Parasitic Infections and Nutrition*

Parasitic Infections and Nutrition*

Parasitic Infections and Nutrition* BY DEAN A. SMITH Department of Physiology, Kitchener School of Medicine, University College of Khartoum, Anglo-Egy...

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Parasitic Infections and Nutrition* BY DEAN A. SMITH Department of Physiology, Kitchener School of Medicine, University College of Khartoum, Anglo-Egyptian Sudan, Africa CONTENTS

Page I. Introduction. . . . . . . . . ....... ..................... 239 11. The Effects of Parasitic Infestation on the Nutritional Status of the Host . 242 1. Appropriation of Nutrients ................................. 244 a. From the Host’s Food.. ............ . . . . . . . . . 244 b. From the Host’s Tissues.. . . . . . . . . . . . . . . . . . . . . 245 2. Impairment of Appetite and Food 3. Disturbance of Intestinal Function 4. Disturbance of the Host’s Metabolism ..................... 248 5. Establishment of Immunity or Res 111. The Effects of the Diet and Nutritional Status of the Host upon the Parasite 251 1. The Diet of the Host and the Survival of the Parasite. . . . . . . . .

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aria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. The Host’s Nutritional Status and His Immunity or Parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Effects of the Nutrition of the Host on Disease Caused b ... . . . . . . . . 257 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I. INTRODUCTION

It has frequently been written and taught that malnutrition and parasitic infestation are, as it were, synergistic in producing ill-health; that, on the one hand, malnutrition decreases the resistance of the host to invasion by parasites and t o their survival in his body and, on the other, that parasites cause or precipitate malnutrition in their host by depriving him of nutrients or by impairing in some way his utilization of them. On this basis and carrying the argument a step further, it has been assumed that where infestation and primary, dietary malnutrition coexist in an individual or in a community a vicious circle may be set up whereby malnutrition tends to favor increased parasitization and parasitization increases malnutrition. That many peoples of the underdeveloped areas of the tropics are caught up in this vicious circle has been suggested by workers in several parts of the world.

* In this chapter the term “infection“ is limited to infestations by protozoal and helminthic parasites. The Editors. 239

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This concept of the mutually adjuvant effects of malnutrition and infestation seems so eminently reasonable and logical, and the common coexistence of poor nutritional status with a high incidence of such diseases as malaria, ancylostomiasis, and schistosomiasis seems to offer such obvious prima facie evidence for its truth, that it is perhaps not surprising that the detailed evidence on which it is based has not often been critically evaluated. It is the purpose of this paper to attempt to assess, without any iconoclastic intent, whether the evidence for these and similar assertions justifies the confidence with which they have been made, and to determine how far it is possible a t present to formulate any broad generalizations about this aspect of host-parasite relationships. Primarily this review is concerned with human nutrition and the infestation of human subjects; to consider animal nutrition per se would be to enter a field far too wide for adequate treatment in the space available. But in some aspects of the human problems, the evidence is scanty. Animal observations are included only when it is reasonable to assume that they reflect, at least t o some extent, the events of human metabolism. Similarly the use of the word “infestation” is limited t o infestation by protozoal and helminthic parasites, though it is impossible to exclude all consideration of bacterial infection as, by analogy and inference, the latter is, in some contexts, of considerable relevance. The bibliography attached to this paper is intended to be representative: it is certainly not comprehensive. I n only few instances is more than one authority quoted for any statement. The choice of references may sometimes seem arbitrary. I n general the writer has chosen illustrations because they seem particularly typical or in some cases because they record work of which he has some personal knowledge. Like every other writer of a review article, he is greatly indebted to his predecessors. As one concerned mainly with human physiology and nutrition, the present writer is particularly grateful to Dr. G. C. Hunter, of the Rowett Research Institute, whose excellent review (1953) provides a lucid guide in a wide field of veterinary literature. It has been said that in some aspects of the relationships between parasites and their human hosts the evidence is scanty. It may be of some value to consider briefly why this is so. It might be that the mutual effects of parasite and host upon one another are so obvious as hardly to require detailed investigation. Such a suggestion has been made in a preceding paragraph. But there are other equally plausible suggestions that are not supported by such evidence as exists. For instance it might be assumed that if a host were well fed, even excessively fed, both he and his parasites would prosper, enough nutrients being available for all, But this does not in general appear to

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be the case. It will be seen later that, except in the case of a few individual nutrients, the better the host’s diet, the poorer is the state of the parasites. Conversely, again with a few special exceptions, it is the host with the poor diet and in a state of low nutritional health who harbors the most prosperous parasites. It does not seem that the evidence is scanty because the questions answer themselves. The fact is that nutrition and infestation in human subjects present problems that are very difficult to investigate. So difficult that both nutritionists and parasitologists have generally attempted to solve their practical problems by attacking the parasites either by chemotherapy or in a stage of their life cycle outside their human hosts. The difficulties of investigating these interrelationships are in the main two :firstly, we know very little about the metabolism or nutritional requirements of parasites, and, secondly, it is often almost impossible, especially in human subjects, t o separate nutrition from among a mass of other environmental influences which may have a bearing on hostparasite balance. The complexities of the former have been admirably set out in a recent review by Hunter (1953) as far as the helminthic parasites of farm and laboratory animals are concerned. Hunter poses as his first question “What are the nutritional requirements of the parasite and how are they satisfied?” and concludes that present knowledge can provide very few direct answers. Direct observation of the parasites in vivo even when infesting laboratory animals is, owing to the inaccessibility of their habitat, difficult. How much more difficult is it in human hosts? In vitro studies, which might provide much information, have so far failed to do so. I n fact no helminth infesting a mammalian host has yet been successfully cultivated in an artificial medium. Only two helminthic parasites of vertebrates have been so cultured, and these tapeworms of fish-eating birds have provided disappointingly little information, as they appear to live, in culture, mainly upon reserves built up during larval stages (Joyeux and Baer, 1942; Smyth, 1946). We can therefore rely only on inferences from observations on the effects of changes in the host’s diet upon the helminth, to form the beginnings of a picture of the parasite’s nutritional requirements (Section 111, 1, below). The second difficulty is greater in. assessing observations on human than on animal subjects. In the latter case it is often possible to provide adequate, otherwise comparable, parasite-free controls and t o eliminate or compensate for many environmental variables. This is seldom possible in observations upon human communities and leads t o great difficulty in the interpretation of findings. A worker may, for instance, find two racially similar groups, or two sections of the same group, one of which

