910
Journal of the Royal Society of Medicine Volume 71 December 1978
Tropical enteritis: a review' S G Wright MRCP Hospitalfor Tropical Diseases, 4 St Pancras Way, London NWI
Lymphocytes and plasma cells are a normal finding in the lamina propria of the gut. The surface epithelium of the mucosa is infiltrated by a few lymphocytes. Antigens absorbed from the gut lumen are thought to be the stimulus for the accumulation of this inflammatory infiltrate (Ferguson & Parrott 1972). These antigens are derived from ingested food or microorganisms. Antigen absorption from the gut has recently been reviewed (Walker 1976). When normal jejunal biopsies from western and tropical control patients are compared, this infiltrate of inflammatory cells in the lamina propria is increased in tropical residents (Lindenbaum 1973) and recurrent infections of the gastrointestinal tract are the cause of this inflammation (Walker 1976). Gerson et al. (1971) reported that when patients left the tropical environment for a temperate area, this tropical enteritis regressed and intestinal absorption improved. With this in mind it is reasonable to consider whether or not inflammation mediated by immune responses to antigens derived from pathogens causing gut infections may damage the mucosa and impair function. In coeliac disease there is evidence of humoral and cellmediated immunity to gluten (Baker et al. 1975, Ferguson et al. 1975), and it is suggested that these responses contribute to maintaining mucosal damage. Viruses Considerable interest was excited by the description of virus-like particles in the small intestinal mucosa of children with diarrhoea (Bishop et al. 1973). Schreiber et al. (1973) showed that infection of volunteers with the Norwalk agent produced the typical changes of a damaged small intestine, i.e. reduction in villous height, crypt hypertrophy with increased numbers of mitoses and a considerable increase in the inflammatory infiltrate of the lamina propria. These changes were obvious 48 hours after ingestion of the virus inoculum. Viral infections seem to be an important cause of infective gastroenteritis in temperate countries, but in the tropics the viral infections of the gastrointestinal tract are much less frequent (Ryder et al. 1976). One important viral enteritis in the tropics is that associated with severe measles. The impact of measles infection on paediatric morbidity and mortality has been indicated by the work of Morley (1973). Though clinical evidence of measles is obtained from examination of the skin and mucous membranes of the mouth, the gastrointestinal tract may be involved with the same pathological process producing inflammation. The principal finding is a syncytial multinucleate giant cell found in all mucosal and lymphoid tissues (Edington & Gilles 1976a). The giant cell contains measles antigen. Severe measles is associated with a chronic relapsing diarrhoeal illness and protein-losing enteropathy (Dossetor & Whittle 1975). Persistence of the measles antigen may maintain the stimulus for local inflammation which in turn causes local damage and increased mucosal permeability. Impaired cell-mediated immunity may be the cause of failure to eradicate the virus. 1 Paper read to Section of Medicine, Experimental Medicine & Therapeutics, 22 November 1977 0 1 41-0768/78/120910-04/$O 1.00/0
C
1978 The Royal Society of Medicine
Journal of the Royal Society of Medicine Volume 71 December 1978
911
Bacteria Gorbach et al. (1969) showed that the upper small intestine in Indian control subjects was sterile. In contrast, an abnormal microflora comprising enterobacteria has been found during and after cholera and acute undifferentiated tropical diarrhoea in Asians (Gorbach et al. 1970). This is similar to findings reported in tropical sprue (Gorbach et al. 1969, Klipstein et al. 1973, Tomkins et al. 1975). Histologically, tropical sprue has no characteristic features, but loss of villous height, crypt hypertrophy and a gross increase in inflammatory infiltrate of the lamina propria are seen (Edington & Gilles 1976b). The number of epithelial lymphocytes is also increased (Montgomery & Shearer 1974). These findings are probably caused by enhanced absorption of antigens from the abnormal flora and from the diet. An increased incidence of serum antibodies to milk protein has been shown in tropical sprue (Bayless et al. 1967). Treatment with tetracycline for one month in this condition resulted in improvement of intestinal function and histological appearances, and