|Malnutrition and Infection - A review - Nutrition policy discussion paper No. 5 (UNSSCN, 1989, 144 p.)|
|MALNUTRITION AND INFECTION - by Andrew Tomkins and Fiona Watson1|
|3. INFECTION AND RISK OF MALNUTRITION|
Most infections are associated with a reduced food intake. In some illnesses such as gastroenteritis, vomiting and abdominal pain are obvious causes. In others there appears to be a centrally controlled anorexia. Infection by endotoxin in experimental animals causes pronounced anorexia. Current studies suggest that this is mediated by Interleukin-1 which is released by infected macrophages. There are many other metabolic effects of Interleukin-1 which are reviewed by Keusch and Farthing (1986). A particularly interesting action is the release of lactoferrin from o9o5 neutrophil-specific granules. The lactoferrin binds iron thus causing a reduction in plasma iron. Similarly, Interleukin-1 stimulates the synthesis of metallothionine causing a reduction of plasma zinc, and stimulates caeruloplasmin production which is reflected in the increase of bound serum copper during infection.
It is well recognised that microbial growth is stimulated by the presence of zinc and iron. Perhaps the reduction of plasma zinc and iron may be a protective mechanism during the early stages of infection. An explanation of the pathophysiology of kwashiorkor in terms of the action of free radicals has been put forward by Golden & Ramdath (1987). The bodys defence against invading organisms is to produce free radicals in sufficient quantities to kill the organisms. Free radicals are chemical compounds such as superoxide and hydrogen peroxide capable of damaging tissues through their action on lipid membranes. Toxins and stimulated leucocytes produce large quantities of free radicals. A major catalyst of free radical reactions is iron. This is because of the ease with which the valency state can be changed between the ferrous and ferric forms through redox cycling. Thus the presence of abundant storage iron enhances the damaging effects of free radicals.
A reduction in dietary intake of iron and possibly other ions could therefore be regarded as a primitive defence mechanism against infection. In many traditional societies there has been a practice of starving a fever. Although this has obvious nutritional implications it may be that this is a cultural infection control strategy which supplements the biological infection control strategy.
Anorexia may be compounded by withholding of certain foods by parents - the patterns of foods allowed in febrile disease vary considerably between cultures. In addition there may be reasons for poor intake related to the mouth and throat. Dehydration during severe diarrhoea may cause a very dry buccal mucosa. Monilia infection of the tongue and measles lesions of the lips may combine to reduce dietary intake.
In such cases solid foods are less easily swallowed than liquids. To an infant receiving most of his dietary energy in the form of breast milk an infection may have little nutritional impact whereas in older children, accustomed to receiving more than half their energy as solids, a considerable reduction in energy intake during infection may result. The physiology of intestinal absorption is relatively well understood and many mechanisms of nutrient malabsorption are described. Destruction of villi, leading to a decrease in surface area and reduction in brush border enzymes are of considerable importance. In addition, deconjugation of bile salts and reduction of their concentration in luminal fluid can lead to steatorrhoea. The secretory response in the intestinal mucosa which is stimulated by bacterial toxins can also result in malabsorption.
A variety of metabolic responses occur during infection which have profound effects on utilisation of diet and endogenous nutrient stores. There is increased energy expenditure, ranging from 10 to 15% increase per 1 degree C rise in body temperature. Although this has nutritional implications for an anorexic individual who is not being offered much food, there are immunological advantages of fever. Most of the immune systems are more active at 39.0 degrees C than 37.0 degrees C. The metabolic changes during infection are reviewed elsewhere but it is now clear that carbohydrate stores for fuel are rapidly depleted, there is o9o5 inhibition of the effective use of fat and obligatory gluconeogenesis and mobilisation of skeletal muscle are needed to provide substrate for the synthesis of acute phase proteins necessary during the various phases of infection. Many of these processes appear to be under the control of Interleukin-1.
Recent studies have also identified cachectin as an important control factor. It has been isolated from endotoxin activated macrophages and has similar molecular properties to Interleukin-1. Among its actions, depression of lipoprotein lipase leading to abnormal clearance of triglyceride from the circulation is important. During infection, Interleukin stimulates the pancreatic cells to release insulin. This probably explains the development of hyperglycaemia and hyperinsulinaemia during systemic infection. It is claimed that Interleukin and cachectin are responsible for the weight loss in chronic infection but the evidence is not established.