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has a high average infestation rate with some parasite and the other a low rate. He carries out a survey designed to assess the nutritional status, in clinical or laboratory terms, of the two groups and finds, perhaps, as many workers have in fact found, that the less infested group appears to be better nourished than the more heavily infested group. But in the process he is very likely to find that it is not only in their nutritional status and parasite load that the two groups differ. He may find differences in social status, wealth or custom, in work or feeding habits, in educational level and standard of hygiene, or in the incidence of some other, apparently unrelated disease. Qualitative or quantitative differences in diet have an obvious bearing on the problem, but the complications do not end there. Even differences in dress may substantially influence exposure to insect-borne parasitic diseases, and the habit of wearing shoes is of importance in assessing extent of exposure to hookworm infestation. In the rare event of a field investigator feeling that he can adequately eliminate or allow for all such differences, he still has a problem in the interpretation of his findings. Which is cause and which effect? Are the poorly nourished more heavily infested because of their poor diet, or does the infestation cause the ill-nourishment? The worker may well find some indication suggesting which of these is true, but there is a third possibility, the vicious circle referred to in the opening paragraph, in which each condition favors the other. The adoption of this solution may seem academically satisfying, but as a guide in planning practical measures for improvement it may be found only to have substituted for the problem of the “cart and the horse” the equally familiar (and insoluble) problem of the “hen and the egg.”

11. THE EFFECTSOF PARASITIC INFESTATION ON THE NUTRITIONAL STATUSOF THE HOST The adverse effects of parasites upon their hosts are sufficiently obvious when they produce specific, general disease or localized tissue reaction. Malaria, trypanosomiasis, and various filariases are examples, and it is not clear that, in their acute phases, they affect the nutrition of the host in any way, and we are not concerned here with this aspect of their effects. Nor need we be concerned with the fact that these diseases produce, in their terminal stages, a condition of cachexia which, though it might strictly be regarded as an effect on nutrition, appears to differ in no way from the terminal cachexia of any other “wasting” disease. Most infestations, whether of a type that does not produce specific disease, or of a weight insufficient to do so, do produce adverse effects on their hosts, many of which can be related directly or indirectly to

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nutrition. The most common effect is loss of weight in the adult host or failure of development in the young. This strongly suggests that the parasites are, directly or indirectly, depriving the host of his nutrients and might be expected to be most apparent when the size of the parasite, or of the aggregate of parasites, is relatively large compared with that of the host. Iri fact, in intestinal helminthiasis in both man and animals, loss of weight is almost universal if the infestation is heavy enough (Hunter, 1953). The evidence that heavy infestation with relatively large parasites causes loss of weight is so abundant that it scarcely needs detailed exposition here. More than 20 years ago Clayton Lane (1932) presented a mass of evidence of the effect of heavy infection with Ancylostoma duodenale and Necator americanus upon the weight, strength, stamina, and performance of his adult human subjects and noted equally the growth retardation, both physical and mental, which such infection caused in children. He further recorded the weight gains and general improvements in physical well-being and performance that resulted from eradication or even substantial reduction of the hookworm load. This has all been universally accepted for many years and has formed the basis of many hookworm campaigns. A similar effect in domestic animals has repeatedly been demonstrated, never more clearly than by Laurence et al. (1951), who infested lambs with larvae of sheep hookworm. Groups of lambs, both infested and uninfested controls, were maintained on both high and low levels of nutrition, and in each case the retardation in growth and poor final growth achievement of the infested as compared with the control animals was most striking. It seems reasonable to suppose that the adverse effect will be greatest when the disparity in weight between the host and his parasites is least, as in the case of infants, and Jelliffe (1951) has pointed out that heavy ascariasis may be a major contributory cause of nutritional deficiency syndromes of the kwashiorkor type in West African babies. Loss of weight and its concomitants, loss of strength, performance, and growth, are not the only effects of parasites on their hosts that can be related to nutrition. At least two parasites cause anemia of a characteristic kind. Hookworms, both in men and some animals, cause a microcytic, hypochromic anemia of the “iron-deficiency ” type: the tapeworm Diphyllobothrium latum causes in man a macrocytic, megaloblastic anemia. The plasmodia of malaria are probably the most widespread parasites that cause anemia, but it is very doubtful if this type of anemia can be regarded as nutritional. There is also some evidence suggesting that some infestations may at least contribute to the production of vitamin deficiencies.

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Of all parasites only those helminths which remain in the intestinal tract have a chance to deprive their host of nutrients directly, that is, before the host absorbs them. And the evidence suggests that even these helminths get most of their nutrients from the host’s tissues or fluids. For reasons outlined above, research in this field is a t present very difficult, and how most helminths satisfy their food requirements is still obscure, but the observations of such workers as Chandler et al. (1950) suggest that they derive only small amounts or limited categories of food from the host’s intestinal contents. (Here perhaps the reservation of species difference may be reiterated : the very difficulty of establishing a species in a foreign host emphasizes the high specificity of these parasites and the relationship between, say, Hymenolepis diminuta, on which Chandler worked, and its rat host may be quite unlike that existing between Taenia saginata and man.) So it is appropriate a t this point to consider how parasites can affect the nutrition of their host, and how far we have any evidence that they do so by these means. 1. Appropriation of nutrients a. from the host’s food, b. from the host’s tissues. 2. Impairment of appetite and hence of food intake. 3. Disturbance of intestinal function in the host, causing impairment of digestion or absorption. 4. Disturbance of metabolism in the host, causing impairment of utilization. 5. Establishment and maintenance of immunity or resistance in the host to the parasite, requiring diversion of nutrients from the normal metabolic channels.