the abnormal microflora was eradicated (Tomkins et al. 1975). This suggests that the abnormal microflora is concerned with the maintenance of this condition. Mucosal inflammation may be a secondary phenomenon but immune responses may contribute to mucosal damage. In tropical sprue it is likely that the pathogenesis is multifactorial and that mucosal abnormalities are maintained by the effects of bacterial metabolites such as alcohol and enterotoxin (Klipstein et al. 1973), local nutritional abnormalities in the mucosa and possibly immunologically-mediated events. Protozoa Giardia lamblia is a flagellate parasite of the small intestine in man. Giardiasis presents a spectrum of disease ranging from the majority of patients who are asymptomatic-cyst passers to a comparatively smaller number who have diarrhoea, weight loss and intestinal malabsorption. In the tropics the paediatric age group bears the brunt of symptomatic infection. In overland travellers to Africa and Asia this parasite is a common cause of gastrointestinal symptoms. In a group of 40 patients with giardiasis studied at the Hospital for Tropical Diseases (Wright et al. 1977), almost half had malabsorption and histological abnormalities. In patients with normal intestinal absorption, jejunal histology was similar to that of control patients. In those with marked malabsorption, decrease in villous height and crypt hypertrophy were present and there was a gross increase in inflammatory infiltrate. In some jejunal biopsies, trophozoites of G. lamblia are seen in the intervillous spaces and applied closely to the microvillous border of the epithelial cells. At this site electron microscopy has shown damage to the microvilli and the fuzzy coat (Tandon et al. 1974). Scanning electron microscopy in murine giardiasis showed impressions of the under surface of the parasite remaining on epithelial cells at sites where the trophozoites had settled (Earlandsen & Chase 1974). Such direct damage to epithelial cells may be the initial cause of mucosal dysfunction. Antigens may be absorbed through the damaged epithelium and elicit mucosal inflammatory responses. Human serum antibodies to Giardia have been demonstrated (Halita & Isaicu 1946, Radulescu et al. 1976, Ridley & Ridley 1976) and their presence is usually associated with symptomatic disease and malabsorption (Ridley & Ridley 1976). The nature of parasite antigens exciting this response has not yet been defined. Malabsorption in giardiasis has been associated with significantly-raised interepithelial lymphocyte counts (Wright & Tompkins 1977). These findings suggest that immunologically-mediated events occur in the intestinal mucosa. The patients studied by Ament & Rubin (1972) had deficiencies of humoral immunity but probably normal cell-mediated immunity. Therefore, responses of this type may have contributed to the jejunal abnormalities seen in multiple biopsies from each patient. The extent to which these events cause or contribute to mucosal damage awaits further elucidation. It is likely that they follow damage caused by the parasite. At present, comparatively little is known about the physiology of G. lamblia. Entamoeba histolytica and Trichomonas vaginalis are pathogenic parasites and can metabolize aerobically or anaerobically. In animal experiments, conjugation of E. histolytica with living bacteria for at least twelve hours is necessary to render the amoeba invasive. I would suggest that the
912
Journal of the Royal Society of Medicine Volume 71 December 1978
bacteria reduce local oxygen tension and allow the amoeba to metabolize anaerobically and become more aggressive. In 50% of patients with giardiasis and malabsorption of two or three test substances, we have found an abnormal enterobacterial flora in the jejunum (Tomkins et al. 1978). This abnormal flora may produce or maintain an anaerobic microenvironment in which the parasite is more damaging to cells either directly or via its metabolites. As in tropical sprue, intestinal damage and dysfunction in giardiasis are probably caused by several factors. Possible mechanisms of mucosal damage include direct damage by the parasite, immune responses to parasite and other antigens, and the effects of parasite and bacterial metabolites. Helminths Two helminthic parasites of man are accepted as the cause of marked intestinal dysfunction. They produce a similar clinical picture of severe diarrhoea with profound weakness and dehydration. Tests of intestinal absorption show malabsorption of d-xylose and