein-calorie deficiency is generally considered to represent the most common nutritional problem in the world. Depending on the precise composition of the diet, protein-calorie deficiency results in three main clinical syndromes - marasmus, kwashiorkor or nutritional growth failure. Marasmus which denotes starvation, results from a deficiency in total calories and is clinically characterized by absence of subcutaneous fat and wasted muscle. In contrast, kwashiorkor is considered to result from consumption of a diet deficient in protein relative to calories and is characterized by wasted muscle and edema. It should be noted that the most important precipitating factor in the pathogenesis of the kwashiorkor state is an infection in the already semistarved or marasmic child. Other clinical manifestations of this clinical entity include growth failure, hepatomegaly, hair changes and dermatoses. There is always hypoalbuminemia and a decrease in the total serum protein. Kwashiorkor has its main incidence during the second year of life or after weaning from the breast. Diets inadequate in total calories with a disproportionate lack of protein will result in either marasmus or kwashiorkor or in a mixed type, marasmic-kwashiorkor. In nutritional growth failure or dwarfing there are no clinical signs, only low weight corresponding to age. Table 2 exemplifies the classification utilized by the Food and Agriculture and World Health Organizations.5
Although severe forms of protein calorie malnutrition can be diagnosed clinically, nutritional assessment provides an objective characterization useful for the diagnosis and management of morbid and premorbid states. Anthropometric measurements including weight as percent of standard, deficit in height for weight, head circumference, triceps skinfold-thickness, arm muscle circumference and age, when compared to a recognized standard have been useful to identify moderate and severe malnutrition. Once existence of this condition is suspected, a biochemical profile including the measurement of serum albumin, transferrin and the creatinine height index provides the objective information. Cell mediated immunity can also serve as an index of protein undernutrition. Assessment should include total lymphocyte count and delayed type hypersensitivity response to common skin test antigens such as mumps and candida.
NUTRITIONAL DEFICIENCY AS ASSOCIATED CAUSE OF DEATH UNDER FIVE YEARS OF AGE BY UNDERLYING CAUSE GROUP IN 13 LATIN AMERICAN PROJECTS COMBINED1
SIMPLIFIED CLASSIFICATION OF PROTEIN-CALORIE MALNUTRITION
The first barrier to an infectious agent is provided by the physical integrity of the skin and mucous membranes. The submucosa of the gastrointestinal and respiratory tracts contains plasma cells which synthesize IgA. Deficiency states which lead to functional and structural changes in epithelial lining of the respiratory and gastrointestinal tracts appear to exert the greatest influence. Deficiencies in protein, vitamin A, B complex, ascorbic acid, and zinc are frequently associated with tissue changes that lower resistance.
Cell Mediated Immunity
The thymus gland is an important regulator of cell mediated immunity. Thymic involution normally occurs with advancing age but can be precipitated by severe stress related to any number of disease states including malnutrition. Prominent atrophy of the thymolymphatic system of severely malnourished children and adults has been documented histopathologically in autopsy studies and functionally in clinical studies of cell mediated immunity.6-8 Additionally, the organ weight of tonsils, lymph nodes and spleens have been reported to be significantly reduced when compared to those of normal children.9 Clinical observations have also reported a decrease in the number of circulating T-lymphocytes and depressed T-cell function as determined by delayed skin test reactivity and in vitro assessment of cellular proliferative response.10-12 Delayed hypersensitivity skin tests have been negative or markedly reduced in malnourished children and their lymphocytes show decreased blast cell transformation and decreased incorporation of thymidine into DNA in the presence of specific mitogens.7-12 Clinically malnourished individuals are more susceptible to opportunistic infections, gram negative septicemia and disseminated herpes virus infections. They also have a tendency to develop gangrene rather than suppuration and their infections tend toruna more severe course.1-15 Thus, studies of T-cell function coupled with clinical observations of increased susceptibility to intracellular and viral infections support the thesis of depressed cell mediated immunity in the malnourished host.