It has also been suggested that parasites may impair their host’s nutrition by acting as a “stress factor.” This somewhat vague concept the writer understands to mean “an additional burden that the host has to cope with somehow, and it costs him nutrients to do so.” Just how it costs nutrients will one day be discovered; for the moment it seems preferable to admit ignorance than to disguise it by using the already overworked word “stress,” which has a quite definite connotation in other contexts. 1. Appropriation of Nutrients a. From the Host’s Food. The megaloblastic anemia associated with infestation by Diphyllobothrium latum was for many years a curiosity and a mystery. It now seems to provide the best-authenticated example

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of a helminth which competes successfully with its host for a nutrient essential t o both. The worm has a voracious appetite for vitamin Blz and assimilates considerable quantities of what is available in the host’s gut (von Bonsdorff and Gordin, 1952), the host is depleted and develops anemia of an Addisonian type, which can be corrected by administration of vitamin Blz parenterally or by Blz plus gastric juice given orally. Moreover the worm has been found t o contain relatively huge amounts of the vitamin, and preparations of dried Diphyllobothrium latum are at least partially curative in patients with macrocytic anemia. This is the only parasite known t o the writer that can be convicted, on apparently sufficient evidence, of pilfering an unabsorbed nutrient from its host t o the extent of depleting him of it. Short of host depletion, the phenomenon may well be common, and is quite likely to be the normal means of livelihood of such apparently free-living inhabitants of the intestinal tract as the numerous flagellates, though they, together with such helminths as Trichuris trichiura and Oxyuris vermicularis, can hardly be said to compete with their host, as they normally inhabit the large intestine, well below the main nutrient-absorbing area in the jejunum and ileum. In this connection the work of Frazer (1949) is of interest and possible importance. As a result of a long series of studies of intestinal function in such conditions as sprue, he and his colleagues in Birmingham have shown that when conditions in the small intestine are changed by disease processes, there may be invasion of the main absorbing area of the small intestine by bacteria which normally live only in the colon. In their normal habitat these bacteria synthesize the greater part of their vitamin requirement. Vitamins so synthesized are sometimes, a t least in part, available to the host, when released from the dead bodies of the bacteria (Najjar and Holt, 1943). Frazer concludes that these bacteria will not synthesize nutrients when the nutrients are present in the medium in which they are living, and thus when they invade the small intestine they compete with their host for vitamins in his food. The further they penetrate up the small bowel the more successfully do they compete, as the less mucosal area remains through which unopposed absorption by the host can take place. This “new mechanism of vitamin deprivation,” t o use Frazer’s own words, has so far been considered only in relation to bacteria, but it is not inconceivable that it might equally apply to some larger parasites dwelling free in the intestinal tract. b. From the Host’s Tissues. The host’s tissues and body fluids appear t o be the source whence most parasites derive their nutrients-certainly all tissue parasites and most intestinal ones. In heavy infestations by parasites of substantial physical magnitude the deleterious effect upon

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the host is obvious, generally accepted, and need not be detailed here. Moreover the deleterious effects are generally similar to those of dietary depletion and may therefore be regarded as effects on the nutritional status of the host. Yet few investigations have been made into the full range of nutrients involved, and detailed information except about individual factors is scanty. Hookworm infestation offers the best example. The anemia associated with this condition is universally recognized, and much work has been done on its hematology and on the metabolism of iron generally. But anemia is not the only consequence of a heavy hookworm load; mention has already been made of the loss of weight, strength, and performance of infected adults and the stunted growth of infected children (Lane, 1932). To produce these effects the hookworms must be removing from the host’s system far more nutrients than just iron. Large amounts of protein, and probably other minerals, must also be involved, being either consumed or wasted by the parasite. That the microcytic, hypochromic anemia of ancylostomiasis is primarily an iron-deficiency anemia is now surely beyond dispute. It differs in no way from the anemia produced by dietary iron depletion or repeated hemorrhage and can be largely cured, and rendered completely orthochromic, by the administration of additional iron without removal of the parasites (Lehmann, 1949a). Many attempts have been made to calculate the actual blood loss occasioned by each worm, and the results have mostly been of the order of 0.5 ml. per day. An early estimate was that of Wells (1931) whose average figure was 0.84 ml. of blood per day consumed or wasted by a single female A . caninum. Recently Lehmann (1949a) arrived a t a figure of 0.3 ml. for A . duodenale and noted that in other cases similar calculations indicated losses of “very much more” blood by the host. All writers have emphasized that by no means all this blood is actually utilized by the parasites; some is passed unchanged through the intestine of the parasite and still more is lost to the host by oozing from abandoned bites. As it is clear that little, if any, of the iron in the hemoglobin is reabsorbed, the actual blood loss is commensurate with the degree of iron-deficiency anemia. But the same is not necessarily true of other blood constituents. If we were certain that none of the plasma protein or of the globin fraction of the hemoglobin is digested and reabsorbed, the loss of protein would be great enough to account, in severe infestations, for the loss of tissue or failure of growth. But a t present this is not clear. It is impossible t o imagine that other parasites, both intestinal and tissue, do not similarly deprive their hosts of nutrients, but in most cases the size and consequently the needs of the parasite are so relatively

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small that the status of the host is unaffected except when his intake is already marginal in respect of one or more nutrients. I n the latter case it is probable that parasitization may be the determining factor in the appearance of clinically recognizable stigmata of deficiency. 2. Impairment of Appetite and Food Intake