fat. Proteinlosing enteropathy has also been demonstrated. The two parasites are Strongyloides stercoralis and Capillaria philippinensis. Malabsorption with the former was reported by O'Brien (1975). The infection of man by the latter was reported by Whalen et al. (1969). S. stercoralis has long been recognized as a human parasite, but in only a few instances such as that quoted above has malabsorption been associated with the infection. A rare clinical entity is hyperinfection with S. stercoralis (Purtillo et al. 1974). This usually fatal syndrome occurs in immunosuppressed patients, and massive systemic invasion by larvae with secondary septicaemia is found. Where strongyloidiasis is associated with malabsorption there are marked changes in the jejunal mucosa, with loss of villous height and a marked inflammatory infiltrate in the lamina propria. In contrast, mucosal changes are minimal in capillarisis. Immediate hypersensitivity is particularly associated with helminthic infections, and immediate hypersensitivity reactions in the gut cause local swelling and the exudation of protein-rich fluid into the gut lumen (Lancet 1975). This type of reaction may occur in both of these infections to produce diarrhoea, malabsorption and protein loss. The way in which immunological mechanisms play a part in mucosal changes in helminthic infections is suggested by studies of the small intestinal mucosa in normal mice and T-cell deficient mice infected with Nippostrongylus braziliensis. In normal mice, infection is associated with villous atrophy, but in T-cell deficient mice there are minimal changes in villous architecture (Ferguson & Jarrett 1975). Absence of T-cells does not only abrogate cellmediated immunity. IgE responses are impaired because of compromised T-cell/B-cell cooperation necessary for an IgE response (Zvaifler 1976). Reaginic antibodies are associated with helminthic infections, and antigen activation of primed mast cells evokes release of histamine and other mediators of immediate hypersensitivity which affect intestinal morphology and function. The effects of inflammation on gut hormones have not yet been studied but interactions are likely and these may affect the host's gut adversely. Conclusion This review has dealt with a number of conditions which are associated with intestinal dysfunction and inflammatory changes in the small intestine. When the small intestine is damaged it probably can respond in only one way. The rate of cells lost into the gut lumen is increased and to compensate for this, cell replication in the crypts is increased. Consequent upon damage to the epithelium, antigens derived from pathogens and food constituents may be absorbed in increased amounts, be directly toxic to the mucosa and evoke damaging immunologically-mediated reactions in the gut mucosa. When the antigen load is decreased as a result of curative treatment or natural eradication of the pathogen, resolution of the inflammation and return of normal functions may ensue. As yet, much more work is required to define the role of these reactions in producing mucosal damage and dysfunction.
Journal of the Royal Society of Medicine Volume 71 December 1978
913
References Ament M E & Rubin C E (1972) Gastroenterology 62, 216 Baker P G, Barry R E & Read A E (1975) British Medical Journal i, 486 Bayless T M, Partin J S & Partin J C (1967) Johns Hopkins Medical Journal 120, 310 Bishop R D, Davidson J P, Holmes I H & Ruck B J (1973) Lancet ii, 1281 Dossetor J F B & Whittle H C (1975) British Medical Journal ii, 592 Earlandsen S L & Chase D G (1974) American Journal of Clinical Nutrition 27, 1277 Edington G M & Gilles H M (1976a) Pathology in the Tropics. 2nd edn. Edward Arnold, London; p 248 Edington G M & Gilles H M (1976b) Pathology in the Tropics. 2nd edn. Edward Arnold, London; p 528 Ferguson A A & Jarrett E E E (1975) Gut 16, 114 Ferguson A A, MacDonald E T, McClure J P & Holden R J (1975) Lancet i, 895 Ferguson A A & Parrott D M V (1972) Clinical and Experimental Immunology 12, 477 Gerson C J, Kent T H, Saha H R, Saddiqui N & Lindenbaum J (1971) Annals of Internal Medicine 75, 41 Gorbach S L, Banwell J G, Chatterjee V D, Jacobs B & Sack R B (1970) Journal of Clinical Investigation 50, 881 Gorbach S L, Banwell J G, Mitra R, Chatterjee V D, Jacobs B & Guha Mazundar D N (1969) Lancet i, 74 Halita M & lsaicu L (1946) Ardealul medical 6, 154 Klipstein F A, Holdeman L V, Corcino J J & Moore W E C (1973) Annals of Internal Medicine 75, 632 Lancet (1975) ii, 1021 Lindenbaum J (1973) Gastroenterology 64, 637 Montgomery R D & Shearer A C I (1974) Gut 12, 387 Morley D C (1973) Paediatric Priorities in the Developing World. Butterworth, London; p 207 O'Brien W (1975) Transactions of the Royal Society of Tropical Medicine and Hygiene 69, 69 Purtillo D T, Meyers W M & Connors B H (1974) American Journal of Medicine 56, 488 Radulescu S, lancu L, Simonescu U & Meyers E A (1976) Journal of Clinical Pathology 29, 863 Ridley M J & Ridley D S (1976) Journal of Clinical Pathology 29, 30 Ryder R W, Sack D A, Kapikian A Z, McLaughin J C, Chakraborti J, Rackman A S M M, Merson M H & Wells J G (1976) Lancet i, 659 Schreiber D S, Blacklow N R & Trier J S (1973) New England Journal of Medicine 288, 1318 Tandon B N, Purl B K, Gandli B C & Tewari S G (1974) Indian Journal of Medical Research 72, 1838 Tomkins A N, Drasar B S & James W P T (1975) Lancet i, 59 Tomkins A N, Wright S G & Drasar B S (1978) Transactions of the Royal Society of Tropical Medicine and Hygiene 72, 33 Walker W A (1976) Paediatric Clinics of North America 22, 731 Whalen G E, Rosenburg E B, Stickland G T, Guttman R A, Cross J H, Whaten R H, Uylargio C & Dizon J J (1969) Lanceti, 13 Wright S G & Tompkins A M (1977) Clinical and Experimental Immunology 29, 408 Wright S G, Tompkins A M & Ridley D S (1977) Gut 18, 343 Zvaifler N J (1976) In: Immunology of Parasite Infections. Ed. S Cohen and E Sadun. Blackwell, Oxford etc; p 422
Journal of the Royal Society of Medicine Volume 71 December 1978
Tropical enteritis: a review' S G Wright MRCP Hospitalfor Tropical Diseases, 4 St Pancras Way, London NWI
Lymphocytes and plasma cells are a normal finding in the lamina propria of the gut. The surface epithelium of the mucosa is infiltrated by a few lymphocytes. Antigens absorbed from the gut lumen are thought to be the stimulus for the accumulation of this inflammatory infiltrate (Ferguson & Parrott 1972). These antigens are derived from ingested food or microorganisms. Antigen absorption from the gut has recently been reviewed (Walker 1976). When normal jejunal biopsies from western and tropical control patients are compared, this infiltrate of inflammatory cells in the lamina propria is increased in tropical residents (Lindenbaum 1973) and recurrent infections of the gastrointestinal tract are the cause of this inflammation (Walker 1976). Gerson et al. (1971) reported that when patients left the tropical environment for a temperate area, this tropical enteritis regressed and intestinal absorption improved. With this in mind it is reasonable to consider whether or not inflammation mediated by immune responses to antigens derived from pathogens causing gut infections may damage the mucosa and impair function. In coeliac disease there is evidence of humoral and cellmediated immunity to gluten (Baker et al. 1975, Ferguson et al. 1975), and it is suggested that these responses contribute to maintaining mucosal damage. Viruses Considerable interest was excited by the description of virus-like particles in the small intestinal mucosa of children with diarrhoea (Bishop et al. 1973). Schreiber et al. (1973) showed that infection of volunteers with the Norwalk agent produced the typical changes of a damaged small intestine, i.e. reduction in villous height, crypt hypertrophy with increased numbers of mitoses and a considerable increase in the inflammatory infiltrate of the lamina propria. These changes were obvious 48 hours after ingestion of the virus inoculum. Viral infections seem to be an important cause of infective gastroenteritis in temperate countries, but in the tropics the viral infections of the gastrointestinal tract are much less frequent (Ryder et al. 1976). One important viral enteritis in the tropics is that associated with severe measles. The impact of measles infection on paediatric morbidity and mortality has been indicated by the work of Morley (1973). Though clinical evidence of measles is obtained from examination of the skin and mucous membranes of the mouth, the gastrointestinal tract may be involved with the same pathological process producing inflammation. The principal finding is a syncytial multinucleate giant cell found in all mucosal and lymphoid tissues (Edington & Gilles 1976a). The giant cell contains measles antigen. Severe measles is associated with a chronic relapsing diarrhoeal illness and protein-losing enteropathy (Dossetor & Whittle 1975). Persistence of the measles antigen may maintain the stimulus for local inflammation which in turn causes local damage and increased mucosal permeability. Impaired cell-mediated immunity may be the cause of failure to eradicate the virus. 1 Paper read to Section of Medicine, Experimental Medicine & Therapeutics, 22 November 1977 0 1 41-0768/78/120910-04/$O 1.00/0