Malnutrition affects the humoral immune system in diverse fashion. The B-lymphocytes when activated by antigens differentiate into immunogiobulin secreting cells. Several studies have shown that in malnourished subjects, B-cell subpopulations, immunogiobulin synthesis and metabolism are normal and that immunogiobulin levels are not usually depressed and are often eleva ted. 16-18 Studies on specific serum antibody responses to several antigens have been made in malnourished individuals with varying results.19 However, few of these studies have carefully defined or standardized the antigens used, comparisons have included subjects of different ages and nutritional status making it difficult to interpret the observed variations. In marked contrast to normal or raised levels of circulating immunoglobulins, secretory immunogiobulin (IgA) levels in the respiratory and gastrointestinal fluids of malnourished children are generally decreased as is their secretory response.18-20 It is reasonable to conclude that impaired mucosal immunity both as a result of changes in the integument and reduced secretory antibody response may explain in part the frequency and severity of gastrointestinal and respiratory infections in malnourished children.
Complement levels appear to be somewhat diminished in malnourished subjects. Studies of serum complement indicate low levels of hemolytic complement activity but varying levels of the complement component C3,:21-22 Similarly, reports on the chemotactic and opsonic activity of the serum of malnourished children are conflicting, making it difficult to draw conclusions.
Many recent studies have investigated the production, mobilization and the bactericidal activity of phagocytic cells. Because of the difficulty in harvesting adequate numbers of monocytes and macrophages, most studies have focused on the polymorphonuclear leukocyte.
Total leukocyte count in malnutrition is usually increased or normal. Functional studies indicate impaired chemotaxis in malnourished children with and without overt evidence of infection."16-23" Several studies have also indicated impaired in vitro microbicidal activity, increased resting metabolism and decreased iodination by polymorphonuclear leukocytes of infected malnourished children."24-25 While the myeloperoxidase bactericidal mechanism appears to be diminished in proportion to the impaired microbiocidal activity, concentration of enzymes themselves have been reported to be normal.20 It appears that while there is a defect in the leukocyte inflammatory response of malnourished children as evidenced by depressed chemotactic activity, phagocytosis is normal.
Thus, available data suggest that aggregate nutritional deficits can be expected to reduce the host's ability to cope with exposure to an infectious agent by altering various components of the immune response. It has been only in recent times that we have begun to understand the very important intermediary role that the immune system plays in the interaction, malnutrition-immunocompetency-infectious disease. We now appreciate that any compromise in what might be considered optimal nutritional state may affect immune function and would be expected to reduce the host's ability to cope with exposure to an infectious agent. NUTRITIONAL CONSEQUENCES OF INFECTION
Infections are accompanied by general and specific symptoms as well as by a sequence of hormonal, metabolic and immunologie responses, all of which have a nutritional cost. The responses to infection may result from a combination of functional and structural alterations of body constituents caused directly by the infectious agent or as a consequence of the host response to the infectious process. In general terms, the outcome of infection may be influenced by decreased food intake, increased requirements, absolute losses and functional wastage in the form of nutrient redistribution and sequestration.
An individual's response to infection is a function of immunological and nutritional status as well as of the type and severity of the insult. The most important factors contributing to the effect of infection on the intake and efficiency of use of food by children include increased losses as a consequence of diarrhea and reduced intake through food withdrawal and anorexia. Anorexia and fever are important physiological responses mediating the effects of infections on nutrition. The anorexia that accompanies infection, although difficult to quantify, results in decreased food intake.27 Similarly, if an infection is accompanied by fever, the associated hypermetabolic events result in an increased caloric expenditure.28 There are often physical reasons for decreasing food intake such as a sore mouth in herpetic stomatitis, cancrum oris of measles, altered mental status in the patient with encephalitis or a child who is ventilator dependent because of necrotizing pneumonia.