The presence of parasites certainly impairs appetite, and hence diminishes food intake, under some conditions. Anorexia is characteristic of the clinical picture of recurrent malaria and even more so of trypanosomiasis. Patients suffering from these conditions waste, often quite rapidly, and diminished intake is undoubtedly a factor in the causation of this loss of weight. Intestinal parasites may also cause anorexia. Laurence et al. (1951) showed that lambs infested with Oesophagostomum and Haemonchus ate less than uninfested lambs of the same age and the same original average weight. Lehmann and Kayser (1949) found dysfunction of the stomach, associated with anorexia, common in Indian soldiers heavily infested with helminths. But it has not been suggested that this loss of appetite so often associated with parasitization is the major or only cause of the host's loss of condition. 3. Disturbance of Intestinal Function in the Host

On the other hand, disturbance of digestion and absorption in the intestinal tract probably is a major cause of impairment of nutritional health in the host, both general and possibly with regard to specific nutrients. Helminths are likely, at least periodically, to cause irritation and inflammation. Intestinal hurry and diarrhea not only leave less time for the absorption of nutrients but may also partly remove or disturb the intestinal bacterial flora whose biosynthesis of vitamins is of benefit to the'host. Smith and Woodruff (1951) recorded that more than half their cases of dysentery among prisoners of war developed beriberi. This was, of course, an effect of bacterial invasion, but it is reasonable to suppose that helminths may interfere with absorption of nutrients in a similar nonspecific manner. Fairly numerous balance studies in farm and laboratory animals have given results suggesting that animals infested with intestinal helminths derive less value from their dietary intake than do uninfested ones. These have been admirably reviewed by Hunter (1953). Most of the studies have related mainly to protein and have shown that protein utilization increases as egg-count (or other index of weight of parasitic infestation) decreases (Stewart, 1933; Rogers, 1941, 1942). Some workers have found

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a similar effect in relation to calcium and phosphorus metabolism (Shearer and Stewart, 1933). Very few investigations of this kind upon human subjects have been reported. Bray (1953) was unable to demonstrate consistent changes in nitrogen balance after anthelmintic treatment of chronically malnourished Gambian boys infested with Ancylostoma duodenale and Ascaris lumbricoides. But Venkatachalam and Patwardhan (1953), working at Coonoor in Southern India, obtained results which conflict with those of Bray. These workers investigated nine children who had heavy A . lumbricoides infections and were kept in a hospital on a very carefully controlled protein intake. Fecal nitrogen excretion was measured over periods of several days before and after what was apparently an effective deworming, and a fall from an average of 1.3 g. per 24 hours to 0.7 g. per 24 hours was found-a difference which is considered highly significant ( p = less than 0.01). Further investigations enabled these workers to reject the possibilities that the change in fecal nitrogen was due to the effect of the anthelmintics themselves, to the removal of ascaris ova from the stools, or to the effects of intestinal hurry. They favor the view that A . lumbricoides (and other intestinal parasites), to protect itself from digestion, secretes an antienzyme capable of inactivating trypsin and possibly other proteolytic enzymes and thus interferes with its host’s digestive processes. This idea that intestinal helminths secrete substances antagonistic to proteolytic enzymes is not new but was put forward a t least 20 years ago (Stewart, 1933). Substances having such activity have been separated from extracts of the bodies of nematodes and cestodes (Bueding, 1949). Hunter (1953) in his review of the subject is cautious in assessing their importance for protein digestion by the host. It seems reasonable t o the present writer to attribute both the disorders of the host’s protein digestion and his inability to digest his helminths to the formation of antienzymes, pending the publication of further evidence on the point.

4. Disturbance of the Host’s Metabolism The presence of parasites in a host’s tissues, blood-cells, bloodstream or liver must to some extent disturb his metabolism. But at present we have no evidence that it does so in a manner that can fairly be described as interfering with his nutrition. Parasites so situated may cause specific disease, but this can hardly be called nutritional : the possible diversion of nutrients from normal metabolic channels in the host’s efforts to deal with his parasites is discussed in the next section. 5. Establishment of Immunity or Resistance

It has been assumed for a long time that hosts can, at least under certain circumstances, develop some form of resistance or immunity t o

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their parasites, and, although the mechanism of this resistance is imperfectly understood, there is considerable evidence, reviewed in a later section (111, 2), that it exists. If we can for the moment assume the development of resistance by the host, it is reasonable also to assume that it costs him something, in terms of nutrients, and that its maintenance may prove a sufficient drain on his resources to cause actual depletion. Although there is no evidence known t o the writer that proves this point, there are observations suggestive of it, of which a fairly typical one may be quoted. The observations of Colbourne et al. (1950) in a Gold Coast village might equally be cited. In the course of a health, nutrition, and parasitological survey in rural West African villages, McGregor and Smith (1952) found some considerable evidence of protein deficiency as judged by clinical standards. The diet of these communities had been exhaustively investigated over a period of three years with results indicating that the protein intake was sufficient to meet the estimated requirements of people of such stature and age-group pattern, although it was mostly derived from vegetable sources (Nutrition Field Working Party, Gambia, 1950). I n calculating the protein requirement, however, no account was taken of the possible influence of parasites, with which there was a heavy infestation rate in the area, malaria being hyperendemic, and filariasis and ancylostomiasis being present in the majority of the population. McGregor and Smith concluded that, quite apart from actual appropriation of nutrients by hookworms, the establishment and maintenance of immunity to malaria might demand the diversion of protein and its constituents from normal metabolic channels in sufficient quantity to cause the signs of protein deficiency that were observed in spite of an apparently adequate dietary protein intake. Observations suggest that the immunity mechanism has a high priority among the systems requiring protein from the common body pool and that its demand may be so insistent and urgent that, though the immunological response may be judged to be adequate, death may ensue from tissue deprivation (Anon., 1950). There may, however, be some physiological stresses that demand withdrawal of protein or other materials from the immunity system. McGregor and Smith observed that although signs and symptoms of clinical malaria were excessively rare in older children and adults, notwithstanding their parasitemia, active febrile malarial recrudescence almost invariably made its appearance during pregnancy, particularly in primigravidae. They surmised that fetal growth was one of the physiological demands that took priority over maintenance of immunity to malaria parasites in the competition for limited supplies of dietary and body protein. Before concluding this section on the effects of the parasites on the host’s nutrition, the dangers of oversimplification and oversystematiza-

