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Therapeutic interventions in diarrhoea
Trace elements and immunity: A synopsis of
current knowledge
Results of a school lunch programme in India
Therapeutic interventions in diarrhoea
Jon E. Rohde
Management Sciences for Health, Port-au-Prince, Haiti
EDITOR'S NOTE
For young children in developing countries, diarrhoeal disease is the most important contributing factor to malnutrition. The adverse nutritional consequences can be greatly reduced by proper oral rehydration and feeding, and mortality can thus be virtually eliminated. Hence the importance of the following article and its selection for the Bulletin. The individuals responsible for it * have had extensive experience in the study and treatment of diarrhoea, and their report was approved by the other participants in the UNU/WHP, Hockefeller Foundation, Ford Foundation, and International Centre for Diarrhoeal Disease Research-sponsored workshop on Interactions of Diarrhoea and Malnutrition, held in Bellagio, Italy, 11-15 May 1981.
* * *
Consideration of the formidable array of recent scientific information on the epidemiology, aetiology, pathogenesis, and physiologic mechanisms of diarrhoea, along with the myriad interrelationships with nutrition, leads, fortunately, to a coherent and relatively concise series of recommendations for the clinical management of these interacting conditions. This summary indicates the practical therapeutic guidelines aimed at the practitioner and community health worker to be derived from the extensive literature. Implementation of these measures will substantially reduce not only the immediate deleterious effects of diarrhoea, dehydration, and in some cases death, but also the longer-term, more prevalent and insidious deleterious effects on nutrition.
FLUID AND ELECTROLYTES
Extensive reviews have documented both the scientific basis and the efficacy of oral rehydration therapy (ORT) in acute diarrhoea. It is safe and more effective, as well as far cheaper, than intravenous fluid replacement. While the World Health Organization ORT formula has proved to be effective and safe in the treatment of millions of cases throughout the world, the greatest emphasis should be given to replacement of diarrhoea fluid and salt losses as early as possible in the illness, before the appearance of dehydration. Thus, availability and acceptability of rehydration measures and accessibility of necessary supplies or ingredients are even more critical than precise composition of the resulting formula. Whenever possible, the "complete formula" should be provided, with compromises made only in order to ensure greater acceptance and widespread coverage.
Sodium: The 90 mEq/litre solution is effective in all diarrhoeas, including cholera, but in infants it must be supplemented with low-sodium fluids, preferably breast milk, or, in its absence, dilute feeds or even plain water. Solutions containing less sodium, 50 to 60 mEq/litre, while not effective in the severe secretory diarrhoeas like cholera, have been used effectively in trials in several countries and may offer a wider margin of safety from electrolyte disorders in the infant age groups.
Bicarbonate: While acidosis invariably accompanies significant fluid loss, the severity is directly related to both volume of diarrhoea and degree of dehydration. Thus, early water and salt replacement to avoid dehydration can reduce acidosis even in the absence of base. The acidosis will then resolve through normal renal and respiratory compensatory mechanisms over several days. While the effects of prolonged hypocarbia are not known, it is preferable to provide some base in rehydration solutions. Acetate and citrate are acceptable alternatives to bicarbonate and are easier to incorporate in packaged or tableted ORT production.
Potassium: Although the deficit of total body potassium characterizing malnutrition is invariably exacerbated by acute diarrhoea because of acidosis and extracellular shifts of potassium, this may not be apparent on admission serum measurements. Potassium losses are high, especially in infant diarrhoeas, and optimal rehydration fluids contain a minimum of 20 mEq/litre (WHO formula) with higher concentrations advocated in several studies. As hypokalemia is associated with apathy, decreased appetite, adynamic ileus, and general disturbance of smooth muscle systems, especially in the early rehydrated stage, replacement is an important part of both electrolyte and nutritional therapy. Greater efforts are needed to identify local sources of high-potassium foods and to encourage their use during both home rehydration and convalescence. The specific effect of low body potassium on appetite, however, needs to be defined.