C
1978 The Royal Society of Medicine
Journal of the Royal Society of Medicine Volume 71 December 1978
911
Bacteria Gorbach et al. (1969) showed that the upper small intestine in Indian control subjects was sterile. In contrast, an abnormal microflora comprising enterobacteria has been found during and after cholera and acute undifferentiated tropical diarrhoea in Asians (Gorbach et al. 1970). This is similar to findings reported in tropical sprue (Gorbach et al. 1969, Klipstein et al. 1973, Tomkins et al. 1975). Histologically, tropical sprue has no characteristic features, but loss of villous height, crypt hypertrophy and a gross increase in inflammatory infiltrate of the lamina propria are seen (Edington & Gilles 1976b). The number of epithelial lymphocytes is also increased (Montgomery & Shearer 1974). These findings are probably caused by enhanced absorption of antigens from the abnormal flora and from the diet. An increased incidence of serum antibodies to milk protein has been shown in tropical sprue (Bayless et al. 1967). Treatment with tetracycline for one month in this condition resulted in improvement of intestinal function and histological appearances, and the abnormal microflora was eradicated (Tomkins et al. 1975). This suggests that the abnormal microflora is concerned with the maintenance of this condition. Mucosal inflammation may be a secondary phenomenon but immune responses may contribute to mucosal damage. In tropical sprue it is likely that the pathogenesis is multifactorial and that mucosal abnormalities are maintained by the effects of bacterial metabolites such as alcohol and enterotoxin (Klipstein et al. 1973), local nutritional abnormalities in the mucosa and possibly immunologically-mediated events. Protozoa Giardia lamblia is a flagellate parasite of the small intestine in man. Giardiasis presents a spectrum of disease ranging from the majority of patients who are asymptomatic-cyst passers to a comparatively smaller number who have diarrhoea, weight loss and intestinal malabsorption. In the tropics the paediatric age group bears the brunt of symptomatic infection. In overland travellers to Africa and Asia this parasite is a common cause of gastrointestinal symptoms. In a group of 40 patients with giardiasis studied at the Hospital for Tropical Diseases (Wright et al. 1977), almost half had malabsorption and histological abnormalities. In patients with normal intestinal absorption, jejunal histology was similar to that of control patients. In those with marked malabsorption, decrease in villous height and crypt hypertrophy were present and there was a gross increase in inflammatory infiltrate. In some jejunal biopsies, trophozoites of G. lamblia are seen in the intervillous spaces and applied closely to the microvillous border of the epithelial cells. At this site electron microscopy has shown damage to the microvilli and the fuzzy coat (Tandon et al. 1974). Scanning electron microscopy in murine giardiasis showed impressions of the under surface of the parasite remaining on epithelial cells at sites where the trophozoites had settled (Earlandsen & Chase 1974). Such direct damage to epithelial cells may be the initial cause of mucosal dysfunction. Antigens may be absorbed through the damaged epithelium and elicit mucosal inflammatory responses. Human serum antibodies to Giardia have been demonstrated (Halita & Isaicu 1946, Radulescu et al. 1976, Ridley & Ridley 1976) and their presence is usually associated with symptomatic disease and malabsorption (Ridley & Ridley 1976). The nature of parasite antigens exciting this response has not yet been defined. Malabsorption in giardiasis has been associated with significantly-raised interepithelial lymphocyte counts (Wright & Tompkins 1977). These findings suggest that immunologically-mediated events occur in the intestinal mucosa. The patients studied by Ament & Rubin (1972) had deficiencies of humoral immunity but probably normal cell-mediated immunity. Therefore, responses of this type may have contributed to the jejunal abnormalities seen in multiple biopsies from each patient. The extent to which these events cause or contribute to mucosal damage awaits further elucidation. It is likely that they follow damage caused by the parasite. At present, comparatively little is known about the physiology of G. lamblia. Entamoeba histolytica and Trichomonas vaginalis are pathogenic parasites and can metabolize aerobically or anaerobically. In animal experiments, conjugation of E. histolytica with living bacteria for at least twelve hours is necessary to render the amoeba invasive. I would suggest that the
