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PERSISTENT DIARRHEA IN THE RETURNED TRAVELER
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PERSISTENT DIARRHEA IN THE RETURNED TRAVELER Nathan M. Thielman, MD, MPH, and Richard L. Guerrant, MD
Of nearly 500 million international travelers each year, almost 50 million, an ever increasing number, travel from industrialized countries to tropical or developing areas. These include more than 27 million North Americans, almost 18 million Europeans, 3 million Japanese, and 1 million Australians and New ZealandersffiOf the many health threats'that affect over half of these travelers, diarrheal diseases are by far the most common, albeit not most serious concern.112 Approximately one third of all travelers to tropical developing areas experience a diarrheal illness. Fortunately, the vast majority of these are either self-limited or promptly responsive to a commonly used short-course of an antimicrobial agent effective against enterotoxigenic Escherichia coli and other enteric bacteria that constitute the majority of pathogens causing travelers diarrhea; however, prospective studies of over 7800 Swiss travelers, 4600 Peace Corps volunteers, and 35 students in Latin America suggest that approximately 3% of illnesses may last longer than 14 days and 1% to 2% longer than 1 month.32Of 7886 Swiss international travelers, 0.9%(73) had a diarrheal illness lasting more than 30 days upon return, with the highest rates being among those visiting West Africa and regions of the Far East."' Of 4607 US Peace Corps volunteers, 1.7"/0 (78) had a diarrheal illness lasting 1 month or longer, with highest rates being among those in Haiti, Central and West Africa, and Nepal: whereas 1 of 35 students traveling in Latin America for longer than 1 month developed a persistent diarrheal illness (2.9%).& DEFINITIONS
The definition of persistent diarrhea has evolved largely from studies of endemic diarrheal illnesses of children in tropical developing areas to be diarrhea ~
From the Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina (Nh4T); and the Division of Geographic and International Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia (RLG)
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lasting greater than 14 days.7 The basis for this definition lies in the fact that diarrhea lasting into a third week tends to identify high-risk children for heavy lo5 diarrheal illness The gastroenterologist’s definition of chronic diarrhea extends the syndrome to lasting greater than 1 month and includes some 20% of cases caused by Among the laxative overuse and 50% that are “functional” or “idiopathi~.”~~ ”organic” causes of chronic diarrhea in 30% of cases are infectious etiologies, including Giardia, Cyptosporidium, Entamoeba kistolytica, Strongyloides, and Clostridium dificile infections as well as inflammatory bowel disease, collagenous or lymphocytic colitis, fat or carbohydrate malabsorption, and use of medications such as antibiotics; antihypertensive, antiarrhythmic, and calcium-channel blocking drugs; magnesium antacids; caffeine; alcohol; or sorbitol (10 g sorbitol in 4-5 sugar-free mints caused diarrhea in 48% of volunteersm).Other causes include previous surgery such as gastrectomy or bowel resection, endocrine causes (including Addison‘s disease, hypothyroidism or hyperthyroidism, diabetes), or tumors (such as villous adenoma or medullary carcinoma of the thyroid gland). In contrast, the causes of persistent diarrhea in travelers have included Giardia lamblia, Cyptosporidium, Cyclospora, and lsospora belli as well as bacterial agents including enteropathogenic, enterotoxigenic, enterohemorrhagic, and enteroaggregative E. coli, Skigella, Campylobacter jejuni, Aeromonas, Plesiomonas, toxigenic c. dificile, and likely small bowel overgrowth, HIV infection, and strongy10idiasis.~~ Other less common parasitic causes of diarrhea include Dientamoeba fragilis, Capillaria pkilippinensis, Fasciolopsis buski, Trickuris trickiura, and Sckistosoma. CLINICAL PRESENTATION
Especially important in evaluation of persistent diarrhea in travelers are where the travelers have been, when they were there, the type of diarrheal illness, medications taken, food intolerance, and any potential immunocompromised state. Geographic exposure might suggest, for example, Cyclospora infection among travelers to Nepal during the spring or summer months. Time of travel includes relevant incubation periods, such as usually 1 to 2 weeks for Giardia, Cryptosporidium or Cyclospora infections. The type of diarrhea is also useful in narrowing the differential diagnosis. Bloody diarrhea suggests E. kistolytica or possibly enterohemorrhagic E. coli infection. Inflammatory illnesses with fever suggest an invasive pathogen such as Campylobacter, Salmonella, Shigella, or possibly C. difficile, whereas noninflammatory diarrhea, especially with weight loss, suggests Giardia, Cypfosporidium, I. belli or possibly Strongyloides infection. In addition, lactose intolerance often follows a traveler’s diarrheal illness and being immunocompromised opens an additional range of diagnostic possibilities. Whenever a diarrheal illness persists beyond 10 to 14 days, especially if there has been no response to commonly used quinolone antibiotics (which are highly effective against most bacterial agents that cause diarrhea), one should consider either antibiotic-associated toxigenic C. dzficile infection or one of the protozoan parasitic causes of diarrhea. If the illness features fever or bloody diarrhea, one should consider amoebic colitis caused by virulent E. histolytica and obtain a trichrome stain for erythrophagocytic amebic trophozoites and often pyknotic or absent fecal leukocytes, or, even better, an enzyme immunoassay for virulent E. kisfolytica antige11.9~
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PROTOZOAL CAUSES The persistent diarrhea associated with protozoal pathogens is usually nonbloody, only mildly or noninflammatory diarrhea, and often accompanied by weight loss. The usual protozoal causes include G. larnblia, Cryptosporidium patwurn, Cyclosporu cuyafenensis (especially with fatigue), I. belli, D. fragilis, and in immunocompromised patients, microsporidia (Enferocyfozounbieneusi or Encephafifozoan intestinalis). Cyptosporidiurn, Cydospora, microsporidia, and to some extent, Isospora infections have been brought to heightened medical attention by the severe, often protracted diarrhea they cause in patients with AIDS. Giardia lamblia Giardiasis is one of the commonest causes of chronic diarrhea in the returned traveler. Although outbreaks among returned travelers from the former Soviet Union, especially St. Peter~burg,’~, 61 the Mediter~anean,”~ and mountainous regions in North A m e r i ~ a ’have ~ , ~ ~received the most press, giardiasis can be acquired with travel to virtually any region. G. larnblia prevalence rates range from 2% to 5% in industrialized countries to up to 20% to 30% in the developing regions.34As few as 10 to 100 cysts ingested with water can establish infection,gsand person-to-person transmission may occur, particularly in settings in which fecal-oral hygiene is poor. The clinical spectrum of giardiasis is broad including asymptomatic cyst passage; acute, often self-limited diarrhea; and chronic severe diarrhea with malabsorption and weight loss. Symptoms typically develop after a 1-to 2-week incubation period; however, the time between ingestion of cysts and detectability of Giardia in stool (the prepatent period) may be longer than the incubation period. Jokipii and JokipiP described a median incubation period of 8 days in a large group of students returning from St. Petersburg (formerly Leningrad) with a median prepatent period of 14 days. In two thirds of these returned travelers, symptoms lasted for at least 1 week before the parasite became detectable in stool. In addition to diarrhea, a majority of symptomatic patients report bloating, cramping, and foul-smelling, greasy stools. Weight loss, also reported in more than 50% of symptomatic infections in several series,’” 17,80,82,92 may be profound, with a mean weight loss of 10 lb reported by 41 patients in one study.82Steatorrhea and malabsorption of a number of nutrients, including vitamins A and B,, may O C C U ~ . ~ ~Lactose ~ ~ ~ deficiency, with resultant symptomatic lactose intolerance, has been reported in some studies30,53, 94, lZ3 but not in others, perhaps owing to baseline differences in host nutritional status or genetic factors.39,53 Diagnosis can be made with traditional microscopy, which requires identification of cysts or motile trophozoites in stool. Repeated stool evaluations appears to increase the sensitivity of microscopy from around 70% for a single stool specimen to up to 85% to 90% after three stools.mc83Newer antigen detection assays using enzyme-linked immunosorbent? 6, loo* lol or immunoflu~resence~~ technology range in sensitivity from 85% to 98% and in specificity from 90% to 100% as compared with microscopy and are comparable to the cost of a stool ova and parasite examination.6 Metronidazole (although not FDA approved for this indication) and tinidazole (not available in the United States) are both highly effective in treating giardiasis, with response rates typically greater than 90%.34 Although less effective, furazolidone is widely used in children in the United States.