The intestinal mucosa is made up of cells that are produced and, usually within a few days, shed into the lumen where they are broken down and nutrients are released. Thus there is a continual enteral-systemic circulation of endogenous nutrients. In health, these nutrients are well absorbed and faecal losses are minimal. During infection, however, there may be increased losses and/or poor absorption. Any cause of intestinal damage is likely to lead to increased rates of shedding. Furthermore there may be increased permeability of the intestinal mucosa allowing leakage of endogenous nutrients between the intestinal cells. In addition certain parasites may cause macroscopic blood loss. If the absorptive mechanisms are intact and the damage is in the upper intestine much of this nutrient leakage will be re-absorbed. If the damage is below the maximally absorptive area of the intestine, however, there will be considerable nutrient loss in the faeces.
Prospective studies of growth and morbidity in children have identified certain infections as particularly important as causes of poor growth. Among these, diarrhoea, respiratory infections and malaria are the most prevalent. The impact of infection on growth may vary according to the previous nutritional status of the child, the availability of food and the time available for feeding, cultural beliefs and access to health facilities. For instance, in a relatively underprivileged community in rural Gambia (Rowland et al 1977) there was a marked negative effect of diarrhoea and malaria on weight gain. Diarrhoea also caused a reduction in rates of height increase. In a study of better off children in urban Gambia, however, the growth faltering was less impressive though there was some relationship with diarrhoea and lower respiratory tract infections (Rowland et al 1988).
There is very little evidence of any impact of infection among exclusively breast fed infants. A cohort of Sudanese infants receiving breast milk only, had a prevalence of diarrhoea of around 30% at each home visit and yet there was minimal impact on rates of weight gain calculated by regressing weight gain against numbers of days ill (Zumwari et al 1987). o9o5 Similarly there was little impact of diarrhoea on growth among the exclusively breast fed urban Gambian infants studied by Rowland et al (1988).
Measurements of breast milk intake by Bangladeshi children showed remarkably little reduction during diarrhoea (Hoyle et al 1980). Interviews with mothers to determine their feeding practice indicated that the majority of Bangladeshi mothers did not reduce the number of times they suckled their infants during diarrhoea (Khan & Ahmed 1986).
The danger of contamination of infant foods with diarrhoea-causing pathogens has been emphasised repeatedly (Black et al 1989). Attention to lifestyle and food technology (e.g., fermentation) may help to reduce the microbial load in food.
Diarrhoea has less impact on the nutritional status of younger infants than on that of older children. Children receiving solid foods in Guatemala (Mata et al 1977), the Gambia (Tomkins 1983) and Bangladesh (Hoyle et al 1980, Molla et al 1983), have been shown to reduce intake of solids during diarrhoea. Interestingly a subsequent study in Bangladesh (Brown et al 1985) showed no significant decrease in solid food intake.
The impact of diarrhoea on intestinal absorption has been reviewed (Tomkins 1981). During acute diarrhoea a high level of absorption of macronutrients (Molla et al 1983) is maintained but in persistent diarrhoea there may be more severe malabsorption with endogenous nutrient loss. This occurs in diseases such as the protein losing enteropathy, complicating post-measles diarrhoea (Sarker et al 1985).
There are many unanswered questions relating to the diarrhoea/malnutrition complex, especially regarding an improved understanding of the mechanisms involved in anorexia, malabsorption and intestinal losses. Studies on appropriate regimes for feeding children during episodes of acute diarrhoea and during recovery show that in general there is as satisfactory an outcome if a rapid return to normal diet is employed as if a slow regrading regime is followed. A satisfactory intake of nutrients may depend on the type of food presented to the child. In this regard attention to household food technologies such as fermentation and germination (Tomkins et al in press) appear to be important. In particular the use of fermented food, a traditionally prepared weaning food in many societies, may have considerable advantages in terms of inhibition of pathogens as well as taste and digestibility (Mensah et al in press).