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tion must be emphasized. I n nature, nutritional deficiencies are very seldom single; parasitization is often multiple; the effects of the latter upon the former may well be produced by a combination of any or all of the mechanisms discussed. It is possible and necessary for fundamental research to deplete an animal in a laboratory or on an experimental farm of one nutrient only or t o infest it with known numbers of a single parasite. The observed effects are of the greatest interest and significance, but it is important t o remember that their application t o field conditions must be undertaken with the greatest caution, as many variables, known and unknown, complicate the picture. It is quite clear that when heavily parasitized and ill- or marginally nourished subjects are freed of their burden, their nutritional state improves in ways explicable by known or postulated mechanisms, but it may also improve in ways not yet readily explainable. Of this type of complex effect the following example is perhaps worth relating. The survey of a West African village referred t o above (McGregor and Smith, 1952) was a baseline survey undertaken as a preliminary t o an attempt to eradicate the common parasitic diseases without interference with the dietary, agricultural, social, or economic aspects of village life, the object being to achieve as accurate an assessment as possible of the part played by the multiplicity of parasites in producing the illhealth and subnutrition so prevalent in the area. I n the year after the initial survey, vigorous control measures were directed against malaria, filariasis, and trypanosomiasis. Ancylostomiasis could not be attacked a t this stage. The village was resurveyed just a year later. It was found that the total malaria parasite load had been reduced by 50% or more in the age groups of childhood and up t o 80% in adolescence. The total load of microfilariae had been reduced by over 90%, and all persons known t o be carrying trypanosomes had been treated. Re-examination showed that a considerable change in health status had occurred. The mean heights and weights of the children in all age and sex groups below six years were consistently higher than in the previous year, the difference, taking all groups together, reaching a high order of significance ( p = less than 0.001). Hemoglobin levels had risen throughout the population, the mean increase being 17%. There was also noted a substantially reduced incidence of many stigmata of nutritional ill-health. The individual physical signs which decreased in incidence significantly were: folliculosis and dyssebacia of the skin of the face, cheilosis and angular stomatitis, indentation, fissuring and discoloration of the tongue, changes in the papillae of the tongue, and xerosis and crackling” of the skin of the limbs. With the exception of the last two skin manifestations, all these signs are generally attributed t o deficiency ((

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of some member or members of the vitamin B complex, particularly riboflavin, niacin, pyridoxine, and possibly pantothenic acid. The investigation, of which some of the preliminary findings have been outlined, is in essence a long-term one, and the results have not yet been published. One year is clearly far too short a period for any final assessment of results, and the work is still continuing under the direction of McGregor. But it is felt that these preliminary short-term results of a reduction, far short of complete eradication, of tissue and blood parasite load are sufficiently striking to justify mention without offering any explanation of the mechanism by which the changes were brought about (McGregor and Smith, 1954). 111. THEEFFECTS OF THE DIETAND NUTRITIONAL STATUS OF THE HOSTUPON THE PARASITE These effects have to be looked at from three points of view: 1. How the diet of the host influences the establishment and survival of the pLrasite. 2. How the nutritional status of the host affects the parasite’s survival. 3. How the diet and status of the host affect the disease or disorder (if any) produced by the parasite. These aspects are closely interrelated and also related to questions already considered, but it is possible, and desirable for the sake of clarity, to attempt to separate them even at the risk of oversimplification. 1. The Diet of the Host and the Survival of the Parasite

a. General. As has already been said, it might readily be assumed that if the diet of a host contains an abundance of all the nutrients necessary, both he and his parasites would flourish. But this is not the usual state of affairs: the majority of parasites flourish in a malnourished host and maintain only a precarious foothold in a thoroughly well-nourished one, if they succeed in establishing themselves at all. It is difficult, if not impossible, to picture any mechanism by which deficiency in the host’s diet makes nutrients more readily available or more plentiful for the parasite. The explanation must surely be that the power of developing some form of immunity in the host is dependent on his supply of nutrients. This will be considered in the next section. There is, however, a small minority of host-parasite relationships in which deprivation of the host of some nutrient is disadvantageous to the parasite, and in these cases it is assumed, reasonably enough, that the critical nutrient is necessary for the parasite and that if there is not sufficient, or if the parasite competes unsuccessfully with the host for it, the parasite starves. These are really the only cases in which we have any

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direct evidence about the dietary requirements of parasites, and it is with them that we are concerned in this section. The literature contains only one report of a helminthic parasite infesting a human host being apparently favored by improvement in the host’s diet. Looss (1911) noted an increased output of hookworm ova when additions of milk and cheese were made to a purely vegetarian diet. Looss had only one human subject (himself), and his observation has never been confirmed. On the contrary, the vast majority of subsequent investigations of a similar nature have indicated that intestinal helminths generally benefit from lack rather than excess of protein in the host’s diet. In the field of animal experiment Chandler and his associates (1943, 1950) have shown that the establishment and development of tapeworms in rats show a positive correlation with the amount of carbohydrate in the diet. The type of carbohydrate provided made some difference to the growth of the worms (Hymenolepis diminuta), starch being be$ter than sugar, but on the whole there were more and bigger worms when the rats’ diets contained more and better carbohydrate. The same worker (Chandler, 1943) was unable to induce H . diminuta to establish itself in female rats whose diet was entirely free of all B complex vitamins. Lack of calcium and phosphorus has been shown to impair the growth and development of some bird helminths. Ascaridia galli failed to thrive in chicks on a low-calcium and -phosphorus diet, and their number and size increased when the chicks were fed a diet adequately supplied with these minerals (Gaafar and Ackert, 1953). It thus appears that for some helminths infesting some animal hosts there are limiting factors in the host’s diet which control the establishment and development of the parasite. This seems to apply t o carbohydrate for rat tapeworms and to calcium and phosphorus for chick roundworms. Some factor or factors in the B complex vitamins may limit the development of rat tapeworms also. In the cases of almost all other nutrients investigated, host deficiency favors parasite development. There is now a considerable literature about this subject which has been comprehensively and most ably reviewed by Hunter (1953). It would be a waste of space to repeat here more than his conclusions. Deficiency of total calories, protein, vitamin A, thiamine, riboflavin, iron, cobalt, and copper in an animal host’s diet have all, at some time or another, been shown to favor the establishment and development of helminth populations. Hunter concludes that protein and vitamin A are of particular importance in this respect and quotes many reports in support of this conclusion. b. Milk and Malaria. Until very recent years nothing whatever was