912
Journal of the Royal Society of Medicine Volume 71 December 1978
bacteria reduce local oxygen tension and allow the amoeba to metabolize anaerobically and become more aggressive. In 50% of patients with giardiasis and malabsorption of two or three test substances, we have found an abnormal enterobacterial flora in the jejunum (Tomkins et al. 1978). This abnormal flora may produce or maintain an anaerobic microenvironment in which the parasite is more damaging to cells either directly or via its metabolites. As in tropical sprue, intestinal damage and dysfunction in giardiasis are probably caused by several factors. Possible mechanisms of mucosal damage include direct damage by the parasite, immune responses to parasite and other antigens, and the effects of parasite and bacterial metabolites. Helminths Two helminthic parasites of man are accepted as the cause of marked intestinal dysfunction. They produce a similar clinical picture of severe diarrhoea with profound weakness and dehydration. Tests of intestinal absorption show malabsorption of d-xylose and fat. Proteinlosing enteropathy has also been demonstrated. The two parasites are Strongyloides stercoralis and Capillaria philippinensis. Malabsorption with the former was reported by O'Brien (1975). The infection of man by the latter was reported by Whalen et al. (1969). S. stercoralis has long been recognized as a human parasite, but in only a few instances such as that quoted above has malabsorption been associated with the infection. A rare clinical entity is hyperinfection with S. stercoralis (Purtillo et al. 1974). This usually fatal syndrome occurs in immunosuppressed patients, and massive systemic invasion by larvae with secondary septicaemia is found. Where strongyloidiasis is associated with malabsorption there are marked changes in the jejunal mucosa, with loss of villous height and a marked inflammatory infiltrate in the lamina propria. In contrast, mucosal changes are minimal in capillarisis. Immediate hypersensitivity is particularly associated with helminthic infections, and immediate hypersensitivity reactions in the gut cause local swelling and the exudation of protein-rich fluid into the gut lumen (Lancet 1975). This type of reaction may occur in both of these infections to produce diarrhoea, malabsorption and protein loss. The way in which immunological mechanisms play a part in mucosal changes in helminthic infections is suggested by studies of the small intestinal mucosa in normal mice and T-cell deficient mice infected with Nippostrongylus braziliensis. In normal mice, infection is associated with villous atrophy, but in T-cell deficient mice there are minimal changes in villous architecture (Ferguson & Jarrett 1975). Absence of T-cells does not only abrogate cellmediated immunity. IgE responses are impaired because of compromised T-cell/B-cell cooperation necessary for an IgE response (Zvaifler 1976). Reaginic antibodies are associated with helminthic infections, and antigen activation of primed mast cells evokes release of histamine and other mediators of immediate hypersensitivity which affect intestinal morphology and function. The effects of inflammation on gut hormones have not yet been studied but interactions are likely and these may affect the host's gut adversely. Conclusion This review has dealt with a number of conditions which are associated with intestinal dysfunction and inflammatory changes in the small intestine. When the small intestine is damaged it probably can respond in only one way. The rate of cells lost into the gut lumen is increased and to compensate for this, cell replication in the crypts is increased. Consequent upon damage to the epithelium, antigens derived from pathogens and food constituents may be absorbed in increased amounts, be directly toxic to the mucosa and evoke damaging immunologically-mediated reactions in the gut mucosa. When the antigen load is decreased as a result of curative treatment or natural eradication of the pathogen, resolution of the inflammation and return of normal functions may ensue. As yet, much more work is required to define the role of these reactions in producing mucosal damage and dysfunction.