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Cryptosporidiumparvum
Only anecdotally reported before 1982, C. parvum was brought to prominent medical attention by severe illnesses in HIV-infected patients and in previously healthy veterinary student^.",^ It is now recognized as a cause of diarrhea in 2% to 6% of immunocompetent patients in industrialized and developing countries, respectively, and in travelers' and is a leading cause of persistent diarrhea in children in tropical developing This hardy, chlorine-resistant parasite infects many mammals including humans and is highly infectious with a low infectious dose. Thus, it is easily spread in water and by direct person-to-person contact.22, 31,67, 86 Cryptosporidiurn oocysts are not only chlorine-resistant and highly infectious but also small (2-5 km), rendering water purification by filtration difficult and unreliable (51 km filters required to remove such small oocysts frequently get clogged). Heat (to >65"C [145"F]) for 30 minutes is probably the surest way to kill C. parvum. Cryptosporidiosis has been noted as a cause of diarrhea in travelers as well as in waterborne and foodborne (apple cider) outbreaks, swimming pool outbreaks, and outbreaks in day care centers, hospitals, and Clinically, cryptosporidiosis typically presents after an incubation period of 1 to 2 weeks with watery diarrhea, abdominal cramps and weight loss, and occasionally vomiting and fever (usually low grade) lasting an average of 12 days but often longer than 2 to 3 weeks.75In patients with AIDS, particularly those with CD, lymphocyte counts less than 50 cells/mm3, cryptosporidiosis may cause prolonged bouts of fulminant, large yolume (2 L/day) diarrhea, often associated with profound wasting and sometimes death.15,36 The impact of cryptosporidiosis may extend beyond the diarrheal illness itself to predispose to heavier diarrheal burdens for up to 1 year after the cryptosporidial illness5,76 or malnutrition even without diarrhea.20 After ingestion of as few as 1 to 100 oocysts, four sporozoites are released from each oocyst in the small bowel. The sporozoites then invade and multiply just beneath the luminal cell membrane of the epithelial cell but (unlike Cyclospora, Isospora, and microsporidia) do not invade the cell cytoplasm. Although it may spread via luminal routes to the gallbladder or even lung (in immunocompromised patients), the primary effect of cryptosporidial infection appears to be disruption of the mucosal barrier function and possibly triggering of secretion via accessory macrophages or fibroblasts and cytokmes.8,45, 72 The diagnosis of cryptosporidiosis is made by acid-fast stain of stool or by using an immunofluorescence antibody; concentration is usually not necessary and may (with formalin-ethyl-acetate concentration) result in loss of many oocysts.118Enzyme immunoassays may also be helpful and polymerase chain reaction (PCR) methods are being developed.", 69 Treatment of cryptosporidiosis has been a difficult challenge. Of more than 100 agents tried, only paromomycin and possibly azithromycin, clarithromycin, and nitazoxanide have shown slight effectiveness or are under current study.37 Because of glutamine's effectiveness in driving sodium cotransport70even in the presence of experimental cryptosporidial infection9we are exploring the effects of glutamine in speeding recovery of damaged intestinal barrier function in children and in HIV infected patients with diarrhea or maln~trition.~~, Cyclospora cayatenensis
First demonstrated by Ashfordlo in three patients with diarrhea in Papua New Guinea, along with its probable sporulation in 1979, the larger cryptospori-
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dium-like Cyclospora was subsequently linked to persistent diarrhea in travelers to the Caribbean and Nepal and HIV-associated diarrhea.7’,IwAlthough it was initially called a cyanobacterium-like body (CLB) thought to be related to bluegreen algaeY4 it was subsequently shown definitively to sporulate and was named Cyclospora cayatenensiss9 and is phylogenetically very closely related by small subunit ribosomal DNA to members of the Eimeria g e n ~ s . 9 ~ It is clear from repeated outbreaks of persistent diarrhea during the summer rainy season in Nepalz1, Iz7 and now the repeated June-July outbreaks associated with Guatemalan raspberries in the United States” that Cyclospora is widespread and strikingly seasonal. From the outbreak among Chicago housestaff in 1990 and from an outbreak among British troops in Pokhara, Nepal, in June 1994, it appears that water, even fully chlorinated, can be a vehicle in addition to fresh berrie~.~” 95 Unlike Cryptosporidium, however, the obligate maturation of Cyclospora oocysts for several days outside its human host means that secondary person-to-person spread does not seem to occur. The clinical hallmarks of cyclosporiasis are diarrhea, anorexia, and severe fatigue or malaise, with illness often lasting a median of 10 days5]to a median of 7 weeks among tourists in Nepal.- The pathologic changes of villous blunting and mild inflammatory infiltrate are similar to that seen with cryptosporidiosis and microsporidial infection.21, It is important to diagnose cyclosporiasis using acid-fast stain (or with microwave heated safranin staining1I7),as it is readily responsive to treatment with sulfamethoxazole-trimethoprim, even in patients with AIDS.55,91 In Haiti, of 450 patients with AIDS and diarrhea lasting longer than 3 weeks, 30% had Cryptosporidium, 12% I. belli, 11%Cyclospora, 3% G. lamblia, and 1% A. k i s t ~ l y t i c a . ~ ~ Like Cyclospora, the larger lsospora belli (with two sporocysts, each with four sporozoites) should also be sought in normal or immunocompromised travelers with persistent diarrhea using acid-fast stain, as it too responds to sulfamethoxazole-trimethoprim treatment.Io7 Microsporidia This group of very primitive tiny eukaryotic organisms (with a membrane bound nucleus but no mitochondria or Golgi) that multiplies by binary fission and constitutes nearly 1000 species was first noted in the mid-1800s in the silkworm industry. Since the initial reports of Desporte et a1 (1985)= and Modigliani et a1 (1985)81of E. bieneusi found by electron microscopy in a patient with AIDS and diarrhea, the two microsporidial species E. bieneusi and Encepkalitazoon (formerly Septata) intestinalis have been increasingly associated with 7% to 39% of persistent diarrheal illnesses in patients with AIDS.’” s7, 12c-122, Iz6 With rare exceptions (a Virchow University medical student who had traveled to a tropical area’”), microsporidia have not been associated with diarrhea in immunocompetent hosts. Hence, it should be sought (with a modified trichrome stain or with a new acid-fast/trichrome stain) in any immunocompromised patient presenting with persistent unexplained diarrhea.5s, This is especially important because E. intestinalis (which may disseminate) and possibly E. bieneusi may respond to albendazole therapy. Chemofluorescent agents such as Calcofluor White 2MR (American Cyanamid, Princeton, NJ) or Uvitex 2B (Ciba Geigy, Basel, Switzerland) lack specificity; however, new immunofluorescence and PCR techniques z ~ z 8 ,35 Other hold promise for improved detection of microsporidia in therapies besides albendazole under study include metronidazole, atovaquone, thalidomide, and nita~oxanide.~~