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known of the nutritional needs of blood and tissue parasites, and certainly there was no instance reported of host deficiency adversely affecting such a parasite. Many general observations suggested that poorly nourished hosts are more readily parasitized than well-nourished, this difference being attributed to breakdown of some form of host resistance dependent on diet (see p. 255). Certain inferences about parasite metabolism were drawn from the results of chemotherapy. Sulfonamides, for instance, have some antimalarial activity, though not a very powerful one, and as it is known that sulfonamides act as bactericides or bacteriostatics by competitive antagonism to p-aminobenzoic acid (PABA), it was inferred that PABA is an essential nutrient for malaria parasites. Similar reasoning, based on the antimalarial action of such drugs as pyrimethamine, established by inference that folic or folinic acid is necessary for t,he normal development of plasmodia, since the diaminopyrimidines are known to be folic acid antagonists. Although the nutritional requirements for growth of malaria parasites had been investigated by Christophers and Fulton (1938a,b, 1939) and several others, it was not until the end of 1952 that a dietary factor was shown to have a definite suppressive effect on a protozoal infection. Maegraith and his colleagues in the Liverpool School of Tropical Medicine (1952) demonstrated the suppression of blood-transmitted Plasmodium berghei malaria in rats fed on diets of human or cow’s milk only or of cow’s milk to which had been added thiamine, calcium pantothenate, and pyridoxine. The mechanism of this suppression was not a t once apparent; it might be a positive phenomenon due to some antimalarial substance present in the milk or be brought about because milk lacks some substance necessary for growth of the parasite. Maegraith’s observation that a normal laboratory diet plus milk had no suppressive effect made the latter the more probable. The possible relationship of this milk suppression to the commonly observed malarial immunity of young infants was soon apparent (Anon., 1952). Maegraith’s most significant experiments were rapidly extended to other protozoal parasites and other hosts. A substantially similar effect of a milk diet was found in the suppression of P. knowlesi and of P. cynomolgi in monkeys (Maegraith, 1953; Hawking, 1953, 1954) and of Trypanosoma congolense in mice (Keppie, 1953). On the other hand, Refaat and Bray (1953) found that a pure milk diet had no suppressive action against T . rhodesiense in rats, and Maegraith (1953) obtained similar negative results in Babesia canis infection of puppies. Meanwhile several laboratories had given considerable attention to the problem of what nutrient essential for parasite growth is deficient

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in a milk diet. Hawking (1953) pointed out that a pure milk diet is deficient in p-aminobenzoate and showed that when the milk diet fed t o rats is adequately supplemented with p-aminobenzoate, infections of P. berghei develop normally-that is to say, the disease runs a course similar to that in animals fed the stock laboratory diet. He concluded that PABA or some derivative is a growth factor for P. berghei and gave his views of its action in the host so succinctly that they may be quoted verbatim. “According to our conception the body fluids of animals usually contain very little p-aminobeneoate (otherwise sulphonamides would not be therapeutically effective against so many bacteria) ; p-aminobeneoate is present in many diets; when ingested in the food it raises the blood concentration sufficiently for malaria parasites to grow; and it is rapidly excreted or destroyed, so that constant renewal is necessary.” Hawking (1954) has now extended his observations to P . lcnowlesi and P. cynomolgi in monkeys and has shown that in these infections also the protection afforded by a milk diet is reversed by addition of PABA. He also showed that other diets deficient in PABA gave a similar protection against malarial invasion. A further finding by Hawking (1954) was not entirely surprising, though it has disconcerted some workers in the field. He showed that the protection afforded by the milk diet against malaria parasites could be reversed by the addition of folic acid in molar amounts corresponding to the quantity of PABA needed. Although many of the actions of PABA remain obscure or controversial, it is clear, as Hawking points out, that much of it is built up in bacterial cells (and probably other cells) into pteroylglutamic acid, folinic acid, or some similar compound. The application of this work to human malaria is clearly of the first importance, and, as Maegraith pointed out in his original communication, it may provide a solution to the problem of why young babies seldom get malaria. In the hyperendemic malaria areas of the tropics, infants are usually breast-fed for many months, and during the period when this is their only source of nourishment, they might be expected to have a complete immunity to malaria. Feeding practices vary very widely but at some stage, not often earlier than two months and not often later than six or seven months, the pure milk diet is supplemented by some cereal gruel, depending on the local staple. Most grains contain enough PABA to allow plasmodia to develop in the baby, and thus the age at which malarial parasitemia develops may depend on the infant-feeding customs of the region and not, as was formerly supposed, on the duration of some serological immunity, inherited or derived from the mother. So far, however, no observations of this kind on human infants have been

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reported, and though the hypotheses are well supported by Hawking’s experiments on suckling rats and monkeys, they need careful testing in the field before they can be finally accepted. Unforeseen complexities may emerge; biochemical relationships are seldom as simple as they seem at first sight; it does, however, appear safe to say that p-aminobenzoic acid is a key substance in the relationship of malaria parasites to their mammalian hosts. The first reported human experiment was performed in India. Chaudhuri and Chakravarty (1953) in Calcutta have very recently demonstrated that adults can be protected against P. vivax infections by diets consisting of milk only. 2. The Host’s Nutritional Status and His Immunity or Resistance to