Substrate: An absorbable concentration of 2 per cent glucose (20 9 glucose or 40 9 sucrose per litre) is required for optimal absorption of the salt water solution. Unfortunately, higher concentrations of sugar are not well tolerated because of high osmotic activity that often exacerbates diarrhoea. Thus, ORT provides very few calories (8 kcal/100 cc) at a time when increased energy sources are badly needed. New research in hypo-osmotically active substrate sources such as cereal powders, where long-chain molecules (dextrins, starch) provide glucose at virtually no osmotic cost, are extremely promising. Using 30 g of rice powder per litre, Molla has data indicating less stool output and better urine flow than with the use of standard ORT containing sucrose; this implies better net absorption. Observations of the effectiveness of K mix for the therapy of kwashiorkor showed marked reduction in deaths from diarrhoea and hypoglycaemia. The easily absorbed, simple carbohydrate (sucrose) combined with casein hydrolysate (a source of small polypeptides) in a liquid mixture contributed to both nutrition and fluid absorption simultaneously. This is supported by earlier work on the synergistic effects of glycine and glucose in an ORT solution. Inclusion of more nutritious substrates absorbed by various non-competing pathways offers the prospect of a more efficacious and nutrient-dense rehydration solution. Exploitation of multiple absorptive mechanisms affords possible benefits in the form of:
a. increased and faster fluid and electrolyte absorption;
b. increased nutrient absorption, providing both energy and amino acids {absorbed by at least four independent or quasi-independent intestinal mechanisms);
c. decreased stool volume, thereby overcoming one of the greatest impediments to lay acceptance of oral rehydration solutions;
d. faster recovery due, first, to shorter cell renewal time as a result of readily available basic nutrients for cell metabolism and, secondly, to better absorption of ORT;
e. better digestion of diet in recovery due to continued enzyme induction, offsetting the known effects of starvation in reducing gut enzymes.
Cereals, legumes, and other locally available, simple foods may thus become, in proper quantities, the basis of a combined fluid-protein-energy oral therapy for diarrhoea, a single antidote for the FEM-PEM cycle.
Water: The quantity of water used to mix ORT is as critical to final composition as is the measurement of solutes, an obvious but often overlooked fact. Each country should identify the most widely available, reproducible volume measure and adapt packaging or home-made formulas to this standard measure. Larger-size volumes (in the range of one litre) have the advantage of cheaper packaging and less per-cent variation in final volume, while smaller volume standards are less subject to bacterial growth through standing and they reinforce volume-for-volume replacement of losses-one loose motion, one glass of ORT-type messages. However, the small packet may suggest to the mother that this amount is sufficient to treat diarrhoea.
The best quality water available should be used to prepare ORT, but standards of purity that inhibit the use of ORT should be avoided. There is no evidence that ingestion of ORT dissolved in normally consumed water is any more detrimental than the routine daily risk of the water alone.
FEEDING DURING DIARRHOEA
The provision of proper and adequate food during the course of diarrhoea is a critical factor both in avoidance of adverse nutritional effects and in hastening recovery from the illness. Children fed throughout the acute phase of watery diarrhoea absorb substantial quantities of nutrients, demonstrate significantly better weight gain over the course of illness, and, in some studies, have a shortened duration of diarrhoea than unfed matched controls. The continued presence of food in the intestine may avoid the development of carbohydrate intolerance and other enzyme-deficiency syndromes reported in some studies where introduction of food following fasting is attended by a recurrence of fluid loss. Patients with chronic diarrhoea have been successfully treated with breast milk and, in some studies, elemental diets. The continuation of feeding throughout diarrhoea, especially with breast milk, may well avoid these complications.
Breast milk should be continued ad lib, even during the rehydration period, alternating with ORT. Important evidence shows that the anorexia of diarrhoea, responsible for a considerable part of nutrient deficiency in diarrhoea, does not affect breast milk intake. Taken in normal or increased quantities, associated with more frequent than usual suckling, breast milk contributes both to rehydration and nutrient needs.
Immediately upon rehydration (four to six hours), other foods consisting of components of adult diets suitably prepared for babies should be provided and offered five or more times daily. Traditionally used paps, gruels, soups, and "baby foods" should be avoided because of their relatively low calorie density and lack of other nutrients. Fats are absorbed during acute diarrhoea, allowing addition of oils to increase caloric density. The food should be offered after breast-feeding to encourage more complete emptying of the breast with consequent stimulus to milk production.