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HELMINTHS
Rarely, the traveler returning from particularly unsanitary situations will acquire dense infections with intestinal helminths, which may contribute to persisting diarrhea. Typically, only the helminths that establish intimate contact with intestinal mucosa (Trichuris trichiura, Strongyloides stercoralis, Capillaria philippinensis, and Schistosoma, particularly Schistosoma mansoni) are associated with chronic diarrhea.40Although similar data are not available for the returned traveler with trichuriasis, in a study of 1229 Mexican patients infected with T. trichiura, a correlation between fecal egg counts and diarrhea rates was observed, suggesting that heavy worm burden (and consequent mucosal irritation) may cause diarrhea.I3 There are occasional reports of such infections having been mistaken for inflammatory bowel disease.lo2* lo4 Although diarrhea does not feature prominently in most infections with S. stercoralis, with hyperinfection profuse watery, mucoid or bloody diarrhea may occur as a result of extensive mucosal injury caused by millions of adult worms and filariform larvae.41,59 C. philippinensis, which, like S. stercoralis, is capable of replicating within the host and heavy infections with S. mansoni may also cause diarrhea probably by ~4,lZ4Finally, Goldsmith reported a case of causing extensive mucosal chronic diarrhea associated with Metagonimus yokagawai in a traveler returned from the Far East where this fluke is endemicM Acute or persistent abdominal pain can also be caused by a number of helminths. Among the hazards of eating undercooked or raw seafood (besides Vibrios, hepatitis A, Norwalk-like viruses) are Anasakis, Eustrogylides, and Heterophyes nematodes, Diphyllobothrium cestodes, and Metorchis trematodes, which typically cause abdominal pain with or without diarrhea.125The latter, M . conjunctus (a fluke of sled dogs) has caused biliary colic and eosinophilia in KoreanCanadians eating carp or “white sucker” sashimi.n Finally, abdominal pain, eosinophilia, and fecal Charcot-Leyden crystals may persist for several weeks after heavy hookworm exposure before the ova appear in the stool.
OTHER INFECTIOUS AGENTS
Whereas most bacterial agents are associated with illness lasting less than 14 days, persisting diarrhea with enterotoxigenic (E. coli, Shigella, Campylobacter, and Aerornonas) have been reported among either returned travelers or expatriates residing in developing countries?sa,11% In addition, enteropathogenic (E. coli), a cause of persistent diarrhea in developing regions, has been implicated in chronic diarrhea among some children returning from the Indian subcontinent and Morocco to the United Kingdom. Although its etiologic role is controversial, Plesiomonas shigelloides has been implicated as an occasional cause of sporadic and epidemic diarrhea56,116 as well as chronic travelers’ diarrhea.@* 96 In a Canadian case-control study, 71% of patients with €! shigelloides diarrhea had a recent history of travel to the tropics, and in 76% of cases the illness persisted for greater than 2 weeks.@ Diarrhea seen with P. shigelloides has been variously characterized as secretory to invasive.16,@ These organisms readily grow on most commonly used nonselective bacteriologic media and are usually detected if present in large numbers.79Rarely agents such as Leishmania, Toxoplasma, and fungi (such as Histoplasma) involve the bowel and cause enteritis in immunocompromised patients.37
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OTHER CAUSES Tropical sprue, possibly an infectious disease, has been described in travelers returning from locations in the tropics (30" to either north or south of the equator), particularly those who had prolonged stays in India, Southeast Asia, Southern Africa, and South America?O In addition to diarrhea and other gastrointestinal symptoms such as abdominal cramping patients often report fatigue and malaise. Weight loss and malabsorption subsequently develop, often with associated deficiencies in folic acid, vitamin BIZ,and other nutrients. Small bowel biopsy, which is required to make the diagnosis, typically shows villous blunting and broadening. Tropical sprue typically responds to tetracyclines and folic acid.&,99 Small bowel overgrowth also has been cited as a cause of chronic or recurrent diarrhea in travelers,19,32 and lactose intolerance, due to widespread damage to intestinal mucosa, with resultant disaccharidase deficiencies, may be a secondary cause of diarrhea following an initial infectious insult. This enzyme deficiency is usually temporary, resolving within several weeks of the initial insult; however, in some patients, possibly those with genetic hypolactasia unmasked by the initial infectious insult, lactose intolerance may Other causes to consider in the differential diagnosis of persisting diarrhea in the returned traveler include other underlying causes of chronic gastrointestinal infection: irritable bowel syndrome, inflammatory bowel diseases, diverticulitis, colorectal carcinoma, Whipple's disease, and laxative abuse?9,49, 90, Io6 Finally, when no clear etiology is identified, the diarrheal illness may last for several months but is usually self-limiting4
SUMMARY
In conclusion, the causes of chronic diarrhea in the returned traveler are protean. Careful evaluation requires an understanding of where the traveler has been, when they were there, the type of diarrheal illness, medications taken, and knowledge of the patients' other medical problems. Protozoa, particularly G. lamblia, C. parvum, and C. cayatenensis, are among the more commonly identified agents. If the patient is immunocompromised, microsporidia and Isospora become more likely, and a prior history of antimicrobial use raises the possibility of C. dificile colitis. Occasionally helminths, which establish intimate contact with the intestinal mucosa, may also cause prolonged diarrhea. If these and other gastrointestinal insults, such as tropical sprue, small bowel overgrowth, lactose intolerance, and processes unrelated to travel are excluded by more invasive studies or clinical history, the patient can be reassured that idiopathic chronic diarrhea is usually self-limited.