Parasites The concept of humoral immunity to bacterial or viral invasion has been universally accepted for decades. Equally, it is stated as a fact in elementary textbooks that the humoral antibodies are y-globulins either naturally present or modified by the action of some antigen. It is further widely recognized that the formation of these antibodies ultimately depends, as does that of other plasma and tissue protein, on an adequate supply of available dietary protein and that in conditions of protein deprivation and hypoproteinemia there may be failure or impairment of antibody synthesis. This latter has been demonstrated in human subjects by Gel1 (1948) and by Wohl et al. (1949)’ and in animals by very many workers. No such immunity mechanism involving an antigen-antibody reaction has been conclusively shown to be directed against invasion of the body by protozoal or helminthic parasites. But there is considerable circumstantial evidence that such a mechanism exists and there are many phenomena of host-parasite relationships that at present cannot be explained in any other way. Indeed the very numerous reports noted in a previous section (111, 1, a) that impoverishment of a host’s diet in respect of one or many nutrients leads frequently to increased prosperity of his parasites are hardly explicable other than in terms of a breakdown of resistance. The evidence that the body reacts defensively to parasites in a way similar to that in which it reacts to bacterial invasion has been reviewed by Culbertson (1941), Taliaferro (1940), and Corkill (1950). Corkill’s review deals entirely with man as a host. Since antibodies active against parasites are presumably proteins, many investigations have been made into the relationships, quantitative and qualitative, between dietary protein and immunity to parasites. An early field enquiry was the now classical nutritional survey of Orr and

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Gilkes (1931) in East Africa, in the course of which it was found th a t the blood- and milk-drinking Masai were much less infested with helminths and less infected with malaria than the relatively vegetarian Kikuyu, the exposure to the parasites and their vectors being considered equal in the two tribes. I n animals it has generally been found that a better resistance to parasites is developed when the dietary protein is mainly of animal rather than of vegetable origin, and when it contains a representative range of amino acids essential to the particular host (Riedel and Ackert, 1950, 1951). An interesting finding was that of Barakat (1949, 1950), who, working with Nippostrongylus muris in rats, found lysine to be a limiting amino acid in the synthesis of antibody globulin, upon which the rat depends for his acquired resistance to this parasite. Looking a t the problem from another viewpoint, Corkill (1950) points out that in a number of diseases such as kala-azar, malaria, trypanosomiasis, and amebic dysentery in which periods of latency exist, there may be breakdown of resistance or disturbance of host-parasite balance leading to relapse or exacerbation in response to a variety of stress conditions. Such stresses are trauma, intercurrent infection, malnutrition, and pregnancy. Corkill puts forward the hypothesis that a n important factor in this lowered resistance is failure of the host to synthesize antibody y-globulin under conditions in which there is excessive breakdown of tissue protein or insufficient intake of dietary essential amino acids. Particularly he incriminates lysine, in which a number of widely used tropical staple cereals are notably deficient. If indeed synthesis of antibody globulin is a main mechanism of resistance against parasites, a high level of plasma globulin might be expected in such infestations. It is certainly a common finding in protozoal diseases, so much so that an inverted albumin-globulin ratio has been regarded as of diagnostic significance in kala-azar and trypanosomiasis. But a high plasma globulin level, with a correspondingly low level of albumin, is a very common finding throughout the poorly nourished (and heavily parasitized) peoples of the tropics (Sic6 and Bonnet, 1936, in French West Africa; Mohun, 1946, in the Gold Coast; Barakat and Smith, 1949, in the Gambia; Symul, 1950, in the Belgian Congo; Stanier, 1953, in Uganda; and many others). This has been interpreted as a n effort on the part of the host to suppress or keep under control a multiplicity of parasites. In hyperendemic malaria areas, for instance, the majority of people over a year or two of age carry malaria parasites but have neither the signs nor symptoms of clinical malaria. Often, as has been noted (McGregor and Smith, 1952; Corkill, 1950) this immunity breaks down under physiological stress. It is a very attractive hypothesis that the high plasma globulin th at these people also commonly carry

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represents the raw material from which they make their antimalarial immune bodies. But it is not the only possible explanation of the high plasma globulin. It might be a racial characteristic, although the work of Symul (1950) makes this unlikely. He showed that the plasma protein fractions of newborn African babies do not differ from those of Europeans and that the high globulin, especially y-globulin, is acquired during childhood. We now know that a great number of ill-nourished children in the tropics suffer some degree of kwashiorkor or one of the related syndromes and carry for the rest of their (often short) lives some irreversible liver damage (Trowel1 and Davies, 1952; Brock and Autret, 1952). Impairment of albumin synthesis is characteristic of liver damage, and this might account for the inverted albumin-globulin ratio found even into adult life. As a third possibility, the low level of animal protein intake and the inadequate amino acid balance of some tropical staple foods might favor globulin synthesis a t the expense of albumin. Relative lymphocytosis is not infrequently found in older children and in adults living in the types of environment that apparently favor the production of an inverted albumin-globulin ratio. To suggest a connection between the two is a t present pure speculation, but here is a field of research worth exploring. 3. E$ects of the Nutrition of the Host on Disease Caused by the Parasite

Most of what might have been said under this heading has already been said under others. I n the great majority of cases (though with a few important exceptions) parasites find it difficult or impossible to effect a lodgement in a really well-nourished host. If a few do succeed in establishing themselves and steal some nutrients from their host, his ample diet more than makes good their depredations, and their foothold is always precarious. “Farmers and shepherds have for long believed that a well-fed sheep will not be troubled with worms” (Hunter, 1953).An exact human parallel is to be found in the observation of Lehmann (1949b). He found that just half of a number of well-to-do, thoroughly well-fed Africans in Uganda carried small numbers of hookworms. They showed no difference in physiological measurements or hematological values from those who were not infested, nor did they show the slightest improvement when relieved of their small hookworm load. REFERENCES

Anon. 1950. Lancet i, 1002. Anon. 1952. Brit. Med. J. ii, 1405. Barakat, M. R. 1949. Ph.D. Thesis. University of London.