CONVALESCENT FEEDING
Immediately following the cessation of diarrhoea there is an apparent rise in appetite, often to supra-normal levels, as shown by consumption studies in hospitalized patients. Molla has shown appetite recovery in acute rotavirus, ETEC (enterotoxigenic Escherichia coli), Shigella and cholera diarrhoeas occurring between the fourth and seventh days of illness, evidenced by spontaneous consumption of RDA quantities or more of usual foods 11). Supra-normal appetite with intake exceeding 130 kcal per kilogram of body weight has been documented in several hospital studies.
While underlying malnutrition could account for some of the supra-normal appetite seen in the hospital studies, limited observations in normally nourished children indicate the same effect.
Field data on episodes of diarrhoeal illness in Guatemalan children indicate resumption of pre-illness intake only, without compensatory intake, but limitation of food available within the home and the variable delay in the convalescent intake study may have obscured post-illness increases in food intake. The observation of a consistent negative growth associated with diarrhoea (average -3.5 9 body weight per day of illness) in this group shows that catch-up growth in fact did not occur, as one might expect in the absence of extra food intake. Martorell calculated the food supplement required to offset the deficit, using weight gains observed in supplemented children, and expresses this requirement as 66 kcal per day spread over the entire six-month period of observation (2). However, expressed per day of illness, his calculations reveal a 600 to 900 kcal deficit per day of diarrhoeal illness.
Another means of calculation involves estimated calorie requirements for observed deficits in growth. Weight deficit during diarrhoea may average as high as 3 g/kg/day {seen in the Gambia), surely a combination of catabolic and absorptive losses plus lack of normal growth. Given the anorexia and absorptive losses during diarrhoea, even with proper dietary management, nutrient balance is below requirements, with perhaps a 25 to 30 per cent shortfall in calories, roughly the requirement above basal needs for normal growth. This expected rate during the ages of one to five years is roughly 0.5 g/kg/day. Body weight deficit can thus be estimated as 3.5 g/kg times the number of days ill untreated, plus 0.5 g/kg for continued days under proper fluid and dietary treatment. Given a caloric cost of growth of some 12 kcal per gram of body mass (it may be as high as 20 kcal/g), this works out to 4270 kcal/kg/day ill to replace lost growth, or, in a 10 kg child, 420 to 700 additional kcal for each day ill.
For comparison with the Martorell data, which use observed growth in response to consumed nutrition supplements, one must make adjustment for absorptive losses, shown to be some 10 to 20 per cent of energy intake about two weeks after cessation of diarrhoea. Thus, according to this calculation, some 500 to 800 additional kilocalories are required for each day of diarrhoeal illness.
Finally, one can simply calculate the catch-up requirement, assuming that unmet RDAs should be fulfilled in the days following illness. Depending upon how much had been consumed during illness (breast-fed children, for instance, may consume normal quantities in spite of illness), the deficit would range from 40 to 100 per cent, or 400 or 900 kcal for a child 12 to 18 months of age. While derived from quite different observations and assumptions, it is evident that all these approaches give comparable estimates that could easily be summarized as:
a. during the early period after illness, feed the child his normal diet plus all the food he did not eat during his illness; or
b. feed the child one and one-half times his normal diet for twice as many days as he was ill; or
c. feed the child extra food daily until he regains or exceeds his pre-illness weight.
The evidence suggests that the food deficits are roughly equal to replacing food not consumed and that this food should be consumed within a period after illness of some two to four times the duration of illness itself. If recovery is prolonged by spreading the nutrient needs over months, stunting will occur and catch-up growth will not be possible after normal weight-for-height ratios are reached.
Food should be a normal mixed diet with attention to increasing caloric density; the desired additional intake could be achieved by increasing the frequency of feeding by perhaps an extra meal or even two per day. Full-strength milk can form a normal part of the diet if it is mixed with other foods and given over the day in small increments. Studies in lactose-deficient, malnourished children, post-diarrhoea, have demonstrated a high acceptance of total daily lactose if it is offered in this manner.
While admittedly difficult to achieve in some patients, especially in the home setting, the accomplishment of supra-normal food intakes (some 25 to 50 per cent above RDA) for a period two to four times the duration of illness is an effective means to restore growth and obviate the nutritional effects of diarrhoea. Nutrition supplement programmes highly targeted to this brief but critical period may be the most nutritionally effective intervention point in the diarrhoea-malnutrition cycle.