The nutritional problems associated with persistent diarrhoea (duration more than 14 days) seem to be more severe and less easily managed than those accompanying acute diarrhoea. The pathogenesis of diarrhoea in persistent diarrhoea syndrome is complex revolving around various infective agents, immunological abnormalities in the intestinal mucosa and variable contributions from dietary allergens and malnutrition (Manuel et al 1986).
In acute diarrhoea:
(1) The importance of breast feeding in prevention and management cannot be overemphasised.
(2) Growth faltering may occur in children receiving solid foods, but efforts to overcome this should be made by encouragement to eat, especially during convalescence. The use of foods with low dietary bulk and attractive taste may assist in feeding sick children.
(3) A reduction in solid food intake, malabsorption and endogenous nutrient loss may occur. Micronutrient malabsorption, especially of vitamin A, may occur.
(4) Impact of diarrhoea on rates of weight gain in exclusively breast fed infants is likely to be minimal.
(5) A favourable response to enthusiastic use of oral rehydration solutions in order to prevent dehydration may maintain appetite.
In persistent diarrhoea there may be:
(1) Severe growth faltering and development of clinical deficiency syndromes.
(2) Poor response to the use of oral rehydration fluids.
Improved disease control and management
(1) Development and evaluation of strategies to promote breast feeding more universally.
(2) Promotion of weaning foods that are less contaminated by diarrhoeal pathogens (e.g., fermented foods).
(3) Promotion of hygienic practices in food preparation.
(1) Development of methods for nutritional assessment (especially micronutrients).
(2) Investigation of mechanisms of malnutrition during episodes of pathogen-specific diarrhoea, including the immunological response to food.
(3) Investigation of cultural determinants of food intake during diarrhoea.
(4) Development and evaluation of appropriate, locally available feeding regimes during acute diarrhoea, persistent diarrhoea and convalescence.
(5) Investigation of the contribution of different dietary factors to prolongation of diarrhoea.
(6) Development and implementation of rehydration solutions using locally available cereals (e.g., rice, maize) aimed at reducing dehydration.
(7) Development of better regimes for the management of persistent diarrhoea syndromes (more than 14 days duration) and associated malnutrition. These will take account of the different factors contributing to the PDS such as infection, food allergy and underlying malnutrition.
(8) Evaluation of the effect of individual micronutrient supplements on outcome (e.g., zinc, vitamin A).
(9) Investigation of the biology of anorexia during diarrhoea.
Weight loss during measles has been described frequently. Early studies of measles in West Africa showed considerable weight loss (Morley 1969) and measles was often reported as the precipitating infection among children with marasmus or kwashiorkor in Nigeria (Laditan & Reeds 1976). The growth faltering was frequently protracted in Bangladeshi children (Koster et al 1981) especially those who developed post-measles dysentery. Indeed measles appears to be a major crisis in the life of a growing child for several reasons. Not only can it be a severe illness in its own right but the immune suppression which may persist for three to four months after infection provides an opportunity for a range of other infections to become established and cause their own nutritional problems.
Poor food intake (as a result of anorexia, dehydration, fever and buccal lesions) is well recognised by experienced health workers but poorly documented. There are certain cultural practices in which food is withdrawn from children as a treatment for measles. The measles virus may damage the intestinal mucosa sufficiently to cause malabsorption and protein loss (Dosseter & Whittle 1975). There are severe metabolic disturbances among Nigerian children during acute measles (Tomkins et al 1983). The rates of whole body protein synthesis and breakdown are increased. The latter usually exceeds the former with a net loss of body protein stores. These abnormalities may persist into convalescence. Studies of energy expenditure among Kenyan children with acute measles show rates during infection that are similar to the rates during recovery (Duggan & Milner 1986). It appears that these results are in conflict with other work which shows that energy expenditure is increased during severe infection. However, the children in the Duggan & Milner 1986 study had been ill for several days and their dietary intake had been very low. Consequently, it would be predicted that the energy expenditure would be lower than normal due to an adaptive response. It may be concluded that there is a considerable energy gap between intake and expenditure during severe measles.
Measles may be associated with:
(1) Growth faltering.
(2) A reduction in food intake, malabsorption and endogenous nutrient loss.