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Barakat, M. R. 1950. J . Egypt. Public Health Assoc. 1, 71. Barakat, M. R., and Smith, D. A. 1949. Lancet ii, 12. Bonsdorff, B. von, and Gordin, R. 1952. Acta Med. Scand. 142, Suppl. 266, 283. Bray, B. 1953. Brit. J. Nutrition 7, 3. Brock, J. F., and Autret, M. 1952. Kwashiorkor in Africa. World Health Organization Monograph Series No. 8. Bueding, E. 1949. Physiol. Revs. 29, 195. Chandler, A. C. 1943. Am. J . Hyg. 37, 121. Chandler, A. C., Read, C. P., and Nicholas, H. 0. 1950. J . Parasitol. 36, 523. Chaudhuri, R. N., and Chakravarty, N. K. 1953. Bull. Calcutta School Trop. Med. 1,8. Christophers, S. R., and Fulton, J. D. 1938a. Ann. Trop. Med. Parasitol. 32, 43. Christophers, S. R., and Fulton, J. D. 1938b. Ann. Trop. Med. Parasitol. 32, 77. Christophers, S. R., and Fulton, J. D. 1939. Ann. Trop. Med. Parasitol. 33, 161. Colbourne, M. J., Edington, G. M., and Hughes, M. H. 1950. Trans. Roy. SOC.Trop. Med. Hyg. 44, 271. Corkill, N. L. 1950. A n n . Trop. Med. Parasitol. 44, 212. Culbertson, J. T. 1941. “Immunity against Parasites.” Columbia University Press, New York. Frazer, A. C. 1949. Brit. Med. J . ii, 731. Gaafar, S. M., and Ackert, J. E. 1953. Exptl. Parasitol. 2, 185. Gell, P. G. H. 1948. Proc. Roy. SOC.Med. 41, 323. Hawking, F. 1953. Brit. Med. J . i, 1201. Hawking, F. 1954. Brit. Med. J . i, 425. Hunter, G. C. 1953. Nutrition Abstr. & Revs. 23, 705. Jelliffe, D. B. 1951. J . Trop. Med. Hyg. 64, 104. Joyeaux, C., and Baer, J. G. 1942. Bull. mushum hist. nat. Marseille. 2, 1. Keppie, A. N. N. 1953. Brit. Med. J . ii, 853. Lane, C. 1932. “Hookworm Infection.” Oxford University Press. Laurence, G. H., Groenewald, J. W., Quin, J. I., Clark, R., Ortlepp, R. J., and Bosman, S. W. 1951. Onderstepoort J . Vet. Research 26, 121. Lehmann, H. I949a. Lancet i, 90. Lehmann, H. 1949b. Nature 163,954. Lehmann, H., and Kayser, F. P. 1949. Trans. Roy. SOC.Trop. Med. Hyg. 43, 209. Looss, A. 1911. “The Anatomy and Life History of Agchylostoma duodenale,” Pt. 11. National Printing Department, Cairo. Maegraith, B. G. 1953. Brit. Med. J . ii, 1047. Maegraith, B. G., Deegan, T., and Sherwood Jones, E. 1952. Brit. Med. J . ii, 1382. McGregor, I. A., and Smith, D. A. 1952. Trans. Roy. SOC.Trop. Med. Hyg. 46, 403. McGregor, I. A., and Smith, D. A. 1954. Unpublished data. Mohun, A. F. 1946. Ann. Trop. Med. Parasitol. 40, 29. Najjar, V. A., and Holt, L. E., Jr. 1943. J . Am. Med. Assoc. 123, 683. Nutrition Field Working Party, Gambia. 1950. Unpublished report to H. M. Colonial Office, London. Orr, J. B., and Gilkes, J. L. 1931. Studies of Nutrition: The Physique and Health of Two African Tribes. Med. Research Council Spec. Rept., Ser. No. 166, p. 34. Refaat, M. A., and Bray, R. S. 1953. Brit. Med. J . ii, 1047. Riedel, B. B., and Ackert, J. E. 1950. Poultry Sci. 29, 437. Riedel, B. B., and Ackert, J. E. 1951. Poultry Sci. SO, 497 Rogers, W. P. 1941. J . Helminthol. 19, 87. Rogers, W. P. 1942. J . Helminthol, 20, 139.

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Shearer, G. D., and Stewart, J. 1933. Repts. Inst. Animal Pathol. Cambridge 3, 87. Sic6, A., and Bonnet, P. 1936. Marseille mdd. ii, 707. Smith, D. A., and Woodruff, M. F. A. 1951. Deficiency Diseases in Japanese Prison Camps. Med. Research Council Spec. Rept., Ser. No. 274, p. 63. Smyth, J. D. 1946. J. Exptl. Biol. 23, 47. Stanier, M. W. 1953. Nature 171, 880. Stewart, J. 1933. Repts. Inst. Animal Pathol. Cambridge 3, 58. Symul, F. 1950. Ann. S O C . belge mdd. trop. 30, 295. Taliaferro, W. H. 1940. Am. J . Trop. Med. 20, 169. Trowell, H. C., and Davies, J. N. P. 1952. Brit. Med. J. ii, 796. Venkatachalam, P. S.,and Patwardhan, V. N. 1953. Trans. Roy. SOC.Trop. Med. Hug. 47, 169. Wells, H. S. 1931. J . Parasitol. 17, 167. Wohl, M. G., Reinhold, J. G., and Rose, S.B. 1949. Arch. Internal Med. 83, 402.