DRUG THERAPY
The effects on nutrition of all pharmaco-therapeutic agents must be considered and carefully documented before endorsing their use in treatment of diarrhoea. Many time-honoured anti-diarrhoeal agents, as well as drugs targeted at newly discovered pa/ho-physiologic mechanisms, have detrimental effects on the digestive and nutrient absorptive function of the gastro-intestinal tract. Several groups are considered:
1. Anti-motility agents (opiates, Lomotil, Loperamide) increase duration of secretion of fluid, prolong passage of pathogens, increase fever and related catabolism, and may decrease absorption of nutrients through stasis and puddling in the gut. Traditional wisdom notwithstanding, there is no evidence for an inverse relationship of gut transit time and nutrient absorption in acute diarrhoea. Antimotility agents should not be used, except for control of severe cramps and tenesmus in children above infant ages.
2. Adsorbents (kaolin, charcoal) have no demonstrated effect on either duration or severity of diarrhoea. While not apparently harmful, they detract from more important therapy and should be avoided.
3. Anti-secretory agents (chlorpromazine, indomethacin, aspirin) work pharmacologically on the various cellular mechanisms responsible for secretion in toxin-produced diarrhoeas. While they can, in certain circumstances, reduce the volume of stool, the effect can be obtained with proper choice of antibiotics (see below), and possible side-effects make their use contra-indicated
4. Membrane-stabilizing agents (quinicrine, steroids) are potential drugs to prevent the permeability effects of toxins. There are insufficient data to suggest their use, which would also require a thorough review of potential side-effects and nutritional effects.
5. Traditional diarrhoea treatment preparations (astringents, herbal teas, etc.). While useful effects of the myriad agents used to treat diarrhoea in traditional cultures around the world are possible, no careful study has been performed demonstrating efficacy. Because diarrhoea is so often a brief and self-limited illness, numerous cures have been used and accepted, ranging from exotic concoctions to injected amino glycosides. None are of proven value-many could be harmful.
6. Anti-microbial agents (sulpha drugs, antibiotics). Although long viewed as a digestive malady largely related to "improper food ingestion," diarrhoea is now clearly recognized as a symptom of infection in a vast majority of cases. This has led to varying use of anti-microbials, from universal treatment for all cases to proscription of consideration of antibiotics for even the most severe cases of dysentery. It is no surprise that current consensus falls in a middle ground:
- Acute diarrhoea of known and documented aetiology should be treated with antibiotics proven appropriate for the illness. Guidelines are given by the World Health Organization for the common bacterial pathogens (cholera, Campylobacter, Shigella, Salmonella). Note that even among these recognized pathogens there are indications and reasons not to treat with antibiotics.
- For the physician faced with a clinical decision, the most useful indicator in favour of antibiotic use is bloody dysentery, especially when accompanied by a fever. Unfortunately, the frequent and varying patterns of resistance seen in Shigella necessitate an up-to-date knowledge of the sensitivity of organisms prevalent at the time in the affected community. Short, high-dose therapy is not effective; a desired course should last over five days. Greater degrees of malnutrition, a more ill-appearing child, and longer duration of diarrhoea are considered increasing indications for use of antibiotics, but the use of multiple agents or changing of antibiotics in brief succession is harmful and may lead to development of chronic, intractable diarrhoea of infancy.
- There is no role for prophylactic antibiotics to prevent diarrhoea, with the possible single exception of doxycycline for brief visits to tropical areas. Development of resistant strains, overgrowth of unusual microbes or fungi, and even chronic diarrhoea can result.
CONCLUSIONS
Management of acute diarrhoea involves replacement by mouth of lost fluid electrolytes, continued breast-milk feeding, and rapid and full reintroduction of the full diet. It should be understood that, while ORT will not necessarily reduce the volume of diarrhoea (it may and will frequently increase for a brief period as hydration is restored), it will prevent dehydration, restore normal fluid electrolyte balance, and improve appetite. Feeding contributes both to early cessation of diarrhoea and to minimizing the detrimental impact of the illness on nutrition.
During convalescence, the days immediately following illness, great attention should be given to increased dietary intake through higher calorie foods and greater frequency of feeding to achieve an additional food intake roughly equivalent to the food not eaten during illness. Catch-up growth to pre-illness levels should be achieved within three to four times the duration of illness.