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48. Guerrant RL, Keystone J S Diarrhea in the returning traveler. In Strickland GT (ed): Hunter’s Tropical Medicine. Philadelphia, WB Saunders, 1991, pp 1031-1034 49. Harries AD, Myers 8, Cook GC: Inflammatory bowel disease: A common cause of bloody diarrhoea in visitors to the tropics. British Medical Journal Clinical Research Ed 291:1686-1687, 1985 50. Hartong WA, Gourley WK, Arvanitakis C: Giardiasis: Clinical spectrum and functional-structural abnormalities of the small intestinal mucosa. Gastroenterology T61-69, 1979 51. Herwaldt BL, Ackers ML, et al: An outbreak in 1996 of cyclosporiasis associated with imported raspberries. N Engl J Med 336:1548-1556, 1997 52. Herwaldt BL, Ackers M L An outbreak in 1996 of cyclosporiasis associated with imported raspberries: The Cyclospora Working Group. N Engl J Med 33615481556, 1997 52a. Hill SM, Phillips AD, Walker-Smith JA: Enteropathogenic escherichia’coli and life threatening chronic diarrhea. GUT 32:154-158, 1991 53. Hjelt K, Paerregaard A, Krasilnikoff PA: Giardiasis causing chronic diarrhoea in suburban Copenhagen: Incidence, physical growth, clinical symptoms and small intestinal abnormality. Acta Paediatr 81:881-886, 1992 54. Hoge CW, Shlii DR, Rajah R, et a1 Epidemiology of diarrhoea1 illness associated with coccidian-like organism among travelers and foreign residents in Nepal. Lancet 341:1175-1179, 1993 55. Hoge CW, Shlim DR, Ghimire M, et al: Placebo-controlled trial of co-trimoxazole for Cyclosporu infections among travelers and forei residents in Nepal [published erratum appears in Lancet 345(8956):1060, 19951. g n c e t 345:691-693, 1995 56. Holmberg SD, Farmer JJD.Aeromonus hydrophila and Plesiomonas shigelloides as causes of intestinal infections. Rev Infect Dis 6633-639, 1984 57. Huang P, Weber JT, Sosin DM, et a1 The first reported outbreak of diarrheal illness associated with Cyclosporu in the United States. Ann Intern Med 123:409-414, 1995 57a. Hutchins P, Hindocha P, Phillips A, et a1 Travellers’ diarrhea with a vengeance in children of UK immigrants visiting their parental homeland. Arch Dis Child 57208-211, 1982 58. Ignatius R, Lehmann M, Miksits K, et al: A new acid-fast trichrome stain for simultaneous detection of Cryptosporidium parvum and microsporidial species in stool specimens. J Clin Microbiol35:446-449, 1997 59. Igra-Siegman Y,Kapila R, Sen P, et al: Syndrome of hyperinfection with Strongyloides sfercorulis. Rev Infect Dis 3397-407, 1981 60. Jain NK, Rosenberg DB, Ulahannan MJ, et al: Sorbitol intolerance in adults. Am J Gastroenterol 80678481,1985 61. Jokipii AM, Jokipii L: Prepatency of giardiasis. Lancet 1:1095-1097, 1977 62. Jokipii L, Jokipii AM: Giardiasis in travelers: A prospective study. J Infect Dis 130295-299, 1974 63. Kain KC, Kelly MT: Clinical features, epidemiology, and treatment of Plesiomonas shigelloides diarrhea. J Clin Microbiol 27998-1001, 1989 64. Kettis AA, Magnius L Giurdiu lumbliu infection in a group of students after a visit to Leningrad in March 1970. Scand J Infect Dis 5:289-292, 1973 65. Keystone JS,Kozarsky PE: Health advice for international travel. In Guerrant RL, Krogstad D, Maguire JH, et a1 (eds): Tropical Infectious Diseases: Principles, Pathogens, and Practice. New York, Churchill Livingstone, in press 66. Klipstein FA, Falaiye J M Tropical sprue in expatriates from the tropics living in the continental United States. Medicine 48475-491, 1969 67. Koch KL, Phillips DJ, Aber RC, et al: Cryptosporidiosis in hospital personnel. Ann Intern Med 102:593-596, 1985 68. Kotler DP, Francisco A, Clayton F, et al: Small intestinal injury and parasitic diseases in AIDS. Ann Intern Med 113444-449,1990 69. Laxer MA, Timblin BK, Pate1 RJ: DNA sequences for the specific detection of Cryptosporidium purvum by the polymerase chain reaction. Am J Trop Med Hyg 45(6):68&694, 1991 70. Lima AAM, Soares AM, Freire JE Jr, et al: Cotransport of sodium with glutamine,
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alanine and glucose in the isolated rabbit ileal mucosa. Braz J Med Biol Res 25637640, 1992 71. Lima AAM, Barboza MS Jr, Silva TMJ, et al: Enteroaggregative E. coli associated with persistent diarrhea: Pathophysiology and treatment with glutamine-based oral rehydration and nutrition therapy (ORNT). Presented at the 6th Annual Meeting of the NIAID International Centers for Tropical Disease Research (ICTDR), Bethesda, MD, May 57,1997 72. Lima AAM, Silva TMJ, Gifoni AMR, et al: Mucosal injury and disruption of intestinal barrier function in HIV-infected individuals with and without diarrhea and cryptosporidiosis in Northeast Brazil. Am J Gastroenterol921861-1866, 1997 73. Long EG, Ebrahimzadeh A, White EH, et al: Alga associated with diarrhea in patients with acquired immunodeficiency syndrome and in travelers. J Clin Microbiol 28(6):1101-1104, 1990 74. Long EG, White EH, Carmichael WW, et al: Morphologic and staining characteristics of a cyanobacterium-like organism associated with diarrhea. J Infect Dis 164:199202, 1991 75. MacKenzie WR, Hoxie NJ, Proctor ME, et al: A massive outbreak in Milwaukee of Cryptosporidium infection transmitted through the public water supply. N Engl J Med 331:161-167, 1994 76. MacKenzie WR, Schell WL, Blair KA, et a1 Massive outbreak of waterborne Cryptosporidium infection in Milwaukee, Wisconsin: Recurrence of illness and risk of secondary transmission. Clin Infect Dis 2L57-62, 1995 77. MacLean JD, Arthur JR, Ward BJ, et a1 Common-source outbreak of acute infection due to the North American liver fluke Metorchis conjunctus. Lancet 347:154-158, 1996 78. McAuliffe JF, Shields DS, de Souza MA, et al: Prolonged and recurring diarrhea in the Northeast of Brazil: Examination of cases from a community-based study. J Pediatr Gastroenterol Nutr 5:902-906, 1986 79. Mickelsen PA, Tompkins L S Use of the bacteriology and mycology laboratories to diagnose gastrointestinal infections. In Blaser MJ, Smith, (ed): Infections of the Gastrointestinal Tract. New York, Raven, 1995, p p 1223-1268 80. Mintz ED, Hudson-Wragg M, Mshar P, et al: Foodbome giardiasis in a corporate office setting. J Infect Dis 167250-253, 1993 81. Modigliani R, Bories C, LeCharpentier Y, et al: Diarrhea and malabsorption in acquired immune deficiency syndrome: A study of four cases with special emphasis on opportunistic protozoan infestations. Gut 26179-187,1985 82. Moore GT, Cross WM, McGuire D, et al: Epidemic giardiasis at a ski resort. N Engl J Med 281:402407, 1969 83. Naik SR, Raue NR, Vinayak VK A comparative evaluation of examinations of three stool samples, jejunal aspirate and jejunal mucosal impression smears in the diagnosis of giardiasis. Ann Trop Med Parasitol 72491492, 1978 84. Nash TE, Cheever AW, Ottesen EA, et al: Schistosome infections in humans: Perspectives and recent findings. NIH conference. Ann Intern Med 97:740-754, 1982 85. Navin TR, Juranek DD: Cryptosporidiosis: Clinical, epidemiologic, and parasitologic review. Rev Infect Dis 6313-327,1984 86. Newman RD, Zu S X , Wuhib T, et al: Household epidemiology of Cryptosporidium purvum infection. Ann Intern Med 120500-505, 1994 87. Orenstein JM, Chiang J, Steinberg W, et a1 Intestinal microsporidiosis as a cause of diarrhea in human immunodeficiency virus-infected patients. Hum Pathol 21:475481, 1990 88. Orenstein JM, Zierdt W, Zierdt C, et a1 Identification of spores of Enterocyfozoon bieneusi in stool and duodenal fluid from AIDS patients. Lancet 336:1127-1128,1990b 89. Ortega YR, Sterling CR, Gilman RH, et a1 Cyclosporu sp-a new protozoan pathogen of humans. N Engl J Med 328130&&1312, 1993 90. Overbosch D, Ledeboer M ‘The tropics in our bathroom’: Chronic diarrhoea after retum from the tropics. Scand J Gastroenterol212:43-47, 1995 Verdier Rl, Boncy M, et al: Cyclospora infection in adults infected with 91. Pape JW, HN: Clinical manifestations, treatment, and prophylaxis. AM Intern Med 121:654657, 1994