(3) Vitamin A deficiency.
(4) Immune suppression which permits other diseases, especially diarrhoea and respiratory infection which then contribute to the measles-malnutrition cycle.
(1) Development and evaluation of methods for improvement in coverage of eligible infants.
(2) Development of vaccines and vaccine schedules such that infants less than nine months are protected.
(3) Evaluation of different methods of nutritional management which would prevent the severe growth faltering and high mortality from measles. (Nutritional management would include better methods of ensuring adequate intakes of energy and protein as well as micronutrients such as vitamin A).
(4) See (2) of the Research Priorities for Respiratory Infections.
The impact of malaria on nutrition varies according to age, immunological status and intensity of infection. There are important effects on birth weight, iron and folate status of the neonate. Impaired growth and anaemia may occur among older children and adolescents. Equally important, however may be the immune suppression which permits the development of other infections which may themselves cause malnutrition.
Malaria has very variable effects on nutrition but anaemia and sometimes growth failure are the most frequent.
(1) Evaluation of the impact of environmental control aimed at reducing malaria transmission (e.g., bed nets) on nutritional status.
(2) Evaluation of prophylaxis during pregnancy in communities with different malaria endemicity and host nutritional status.
Although studies in the Gambia (Rowland 1977) and Guatemala (Mata 1978) show an association between various respiratory infections and growth faltering, there is little information on the mechanisms by which these cause an effect. Nevertheless, anorexia, fever, pain, vomiting (especially in pertussis) and associated diarrhoea may all be important contributory factors.
Respiratory infection may cause growth faltering.
Management of respiratory disease
(1) Evaluation of the nutritional impact of Acute Respiratory Infection (ARI) control programme.
(2) Studies of the relative importance of crowding and malnutrition as risk factors for attack rates and severity of diseases such as measles should be established.
(3) Evaluation of the best methods for nutritional management of respiratory infection.
(4) Evaluation of the nutritional impact of prevention of respiratory infection.
There are close associations between intestinal parasites and malnutrition. The most prevalent are Schistosoma, Giardia lamblia, Ascaris lumbricoides, hookworm, Trichuris trichiura and Strongyloides stercoralis. Several recent reviews have concentrated on the intestinal abnormalities (Stephenson 1987, Hall 1986) and the systemic effects (Tomkins 1985). There are several problems in assessing the impact of intestinal parasites. Firstly there is increasing evidence that, for some parasites at least, there are wormy people. In other words some individuals have particularly high worm loads. Unless this is taken account of during intervention studies it may be difficult to assess the impact of a deworming programme in a community.
Successful deworming in ascariasis shows different nutritional effects in different studies. Gupta (1977) showed that deworming of Indian children resulted in a small but significant improvement in weight for age. Stephenson et al (1980) showed a similar finding among Kenyan children and Willett et al (1979) showed quite striking rates of weight gain among Tanzanian children receiving levamisole every three months.
A study among Ethiopian children is quoted as showing no nutritional benefit after deworming, but in this study nutritional status was assessed by mid upper arm circumference, which is not a satisfactory means of monitoring growth.(Freij et al 1979). Studies in Guatemala (Gupta & Urrutia 1982) and Bangladesh (Greenberg et al 1981) have sometimes been quoted as showing no impact of deworming on growth. However, in neither o9o5 study were worms successfully eliminated. Studies in Papua New Guinea (Pust et al 1985) and Brazil (Kloetzel et al 1982) showed no significant impact of deworming on nutritional status but the children were relatively well nourished in the first place.
Different nutritional problems are associated with the different species. Schistosoma haematobium is associated with thinness; a low body mass index was noted in Nigerian boys with Schistosoma haematobium (Oomen et al 1979). Similarly there was improvement in a range of anthropometric indices among a group of Kenyan children with Schistosoma haematobium following metrifonate therapy (Stephenson et al 1985). The mechanisms for growth impairment have not been studied but it is of interest that animals with Schistosomiasis have anorexia (Cheever 1985). Schistosoma mansoni is associated with anaemia and poor growth, sometimes with decrease in plasma proteins and low ferritin levels (Mansour et al 1985). However, there does not appear to be a study in which the impact of deworming on nutritional status has been assessed. Schistosoma japonicum and malnutrition (both stunting and anaemia) are well described in the vivid writings of Horn (1969) but there is no data on how these features change after deworming.