While antibiotics are indicated in cases of dysentery and certain other diarrhoeas with clear bacterial aetiologies, their indiscriminate use can be harmful. Indeed, the typical history of a child with intractable diarrhoea of infancy, an often fatal chronic disease, includes cessation of breast-feeding, indiscriminate use of multiple antibiotics, and intermittent or prolonged periods of fasting in response to an initial acute diarrhoeal episode. While chronic diarrhoea presents a difficult clinical management problem for which clear therapeutic guidelines are lacking, an effective treatment of acute diarrhoea, as outlined in this report, is an important means to avoid the emergence of chronic cases.
REFERENCES
1. A.M. Molla, Ayesha Molla, S.A. Sarker, and M.M. Rahaman, "Food Intake during and after Recovery from Diarrhea in Children," in L.C. Chen and N.S. Scrimshaw, eds., Diarrhea and Malnutrition: Interactions, Mechanisms, and Interventions (Plenum Publishing Corporation, New York, forthcoming).
2. R. Martorell and C. Yarbrough, "The Energy Cost of Diarrheal Diseases in Children," in Chen and Scrimshaw, ads., Diarrhea and Malnutrition.
Trace elements and immunity: A synopsis of current knowledge
R.K. Chandra
Department of Pediatrics, Memorial University of Newfoundland
Janeway Child Health Centre, St. John's, Newfoundland, Canada
Early studies on the interaction between nutrition and immunity focused on protein-energy malnutrition. it haa been demonstrated that children with kwashiorkor and marasmus show profound alterations in immunocompetence. Clinical malnutrition, however, is a composite of deficiencies of proteins, energy, vitamins, minerals, and trace elements. Thus it is of both fundamental and practical importance that the role of various individual nutrients in immune regulation be carefully investigated. Recent data point to the significant physiological role of many trace elements in the development, maturation, and sustenance of the morphologic integrity and function of the Iymphoid organs concerned with immunity. This selective review will summarize the salient effects of trace element deficiencies and excesses on immune response and resistance to disease. The subject is discussed at length elsewhere (1-9); the links between iron, immunity, and infection were described in an earlier paper in the Bulletin, which also discussed the network of immunity and host resistance mechanisms (10).
Nutrients required by the body in amounts of less than a few milligrams per day are commonly and collectively referred to as trace elements. They form a heterogeneous group of minerals and metals that currently includes arsenic, iron, manganese, molybdenum, nickel, selenium, silicon, tin, vanadium, and zinc. It is felt that this list will require periodic revision and extension. Their essential role in the nutrition of many animal species is fairly adequately documented, but human needs are less well defined. The physiologic role of several trace elements as catalysts of critical enzyme-mediated biochemical metabolic reactions is recognized, particularly in animals. They are intimately associated with deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), and with cell membranes. The absorption, transfer, and distribution of many trace elements are largely dependent on specific binding and transport proteins. Thus it is not surprising that changes in the concentration of trace elements exert profound effects on immune responses.
Zinc
The ubiquitousness of zinc in food, water, and other sources makes it surprising that this trace element can be deficient in man. Human zinc deficiency was first observed and described among young individuals living in the rural areas of the Middle East. It was associated with growth failure, anaemia, and hypogonadism. Many children with protein-calorie malnutrition show biochemical evidence of zinc depletion and the provision of zinc supplements promotes weight gain and clinical recovery. In industrialized countries, hypozincaemia has been found in some formula-fed infants. In hospitalized patients with chronic systemic diseases, e.g., inflammatory bowel disorders, cancer, major bowel surgery, etc., especially those on total parenteral nutrition, low serum zinc is associated with characteristic skin rash and delayed wound healing. The inherited zinc malabsorption syndrome acrodermatitis enteropathica is characterized by severe mucocutaneous lesions, gastro-intestinal malfunction, and marked susceptibility to infections, particularly with fungi. It responds dramatically to oral zinc supplementation.
The link between zinc and immunity is best illustrated by observations on the A-46 mutant of Holstein-Friesian cattle. These animals are unable to absorb zinc normally and are stunted, lethargic, and prone to infections that often prove fatal. The thymus is small, associated with defective cellmediated immunity. The clinical and immunologic abnormalities are reversed by zinc therapy. Similar observations have been made in the human counterpart of the cattle disorder, acrodermatitis enteropathica. Infants with this condition show impaired cell-mediated immunity and neutrophil chemotaxis. Zinc supplements result in a complete cure. The similarities between clinical and pathological features of protein-energy malnutrition and zinc deficiency are striking. Malnourished children have a small thymus, which increases in size following zinc supplementation. Even local cutaneous application of zinc improves delayed hypersensitivity skin responses. Recent studies indicate that feeding of sufficient zinc is associated with clinical and immunologic improvement in some other disease states as well, although results of controlled trials are still not available.