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92. Petersen LR, Cartter ML, Hadler J L A food-borne outbreak of Giurdiu lumbliu. J Infect Dis 1 5 7 8 4 W , 1988 93. Petri WA Jr: Amebiusis and the Entumoeba histolyticu Gal/GalNAc lectin: From lab bench to bedside. J Invest Med 44:24-36, 1996 94. Pettoello Mantovani M, Guandalini S, Ecuba P, et a1 Lactose malabsorption in children with symptomatic Giardiu lurnbliu infection: Feasibility of yogurt supplementation. J Pediatr Gastroenterol Nutr 9295-300, 1989 95. Rabold JG, Hoge CW, Shlim DR, et a 1 Cyclosporu outbreak associated with chlorinated drinking water [letter]. Lancet 344:136&1361, 1994 96. Rautelin H, Sivonen A, Kuikka A, et a 1 Enteric Plesiomonus shigelloides infections in Finnish patients. Scand J Infect Dis 27495498,1995 97. Relman DA, Schmidt TM, Gajadhar A, et a1 Molecular phylogenetic analysis of Cyclosporu, the human intestinal pathogen, suggests that it is closely related to Eimeriu species. J Infect Dis 173:440-445, 1996 98. Rendtorff R, Holt C: The experimental transmission of human intestinal protozoan parasites. IV Attempts to transmit Entumoeba coli and Giuridu lurnbliu cysts by water. Am J Hyg 60327-338,1954 99. Rickles FR, Klipstein FA, Tomasini J, et a 1 Long-term follow-up of antibiotic-treated tropical sprue. Ann Intern Med 76203-210, 1972 100. Rosenblatt JE, Sloan LM, Schneider SK Evaluation of an enzyme-linked immunosorbent assay for the detection of Giurdiu lumbliu in stool specimens. Diagn Microbiol Infect Dis 16337-341,1993 101. Rosoff JD, Sanders CA, Sonnad SS, et a 1 Stool diagnosis of giardiasis using a commercially available enzyme immunoassay to detect Giardia-specific antigen 65 (GSA 65). J Clin Microbiol271997-2002, 1989 102. Ross D F Chronic diarrhoea due to Trichocephalus trichiurus. Lancet 297-99, 1942 103. Sandfort J, Hannemann A, Gelderblom H, et al: Enterocytozoon bieneusi infection in an immunocompetent patient who had acute diarrhea and who was not infected with the human immunodeficiency virus. Clii Infect Dis 19514516,1994 104. Sandler M: Whipworm infestation in the colon and rectum stimulating Crohn’s colitis. Lancet 2210, 1981 105. Schorling JB, Wanke CA, Schorling SK, et a 1 A prospective study of persistent diarrhea among children in an urban Brazilian slum. Am J Epidemiol 132144-156, 1990 106. Schumacher G, Kollberg 8, Ljungh A Inflammatory bowel disease presenting as travelers’ diarrhoea. Lancet 341:241-242, 1993 107. Shaffer N, Moore L Chronic travelers’ diarrhea in a normal host due to Zsosporu belli. J Infect Dis 159596-597, 1989 108. Shlim DR, Cohen MT, Eaton M, et a 1 An alga-like organism associated with an outbreak of prolonged diarrhea among foreigners in Nepal. Am J Trop Med Hyg 45383-389, 1991 109. Soave R, Dubey JE’, Ramos LJ, et al: A new intestinal pathogen? Clin Res 34:533A, 1986 110. Solomons Nw: Giardiasis: Nutritional implications. Rev Infect Dis 48594369, 1982 111. Steffen R, Rickenbach M, Wilhelm U, et al: Health problems after travel toadeveloping countries. J Infect Dis 156384-91, 1987 112. Steffen R, Lobe1 HO Epidemiologic basis for the practice of travel medicine. Journal of Wilderness Medicine 5:5666, 1994 113. Sutton DL, Kamath KR: Giardiasis with protein-losing enteropathy. J Pediatr Gastroenterol Nutr 456-59, 1985 113a. Taylor DN, Houston R, Shlii DR, et a 1 Etiology of diarrhea among travellers and foreign residents in Nepal. JAMA 260:1245-1248, 1988 114. Thielman NM, Guerrant RL An algorithmic approach to the workup and management of HIV-related diarrhea. Journal of Clinical Outcomes Management 436-47, 1997 115. Thompson RG, Karandikar DS, Leek J: Giardiasis: An unusual cause of epidemic diarrhoea. Lancet 1:615-616, 1974
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116. Tsukamoto T, Kinoshita Y, Shimada T, et al: Two epidemics of diarrhoea1 disease possibly caused by Plesiomonas shigelloides. J Hyg 80275-280, 1978 117. Visvesvara GS, Moura H, Kovacsnace E, et a1 Uniform staining of Cyclosporu oocysts in fecal smears by a modified safranin technique with microwave heating. J Clin Microbiol 35730-733, 1997 118. Weber R, Bryan RT, Bishop HS, et a1 Threshold of detection of Cryptosporidium oocysts in human stool specimens: Evidence for low sensitivity of current diagnostic methods. J Clin Microbiol29132%1327, 1991 119. Weber R, Bryan RT, Owen RL, et a1 Improved light-microscopical detection of microsporidia spores in stool and duodenal aspirates. N Engl J Med 326161-166, 1992 120. Weber R, Bryan RT, Schwartz DA, et a1 Human microsporidial infections. Clinical Microbiology Review 7426461,1994 121. Weber R, Sauer B, Spycher MA, et a1 Detection of Septutu intestinalis in stool specimens and coprodiagnostic monitoring of successful treatment with albendazole. Clin Infect Dis 1932-345, 1994 122. Weber R, Bryan R T Microsporidial infections in immunodeficient and immunocompetent patients. Clin Mect Dis 19:517-521,1994 Poley JR, Hensley J, et a1 Intestinal disaccharidase and alkaline phospha123. Welsh JD, tase activity in giardiasis. J Pediatr Gastroenterol Nutr 33740, 1984 124. Whalen GE, Rosenberg EB, Strickland GT, et a1 Intestinal capillariasis: A new disease in man. Lancet 13-16, 1969 125. Wittner M, Turner JW, Jacquette G, et a1 Eustrongylidiasis-a parasitic infection acquired by eating sushi. N Engl J Med 3201124-1126,1989 126. Wuhib T, Silva TM, Newman RD, et ak Cryptosporidial and microsporidialinfections in human immunodeficiency virus-infected patients in northeastern Brazil. J Infect Dis 170494-497,1994 127. Wurtz R Cyclosporu: A newly identified intestinal pathogen of humans. C l i Infect Dis 18620423,1994
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.OO
PERSISTENT DIARRHEA IN THE RETURNED TRAVELER Nathan M. Thielman, MD, MPH, and Richard L. Guerrant, MD
Of nearly 500 million international travelers each year, almost 50 million, an ever increasing number, travel from industrialized countries to tropical or developing areas. These include more than 27 million North Americans, almost 18 million Europeans, 3 million Japanese, and 1 million Australians and New ZealandersffiOf the many health threats'that affect over half of these travelers, diarrheal diseases are by far the most common, albeit not most serious concern.112 Approximately one third of all travelers to tropical developing areas experience a diarrheal illness. Fortunately, the vast majority of these are either self-limited or promptly responsive to a commonly used short-course of an antimicrobial agent effective against enterotoxigenic Escherichia coli and other enteric bacteria that constitute the majority of pathogens causing travelers diarrhea; however, prospective studies of over 7800 Swiss travelers, 4600 Peace Corps volunteers, and 35 students in Latin America suggest that approximately 3% of illnesses may last longer than 14 days and 1% to 2% longer than 1 month.32Of 7886 Swiss international travelers, 0.9%(73) had a diarrheal illness lasting more than 30 days upon return, with the highest rates being among those visiting West Africa and regions of the Far East."' Of 4607 US Peace Corps volunteers, 1.7"/0 (78) had a diarrheal illness lasting 1 month or longer, with highest rates being among those in Haiti, Central and West Africa, and Nepal: whereas 1 of 35 students traveling in Latin America for longer than 1 month developed a persistent diarrheal illness (2.9%).& DEFINITIONS