The iron and protein deficiency that results from hookworm infection is well described (Gilles et al 1964). Weight loss is also experienced but unexplained. Anorexia associated with the itchiness and respiratory symptoms of the infection has been suggested as important (Latham 1982).
Trichuris trichiura is rather underestimated as a cause of malnutrition (Cooper et al 1980) but several studies indicate that it may cause anaemia and weight loss (Cooper & Bundy 1986).
Strongyloides stercoralis is associated with anorexia, malabsorption and loss of endogenous nutrients (OBrien 1975). In severe cases there may be sub-total villus atrophy (Tomkins 1979) but the nutritional consequences of milder infection are unknown.
Giardia lamblia appears to cause diarrhoea and malabsorption in some subjects more than others (Wright & Tomkins 1978). This may be due to differences in immune response to the parasite; the intestinal response to the first exposure appears to be more severe than subsequent exposure. Studies in Guatemala (Farthing & Mata 1986) show that ULLGiardia is associated with growth faltering among young children but not in older children. Longitudinal studies suggest that only some subjects with Giardia have any symptoms at all; This has given rise to the suggestion that there may be strain differences in pathogenicity. Among children with marasmus or kwashiorkor there is an especially high prevalence of large numbers of ULLGiardia lamblia in the upper intestine.
Intestinal infection may be associated with:
(1) Growth faltering.
(2) A reduction in food intake, malabsorption, endogenous nutrient loss and anaemia.
(3) Intervention studies have not all found improvements in nutritional status after deworming. This may be explained by:
(a) Failure of therapy.
(b) Differences in worm load.
(c) Differences in worm strain.
(d) Differences in pre-treatment nutritional status of host.
(1) Evaluation of the nutritional benefits of disease control whether by environmental protection, vaccine, chemotherapy - including special attention to physical work capacity and food production.
(1) Investigation of the mechanisms of malnutrition associated with ascariasis - especially in studies where chemotherapy is used.
(2) Assessment of the contribution of ascariasis to malnutrition in communities - especially those where there are other social and environmental causes of malnutrition.
(3) Investigations of the biology of anorexia in ascariasis.
(4) Investigation of the cultural determinants of food intake during ascariasis.
(5) Investigation of ascariasis as a co-factor with other pathogens in the development of diarrhoeal and respiratory disease.
(6) Investigation of the rates of re-acquisition of Ascaris lumbricoides following chemotherapy and the nutritional consequences of the same.
(1) Investigation of intestinal losses of nutrients other than protein and iron.
(2) Evaluation of deworming on physical work capacity and production.
Protracted diarrhoea and weight loss are almost universally associated with the full clinical picture of AIDS - to the extent that it has been referred to as the slim disease. The various immunological dysfunctions in AIDS, may be due to multiple pathogen-induced alterations in the gastrointestinal tract which result in malabsorption and malnutrition. A variety of micronutrient deficiency syndromes have been observed in AIDS patients and special dietary therapy may be necessary.
The growing incidence of AIDS may also increase levels of malnutrition in an indirect way, through its effect on food production. In certain parts of Africa, where AIDS is spreading at a voracious speed, there are fears that the economically active population (who are also sexually active) will be wiped out to the extent that agricultural work will be adversely o9o5 affected. With no strong, healthy adults to carry out farm work, food production will decrease and the HIV-negative population will become prone to malnutrition.
Furthermore there have been reports that the orphans of AIDS victims have been stigmatised and abandoned by other members of the community. They may therefore become neglected and malnourished as a result.
AIDS may be associated with:
(1) Weight loss and diarrhoea.
(2) Micronutrient deficiencies as a result of AIDS-related syndromes.
(1) Evaluation of impact of AIDS on food production system.
(2) Evaluation of the impact of AIDS on child care and nutrition of young children, orphaned by their parents death.
(3) Evaluation of the effect of the nutritional status on acquisition of the virus, development of seropositivity and development of clinical AIDS.