Many recent studies have documented the crucial role of zinc in immunocompetence. This may largely be due to the essentiality of zinc in over 60 metallo-enzymes, particularly those necessary to the synthesis of DNA and RNA, namely, thymidine kinase, DNA polymerase, and DNA-dependent RNA polymerase. Zinc deficiency will severely limit rapid cell division and growth, processes essential for optimal immune responses. Zinc-deprived laboratory animals have a small hypoplastic thymus and profound deficits in T-cell number and function. The number of mononuclear cells in the thymus and spleen is decreased. Morphologically, the T-cell areas of the tissues are most severely affected. Antibody-forming cell response to both in vitro and in vivo challenge with thymus-dependent antigens, e.g., sheep red blood cells, is reduced, especially the secondary response, which requires the assistance of helper T lymphocytes. The ability of spleen cells to kill tumour cells in vitro deteriorates, mainly when initial sensitization is carried out in vivo. Mitogen responses are depressed. Clearly, zinc exerts profound effects on the maturation and function of immunocompetent cells. Further support for this explanation is provided by the marked reduction in levels of thymic hormone in zinc-deprived animals. Data on changes in lymphocyte subsets are not available. Zinc may also potentiate fever and temperature-dependent host defences.
Very little attention has been given to the effects of excess zinc on leucocyte function. Experimental data suggest that high concentrations of zinc impair phagocytosis and metabolic function of neutrophils. The T-lymphocyte function may also be reduced in individuals ingesting excessively large quantities (> 100 mg per day) of zinc in their diet.
Selenium
The importance of selenium in poultry and ruminant nutrition is accepted. This is evidenced by the occurrence in these species of pathologic disorders that respond to selenium supplementation. In man, the essentiality of selenium has been suggested on the basis of two case reports. In the first, a New Zealand patient receiving total parenteral nutrition developed severe muscular spasm that was relieved by the administration of selenomethionine. In the second, a man receiving long-term parenteral nutrition showed clinical, radiologic, and electrocardio-graphic evidence of cardiomyopathy, which was further supported by cardiac blood-pool scan and finally by autopsy findings. These features were associated with reduced concentrations of selenium and glutathione peroxidase, a selenium-dependent enzyme, in erythrocytes and heart. Epidemiologic data on Keshan disease, a serious, commonly fatal cardiomyopathy syndrome in Chinese children consuming foods with low selenium content, also suggest the importance of selenium in normal human nutrition.
There are very few studies relating selenium status to immunocompetence. Animals given diets deficient in selenium show impaired T dependent humoral responses. On the other hand, the addition of moderate amounts of selenium to the diet enhances spleen plaque-forming cell response and serum antibody titre. Both primary and secondary responses are stimulated. The immunosuppressive effect of methylmercury is partly overcome by simultaneous administration of selenium. The metal potentiates the protective effects of a killed Plasmodium berghei vaccine in mice. In many of these effects, selenium may be acting in concert with vitamin E.
Copper
Copper deficiency in laboratory animals impairs Iymphocyte response to mitogens and enhances susceptibility to infection with Salmonella typhimurium. The metal improves phagocytosis and oxidative metabolism of granulocytes. Human copper deficiency is extremely rare and there is no information on the immunity status of copper-deficient individuals.
Magnesium
Magnesium deficiency frequently complicates diarrhoeal disease, particularly in infants and children with protein-energy malnutrition. There are no data on the immunocompetence of human subjects manifesting magnesium deficiency. On the other hand, rats and other laboratory animals deprived of magnesium show significant changes in immune responses. Immunoglobulin levels are reduced and antibody response is generally decreased. Susceptibility to parasites is increased. Interestingly, chronic magnesium deficiency is associated with thymic hyperplasia. Leucocytosis involves all white cell types. Lymphoid hyperplasia may be followed by malignant transformation of leucocytes resulting in the development of spontaneous malignant Iymphomas and myelogenous leukaemia. The tumour cells can be easily transferred and transplanted to other magnesium-deficient rats. Careful immunological studies of patients with magnesium deficiency are clearly indicated.