The definition of persistent diarrhea has evolved largely from studies of endemic diarrheal illnesses of children in tropical developing areas to be diarrhea ~
From the Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina (Nh4T); and the Division of Geographic and International Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia (RLG)
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lasting greater than 14 days.7 The basis for this definition lies in the fact that diarrhea lasting into a third week tends to identify high-risk children for heavy lo5 diarrheal illness The gastroenterologist’s definition of chronic diarrhea extends the syndrome to lasting greater than 1 month and includes some 20% of cases caused by Among the laxative overuse and 50% that are “functional” or “idiopathi~.”~~ ”organic” causes of chronic diarrhea in 30% of cases are infectious etiologies, including Giardia, Cyptosporidium, Entamoeba kistolytica, Strongyloides, and Clostridium dificile infections as well as inflammatory bowel disease, collagenous or lymphocytic colitis, fat or carbohydrate malabsorption, and use of medications such as antibiotics; antihypertensive, antiarrhythmic, and calcium-channel blocking drugs; magnesium antacids; caffeine; alcohol; or sorbitol (10 g sorbitol in 4-5 sugar-free mints caused diarrhea in 48% of volunteersm).Other causes include previous surgery such as gastrectomy or bowel resection, endocrine causes (including Addison‘s disease, hypothyroidism or hyperthyroidism, diabetes), or tumors (such as villous adenoma or medullary carcinoma of the thyroid gland). In contrast, the causes of persistent diarrhea in travelers have included Giardia lamblia, Cyptosporidium, Cyclospora, and lsospora belli as well as bacterial agents including enteropathogenic, enterotoxigenic, enterohemorrhagic, and enteroaggregative E. coli, Skigella, Campylobacter jejuni, Aeromonas, Plesiomonas, toxigenic c. dificile, and likely small bowel overgrowth, HIV infection, and strongy10idiasis.~~ Other less common parasitic causes of diarrhea include Dientamoeba fragilis, Capillaria pkilippinensis, Fasciolopsis buski, Trickuris trickiura, and Sckistosoma. CLINICAL PRESENTATION
Especially important in evaluation of persistent diarrhea in travelers are where the travelers have been, when they were there, the type of diarrheal illness, medications taken, food intolerance, and any potential immunocompromised state. Geographic exposure might suggest, for example, Cyclospora infection among travelers to Nepal during the spring or summer months. Time of travel includes relevant incubation periods, such as usually 1 to 2 weeks for Giardia, Cryptosporidium or Cyclospora infections. The type of diarrhea is also useful in narrowing the differential diagnosis. Bloody diarrhea suggests E. kistolytica or possibly enterohemorrhagic E. coli infection. Inflammatory illnesses with fever suggest an invasive pathogen such as Campylobacter, Salmonella, Shigella, or possibly C. difficile, whereas noninflammatory diarrhea, especially with weight loss, suggests Giardia, Cypfosporidium, I. belli or possibly Strongyloides infection. In addition, lactose intolerance often follows a traveler’s diarrheal illness and being immunocompromised opens an additional range of diagnostic possibilities. Whenever a diarrheal illness persists beyond 10 to 14 days, especially if there has been no response to commonly used quinolone antibiotics (which are highly effective against most bacterial agents that cause diarrhea), one should consider either antibiotic-associated toxigenic C. dzficile infection or one of the protozoan parasitic causes of diarrhea. If the illness features fever or bloody diarrhea, one should consider amoebic colitis caused by virulent E. histolytica and obtain a trichrome stain for erythrophagocytic amebic trophozoites and often pyknotic or absent fecal leukocytes, or, even better, an enzyme immunoassay for virulent E. kisfolytica antige11.9~
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PROTOZOAL CAUSES The persistent diarrhea associated with protozoal pathogens is usually nonbloody, only mildly or noninflammatory diarrhea, and often accompanied by weight loss. The usual protozoal causes include G. larnblia, Cryptosporidium patwurn, Cyclosporu cuyafenensis (especially with fatigue), I. belli, D. fragilis, and in immunocompromised patients, microsporidia (Enferocyfozounbieneusi or Encephafifozoan intestinalis). Cyptosporidiurn, Cydospora, microsporidia, and to some extent, Isospora infections have been brought to heightened medical attention by the severe, often protracted diarrhea they cause in patients with AIDS. Giardia lamblia Giardiasis is one of the commonest causes of chronic diarrhea in the returned traveler. Although outbreaks among returned travelers from the former Soviet Union, especially St. Peter~burg,’~, 61 the Mediter~anean,”~ and mountainous regions in North A m e r i ~ a ’have ~ , ~ ~received the most press, giardiasis can be acquired with travel to virtually any region. G. larnblia prevalence rates range from 2% to 5% in industrialized countries to up to 20% to 30% in the developing regions.34As few as 10 to 100 cysts ingested with water can establish infection,gsand person-to-person transmission may occur, particularly in settings in which fecal-oral hygiene is poor. The clinical spectrum of giardiasis is broad including asymptomatic cyst passage; acute, often self-limited diarrhea; and chronic severe diarrhea with malabsorption and weight loss. Symptoms typically develop after a 1-to 2-week incubation period; however, the time between ingestion of cysts and detectability of Giardia in stool (the prepatent period) may be longer than the incubation period. Jokipii and JokipiP described a median incubation period of 8 days in a large group of students returning from St. Petersburg (formerly Leningrad) with a median prepatent period of 14 days. In two thirds of these returned travelers, symptoms lasted for at least 1 week before the parasite became detectable in stool. In addition to diarrhea, a majority of symptomatic patients report bloating, cramping, and foul-smelling, greasy stools. Weight loss, also reported in more than 50% of symptomatic infections in several series,’” 17,80,82,92 may be profound, with a mean weight loss of 10 lb reported by 41 patients in one study.82Steatorrhea and malabsorption of a number of nutrients, including vitamins A and B,, may O C C U ~ . ~ ~Lactose ~ ~ ~ deficiency, with resultant symptomatic lactose intolerance, has been reported in some studies30,53, 94, lZ3 but not in others, perhaps owing to baseline differences in host nutritional status or genetic factors.39,53 Diagnosis can be made with traditional microscopy, which requires identification of cysts or motile trophozoites in stool. Repeated stool evaluations appears to increase the sensitivity of microscopy from around 70% for a single stool specimen to up to 85% to 90% after three stools.mc83Newer antigen detection assays using enzyme-linked immunosorbent? 6, loo* lol or immunoflu~resence~~ technology range in sensitivity from 85% to 98% and in specificity from 90% to 100% as compared with microscopy and are comparable to the cost of a stool ova and parasite examination.6 Metronidazole (although not FDA approved for this indication) and tinidazole (not available in the United States) are both highly effective in treating giardiasis, with response rates typically greater than 90%.34 Although less effective, furazolidone is widely used in children in the United States.