Journal of the Royal Society of Medicine Volume 71 December 1978
913
References Ament M E & Rubin C E (1972) Gastroenterology 62, 216 Baker P G, Barry R E & Read A E (1975) British Medical Journal i, 486 Bayless T M, Partin J S & Partin J C (1967) Johns Hopkins Medical Journal 120, 310 Bishop R D, Davidson J P, Holmes I H & Ruck B J (1973) Lancet ii, 1281 Dossetor J F B & Whittle H C (1975) British Medical Journal ii, 592 Earlandsen S L & Chase D G (1974) American Journal of Clinical Nutrition 27, 1277 Edington G M & Gilles H M (1976a) Pathology in the Tropics. 2nd edn. Edward Arnold, London; p 248 Edington G M & Gilles H M (1976b) Pathology in the Tropics. 2nd edn. Edward Arnold, London; p 528 Ferguson A A & Jarrett E E E (1975) Gut 16, 114 Ferguson A A, MacDonald E T, McClure J P & Holden R J (1975) Lancet i, 895 Ferguson A A & Parrott D M V (1972) Clinical and Experimental Immunology 12, 477 Gerson C J, Kent T H, Saha H R, Saddiqui N & Lindenbaum J (1971) Annals of Internal Medicine 75, 41 Gorbach S L, Banwell J G, Chatterjee V D, Jacobs B & Sack R B (1970) Journal of Clinical Investigation 50, 881 Gorbach S L, Banwell J G, Mitra R, Chatterjee V D, Jacobs B & Guha Mazundar D N (1969) Lancet i, 74 Halita M & lsaicu L (1946) Ardealul medical 6, 154 Klipstein F A, Holdeman L V, Corcino J J & Moore W E C (1973) Annals of Internal Medicine 75, 632 Lancet (1975) ii, 1021 Lindenbaum J (1973) Gastroenterology 64, 637 Montgomery R D & Shearer A C I (1974) Gut 12, 387 Morley D C (1973) Paediatric Priorities in the Developing World. Butterworth, London; p 207 O'Brien W (1975) Transactions of the Royal Society of Tropical Medicine and Hygiene 69, 69 Purtillo D T, Meyers W M & Connors B H (1974) American Journal of Medicine 56, 488 Radulescu S, lancu L, Simonescu U & Meyers E A (1976) Journal of Clinical Pathology 29, 863 Ridley M J & Ridley D S (1976) Journal of Clinical Pathology 29, 30 Ryder R W, Sack D A, Kapikian A Z, McLaughin J C, Chakraborti J, Rackman A S M M, Merson M H & Wells J G (1976) Lancet i, 659 Schreiber D S, Blacklow N R & Trier J S (1973) New England Journal of Medicine 288, 1318 Tandon B N, Purl B K, Gandli B C & Tewari S G (1974) Indian Journal of Medical Research 72, 1838 Tomkins A N, Drasar B S & James W P T (1975) Lancet i, 59 Tomkins A N, Wright S G & Drasar B S (1978) Transactions of the Royal Society of Tropical Medicine and Hygiene 72, 33 Walker W A (1976) Paediatric Clinics of North America 22, 731 Whalen G E, Rosenburg E B, Stickland G T, Guttman R A, Cross J H, Whaten R H, Uylargio C & Dizon J J (1969) Lanceti, 13 Wright S G & Tompkins A M (1977) Clinical and Experimental Immunology 29, 408 Wright S G, Tompkins A M & Ridley D S (1977) Gut 18, 343 Zvaifler N J (1976) In: Immunology of Parasite Infections. Ed. S Cohen and E Sadun. Blackwell, Oxford etc; p 422