Iodine
Halogens are of critical importance in the bactericidal capacity of polymorphonuclear leucocytes, particularly the myeloperoxidase system. In protein-energy malnutrition, both iodination and intracellular microbial killing are deficient. In iodine-deficient hypothyroid subjects, phagocyte dysfunction has been documented. This was reversed on administration of triiodothyronine and correction of the hypothyroid state. On the other hand, large doses of iodine depress antibody response, reduce phagocytosis, and impair mitogen stimulation response of lymphocytes.
Lead
The results of many studies in several animal species suggest that lead exerts adverse effects on the resistance of the body to infectious disease. Exposure to lead increases susceptibility to endotoxicosis, gram-negative bacterial disease, viruses, and parasites. These effects are possibly mediated through changes in the reticuloendothelial system. In addition, suppression of phagocytic activity of neutrophils, mitogen stimulation response of T cells, complement activity, and certain non-specific defences have been observed in leadtreated animals. Both primary and secondary antibody responses are decreased. Lead also interferes with complement receptors on B Iymphocytes. Although delayed type hypersensitivity is impaired by lead administration, mixed lymphocyte culture response is unchanged. The clearance of bacteria from lungs is impaired. In part as a result of these immunological alterations, lead-treated animals show an increased susceptibility to develop infections as well as viral and chemically induced tumours, It would be important to look at the immunocompetence of children chronically exposed to environmental lead.
Mercury
Both inorganic and organic mercury increase susceptibility of laboratory animals to viruses. Primary antibody response is affected to a greater extent than secondary response. Mitogen stimulation of Iymphocytes is inhibited. However, there is little effect on phagocytic function or mixed lymphocyte reaction.
Cadmium
The effects of cadmium on the immune system are inconsistent and controversial. Part of the discrepancies between the results of various studies can be explained by differences in dose, length of exposure, species, type of microbial challenge, etc. In general, chronic administration of cadmium decreases antibody response and interferes with complement receptors on B Iymphocytes. Macrophage function is impaired. Data on T-cell responses are variable. Mitogen responses may be decreased, normal, or even enhanced, whereas cell-mediated cytotoxicity in vitro is increased by exposure to cadmium.
Other Trace Elements
Arsenic increases susceptibility to infectious disease, possibly by inhibiting antibody production. Cell-mediated immunity is generally preserved. Cobalt in large amounts also increases infection-related mortality. Silica depresses Tcell mitogen response and antibody production. The phagocytic and intracellular bactericidal capacity of phagocytes is decreased, possibly as a result of disruption of Iysosomes. Large doses of nickel and chromium also suppress immune responses. There are no data on the effects of chronic exposure to an environment heavily contaminated with these metals or accidental poisoning on the immunocompetence of man.
REFERENCES
1. R.K. Chandra and P.M. Newberne, Nutrition, Immunity and Infection: Mechanisms of Interactions (Plenum, New York, 1977).
2. R.K. Chandra, Immunology of Nutritional Disorders [Arnold, London, 1980).
3. R.L. Gross and P.M. Newberne, "Role of Nutrition in Immunologic Function," Physiol. Rev., 60:188-302 (1980).
4. L.D. Koller, "Immunotoxicology of Heavy Metals," Int. J. Immunopharmacol., 2:269-279 (1980).
5. R.K. Chandra, "Acrodermatitis Enteropathica: Zinc Levels and Cell-Mediated immunity," Pediatrics, 66:789-791 (1980)
6. W.R. Beisel, R. Edelman, K. Nauss, and R.M. Suskind, "Single Nutrient Effects on Immunologic Function," J. Am. Med. Ass., 245:53-58 (1981).
7. R.A. Good, "Nutrition and Immunity," J. Clin. Immunol., 1:3-11 (1981).
8. R.K. Chandra, Immunodeficiency Disorders (Churchill Livingstone, Edinburgh, 1981).
9. R.K. Chandra, Trace Elements and Immune Response (Wiley, New York, forthcoming).
10. R.K. Chandra, "Iron, Immunity, and Infection: Is There a Causal Link?" Food and Nutrition Bulletin, 3 (no. 3): 49 (1981).