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Cryptosporidiumparvum
Only anecdotally reported before 1982, C. parvum was brought to prominent medical attention by severe illnesses in HIV-infected patients and in previously healthy veterinary student^.",^ It is now recognized as a cause of diarrhea in 2% to 6% of immunocompetent patients in industrialized and developing countries, respectively, and in travelers' and is a leading cause of persistent diarrhea in children in tropical developing This hardy, chlorine-resistant parasite infects many mammals including humans and is highly infectious with a low infectious dose. Thus, it is easily spread in water and by direct person-to-person contact.22, 31,67, 86 Cryptosporidiurn oocysts are not only chlorine-resistant and highly infectious but also small (2-5 km), rendering water purification by filtration difficult and unreliable (51 km filters required to remove such small oocysts frequently get clogged). Heat (to >65"C [145"F]) for 30 minutes is probably the surest way to kill C. parvum. Cryptosporidiosis has been noted as a cause of diarrhea in travelers as well as in waterborne and foodborne (apple cider) outbreaks, swimming pool outbreaks, and outbreaks in day care centers, hospitals, and Clinically, cryptosporidiosis typically presents after an incubation period of 1 to 2 weeks with watery diarrhea, abdominal cramps and weight loss, and occasionally vomiting and fever (usually low grade) lasting an average of 12 days but often longer than 2 to 3 weeks.75In patients with AIDS, particularly those with CD, lymphocyte counts less than 50 cells/mm3, cryptosporidiosis may cause prolonged bouts of fulminant, large yolume (2 L/day) diarrhea, often associated with profound wasting and sometimes death.15,36 The impact of cryptosporidiosis may extend beyond the diarrheal illness itself to predispose to heavier diarrheal burdens for up to 1 year after the cryptosporidial illness5,76 or malnutrition even without diarrhea.20 After ingestion of as few as 1 to 100 oocysts, four sporozoites are released from each oocyst in the small bowel. The sporozoites then invade and multiply just beneath the luminal cell membrane of the epithelial cell but (unlike Cyclospora, Isospora, and microsporidia) do not invade the cell cytoplasm. Although it may spread via luminal routes to the gallbladder or even lung (in immunocompromised patients), the primary effect of cryptosporidial infection appears to be disruption of the mucosal barrier function and possibly triggering of secretion via accessory macrophages or fibroblasts and cytokmes.8,45, 72 The diagnosis of cryptosporidiosis is made by acid-fast stain of stool or by using an immunofluorescence antibody; concentration is usually not necessary and may (with formalin-ethyl-acetate concentration) result in loss of many oocysts.118Enzyme immunoassays may also be helpful and polymerase chain reaction (PCR) methods are being developed.", 69 Treatment of cryptosporidiosis has been a difficult challenge. Of more than 100 agents tried, only paromomycin and possibly azithromycin, clarithromycin, and nitazoxanide have shown slight effectiveness or are under current study.37 Because of glutamine's effectiveness in driving sodium cotransport70even in the presence of experimental cryptosporidial infection9we are exploring the effects of glutamine in speeding recovery of damaged intestinal barrier function in children and in HIV infected patients with diarrhea or maln~trition.~~, Cyclospora cayatenensis
First demonstrated by Ashfordlo in three patients with diarrhea in Papua New Guinea, along with its probable sporulation in 1979, the larger cryptospori-
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dium-like Cyclospora was subsequently linked to persistent diarrhea in travelers to the Caribbean and Nepal and HIV-associated diarrhea.7’,IwAlthough it was initially called a cyanobacterium-like body (CLB) thought to be related to bluegreen algaeY4 it was subsequently shown definitively to sporulate and was named Cyclospora cayatenensiss9 and is phylogenetically very closely related by small subunit ribosomal DNA to members of the Eimeria g e n ~ s . 9 ~ It is clear from repeated outbreaks of persistent diarrhea during the summer rainy season in Nepalz1, Iz7 and now the repeated June-July outbreaks associated with Guatemalan raspberries in the United States” that Cyclospora is widespread and strikingly seasonal. From the outbreak among Chicago housestaff in 1990 and from an outbreak among British troops in Pokhara, Nepal, in June 1994, it appears that water, even fully chlorinated, can be a vehicle in addition to fresh berrie~.~” 95 Unlike Cryptosporidium, however, the obligate maturation of Cyclospora oocysts for several days outside its human host means that secondary person-to-person spread does not seem to occur. The clinical hallmarks of cyclosporiasis are diarrhea, anorexia, and severe fatigue or malaise, with illness often lasting a median of 10 days5]to a median of 7 weeks among tourists in Nepal.- The pathologic changes of villous blunting and mild inflammatory infiltrate are similar to that seen with cryptosporidiosis and microsporidial infection.21, It is important to diagnose cyclosporiasis using acid-fast stain (or with microwave heated safranin staining1I7),as it is readily responsive to treatment with sulfamethoxazole-trimethoprim, even in patients with AIDS.55,91 In Haiti, of 450 patients with AIDS and diarrhea lasting longer than 3 weeks, 30% had Cryptosporidium, 12% I. belli, 11%Cyclospora, 3% G. lamblia, and 1% A. k i s t ~ l y t i c a . ~ ~ Like Cyclospora, the larger lsospora belli (with two sporocysts, each with four sporozoites) should also be sought in normal or immunocompromised travelers with persistent diarrhea using acid-fast stain, as it too responds to sulfamethoxazole-trimethoprim treatment.Io7 Microsporidia This group of very primitive tiny eukaryotic organisms (with a membrane bound nucleus but no mitochondria or Golgi) that multiplies by binary fission and constitutes nearly 1000 species was first noted in the mid-1800s in the silkworm industry. Since the initial reports of Desporte et a1 (1985)= and Modigliani et a1 (1985)81of E. bieneusi found by electron microscopy in a patient with AIDS and diarrhea, the two microsporidial species E. bieneusi and Encepkalitazoon (formerly Septata) intestinalis have been increasingly associated with 7% to 39% of persistent diarrheal illnesses in patients with AIDS.’” s7, 12c-122, Iz6 With rare exceptions (a Virchow University medical student who had traveled to a tropical area’”), microsporidia have not been associated with diarrhea in immunocompetent hosts. Hence, it should be sought (with a modified trichrome stain or with a new acid-fast/trichrome stain) in any immunocompromised patient presenting with persistent unexplained diarrhea.5s, This is especially important because E. intestinalis (which may disseminate) and possibly E. bieneusi may respond to albendazole therapy. Chemofluorescent agents such as Calcofluor White 2MR (American Cyanamid, Princeton, NJ) or Uvitex 2B (Ciba Geigy, Basel, Switzerland) lack specificity; however, new immunofluorescence and PCR techniques z ~ z 8 ,35 Other hold promise for improved detection of microsporidia in therapies besides albendazole under study include metronidazole, atovaquone, thalidomide, and nita~oxanide.~~