The nutritional cost of infection or recurrent mild infections ina well nourished child may not beassociated with clinical overt manifestations or loss of specific function. In the marginally nourished child, the child with chronic illness, or in settings where the prevailing diet is barely sufficient to sustain normal growth, recurrent bouts of infection will precipitate or aggravate protein calorie malnutrition and can result in impaired growth, particularly in its linear expression. The relationship between frequency of infection and growth and development is illustrated in Figure I . During the first six months while still being breast fed, the infant who is born perhaps weighing less than his expected potential because of maternal under-nutrition, does quite well and is actually able to surpass the median weight for age standard. However, coincident with being weaned from the breast, and being introduced to a gruel, or milk formula diet prepared in water from a non-potable source, the child experiences recurrent and prolonged bouts of diarrhea and other infectious illnesses. The nutritional wastage and metabolic cost associated with these recurrent infections results in net energy deficiency which culminates in growth failure so that by three years of age his body weight is under 60% of the reference standard.28
Other consequences of infection include nutrient redistribution and sequestration. During infectious illness most intracellular minerals undergo functional sequestration within body pools or depots. For example, the concentrations of iron and zinc in the serum generally decrease and the concentration of copper generally increases.30-32
In general it has been found that in many infectious diseases, the serum iron level drops significantly usually before there are other signs of infection such as fever. The iron is not lost from the body but is sequestered in the liver, reticutoendothelial system and bone marrow. While this does not represent an absolute loss, this sequestration does represent a functional wastage as the nutrient is essentially nonavailable for its normal metabolic or physiologic purposes. It has been suggested by Weinberg33 and others that the decrease in serum iron might reduce the growth of pathogenic microorganisms. In fact, many studies have shown that certain species of bacteria grow poorly in medium containing low concentrations of iron and that iron supplements increase the growth of bacteria in vitro and in vivo.34-35
In contrast to the hypoferremia observed with the majority of infectious illnesses, hyperferremia has been reported during bacillary dysentery, typhoid, and acute hepatitis.33'36 Similar changes in zinc concentrations also occur. Zinc plasma levels also increase and their role in wound healing has been postulated as an aid in the development of immunity.37 In contrast, serum copper rises in proportion to the synthesis and release of coppercarrying protein, ceruloplasmin. A possible role for the increase in plasma copper in the form of ceruloplasmin may be in regulating catecholamine levels and serotonin.37
The most important nutritional consequence of infection is negative nitrogen balance. An initial decrease in the plasma concentration of amino acids is followed by an increased breakdown of body protein resulting in an increased synthesis of urea. The concomitant breakdown and increase in protein synthesis can be related to the host's immune response. Every host defense mechanism from phagocytes to acute phase proteins is ultimately dependent upon the synthesis of specific key proteins in sufficient quantity.
Infectious illness causes the host to undergo a large number of very acute metabolic responses. As depicted in Figure 2, these responses contribute to the loss of nutrients either through absolute wastage or increased utilization for body defense to keep the host alive. The impact will obviously be greater in the nutritionally compromised host.38
Figure 1. The effect of repeated infections on the nutritional status and growth of a male infant in first three years of life. Solid line is the weight of the child; broken line represents median of reference standard. Length of each horizontal line indicates duration of infection. Each mark represents a week positive for specific infectious agent. Bottom: Observed weight gain (vertical bars) versus median increments of the standard (solid circles) (From Mata et al.29 with permission).
From a nutritional point of view, this process of nutrient loss and redistribution has the potential for being exploited to the benefit of the host. By either selectively replacing nutrients being rapidly metabolized which are essential to optimal immune fuction and/ or by withdrawing nutrients that the parasite or invading organism needs, we may be able to improve the host response to infection.
The triad of malnutrition-infection-immunity describes a phenomenon well recognized but not completely understood. An infectious disease, depending upon type and severity will have a varying effect on nutrient metabolism which will be modulated to a great extent by the host's underlying nutritional status. Nutritional factors playa significant role in resistance to infection and almost any nutritional deficiency adversely affects one or more components of the immune system. For example, specific nutrients may be more essential for the multiplication of pathogenic organisms than for the maintenance of the host.
The future may see situations where withholding specific nutrients from the host's diet we might be able to influence favorably the outcome of specific disease. Situations may also arise in which dietary modulation of specific host defense mechanisms may be used selectively to the advantage of the infected individual. Obviously we are at the frontiers of our understanding of the complex interactions among nutrients, immunocompetency and infection.
Figure 2. Possible pathways by which an infectious agent may alter nutritional status which in turn can impinge on immunocompetence leading to a viscious cycle involving the triad, nutrition-infection-immunocompentence Adapted from Santos and Vitale 38).
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NUTRITIONAL DEFICIENCY AS ASSOCIATED CAUSE OF DEATH UNDER FIVE YEARS OF AGE BY UNDERLYING CAUSE GROUP IN 13 LATIN AMERICAN PROJECTS COMBINED1
SIMPLIFIED CLASSIFICATION OF PROTEIN-CALORIE MALNUTRITION