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HELMINTHS
Rarely, the traveler returning from particularly unsanitary situations will acquire dense infections with intestinal helminths, which may contribute to persisting diarrhea. Typically, only the helminths that establish intimate contact with intestinal mucosa (Trichuris trichiura, Strongyloides stercoralis, Capillaria philippinensis, and Schistosoma, particularly Schistosoma mansoni) are associated with chronic diarrhea.40Although similar data are not available for the returned traveler with trichuriasis, in a study of 1229 Mexican patients infected with T. trichiura, a correlation between fecal egg counts and diarrhea rates was observed, suggesting that heavy worm burden (and consequent mucosal irritation) may cause diarrhea.I3 There are occasional reports of such infections having been mistaken for inflammatory bowel disease.lo2* lo4 Although diarrhea does not feature prominently in most infections with S. stercoralis, with hyperinfection profuse watery, mucoid or bloody diarrhea may occur as a result of extensive mucosal injury caused by millions of adult worms and filariform larvae.41,59 C. philippinensis, which, like S. stercoralis, is capable of replicating within the host and heavy infections with S. mansoni may also cause diarrhea probably by ~4,lZ4Finally, Goldsmith reported a case of causing extensive mucosal chronic diarrhea associated with Metagonimus yokagawai in a traveler returned from the Far East where this fluke is endemicM Acute or persistent abdominal pain can also be caused by a number of helminths. Among the hazards of eating undercooked or raw seafood (besides Vibrios, hepatitis A, Norwalk-like viruses) are Anasakis, Eustrogylides, and Heterophyes nematodes, Diphyllobothrium cestodes, and Metorchis trematodes, which typically cause abdominal pain with or without diarrhea.125The latter, M . conjunctus (a fluke of sled dogs) has caused biliary colic and eosinophilia in KoreanCanadians eating carp or “white sucker” sashimi.n Finally, abdominal pain, eosinophilia, and fecal Charcot-Leyden crystals may persist for several weeks after heavy hookworm exposure before the ova appear in the stool.
OTHER INFECTIOUS AGENTS
Whereas most bacterial agents are associated with illness lasting less than 14 days, persisting diarrhea with enterotoxigenic (E. coli, Shigella, Campylobacter, and Aerornonas) have been reported among either returned travelers or expatriates residing in developing countries?sa,11% In addition, enteropathogenic (E. coli), a cause of persistent diarrhea in developing regions, has been implicated in chronic diarrhea among some children returning from the Indian subcontinent and Morocco to the United Kingdom. Although its etiologic role is controversial, Plesiomonas shigelloides has been implicated as an occasional cause of sporadic and epidemic diarrhea56,116 as well as chronic travelers’ diarrhea.@* 96 In a Canadian case-control study, 71% of patients with €! shigelloides diarrhea had a recent history of travel to the tropics, and in 76% of cases the illness persisted for greater than 2 weeks.@ Diarrhea seen with P. shigelloides has been variously characterized as secretory to invasive.16,@ These organisms readily grow on most commonly used nonselective bacteriologic media and are usually detected if present in large numbers.79Rarely agents such as Leishmania, Toxoplasma, and fungi (such as Histoplasma) involve the bowel and cause enteritis in immunocompromised patients.37
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OTHER CAUSES Tropical sprue, possibly an infectious disease, has been described in travelers returning from locations in the tropics (30" to either north or south of the equator), particularly those who had prolonged stays in India, Southeast Asia, Southern Africa, and South America?O In addition to diarrhea and other gastrointestinal symptoms such as abdominal cramping patients often report fatigue and malaise. Weight loss and malabsorption subsequently develop, often with associated deficiencies in folic acid, vitamin BIZ,and other nutrients. Small bowel biopsy, which is required to make the diagnosis, typically shows villous blunting and broadening. Tropical sprue typically responds to tetracyclines and folic acid.&,99 Small bowel overgrowth also has been cited as a cause of chronic or recurrent diarrhea in travelers,19,32 and lactose intolerance, due to widespread damage to intestinal mucosa, with resultant disaccharidase deficiencies, may be a secondary cause of diarrhea following an initial infectious insult. This enzyme deficiency is usually temporary, resolving within several weeks of the initial insult; however, in some patients, possibly those with genetic hypolactasia unmasked by the initial infectious insult, lactose intolerance may Other causes to consider in the differential diagnosis of persisting diarrhea in the returned traveler include other underlying causes of chronic gastrointestinal infection: irritable bowel syndrome, inflammatory bowel diseases, diverticulitis, colorectal carcinoma, Whipple's disease, and laxative abuse?9,49, 90, Io6 Finally, when no clear etiology is identified, the diarrheal illness may last for several months but is usually self-limiting4
SUMMARY
In conclusion, the causes of chronic diarrhea in the returned traveler are protean. Careful evaluation requires an understanding of where the traveler has been, when they were there, the type of diarrheal illness, medications taken, and knowledge of the patients' other medical problems. Protozoa, particularly G. lamblia, C. parvum, and C. cayatenensis, are among the more commonly identified agents. If the patient is immunocompromised, microsporidia and Isospora become more likely, and a prior history of antimicrobial use raises the possibility of C. dificile colitis. Occasionally helminths, which establish intimate contact with the intestinal mucosa, may also cause prolonged diarrhea. If these and other gastrointestinal insults, such as tropical sprue, small bowel overgrowth, lactose intolerance, and processes unrelated to travel are excluded by more invasive studies or clinical history, the patient can be reassured that idiopathic chronic diarrhea is usually self-limited.
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