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INFECTIOUS CAUSES OF CHRONIC DIARRHEA
INFECTIOUS DIARRHEA
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INFECTIOUS CAUSES OF CHRONIC DIARRHEA Scott D. Lee, MD, and Christina M. Surawicz, MD
Most infectious diarrhea is acute. Chronic diarrhea can occur as a result of infections in several situations, as follows: 1. Some pathogens cause chronic symptoms, usually parasites, but sometimes bacteria. 2. Immunosuppressed individuals, such as those with human immunodeficiency virus (HIV) infection or on steroids or other immunosuppressants, cannot clear pathogens effectively and can develop chronic diarrhea. Campylobacter and Salmonella can cause persistent diarrhea in patients with HIV infection. 3. Some infections clear, but persons develop chronic symptoms, such as irritable bowel syndrome with diarrhea. Occasionally, ulcerative colitis develops after an acute infection.
This article focuses on the pathogens that can cause chronic diarrhea in immunocompetent individuals (Table 1). BACTERIA
Bacterial causes of chronic diarrhea are uncommon, but include Aeromonas, Plesiomonas, Campylobacter jejuni, Yersinia enterocolitica, Clostridium dificile, Salmonella, and Mycobacterium tuberculosis. Aeromonas
Aeromonas species are non-lactose-fermenting, facultative anaerobic, gramnegative rods found in fresh or brackish water. Three major species have been From the Department of Medicine (SDL, CMS), Section of Gastroenterology; and the Harborview Medical Center (CMS), University of Washington, Seattle, Washington
GASTROENTEROLOGY CLINICS OF NORTH AMERICA VOLUME 30 * NLTMBER 3 * SEPTEMBER 2001
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Table 1. INFECTIONS CAUSING CHRONIC DIARRHEA Colonic
Small Intestinal
Bacteria Aeromonas Plesiomonas Campylobactw Recurrent Clostridium difFcile Salmonella Mycobacterium tuberculosis Parasites Amoeba Trichuris Schis tosoma
Parasites Cryptosporidium Cyclospora Giardia lamblia lsospora belli Strongyloides
implicated as being pathogenic in humans: A. hydrophila, A. caviae, and A. sobria. The virulence of the organism is related to its ability to produce several toxins: enterotoxin, hemolysin, and cytotoxin. Aeromonas infections usually are associated with ingestion of untreated water.16 Infections tend to occur during warm months. Several studies have found that Aeromonas can be isolated in symptomatic children, implicating it as a pathogenic cause of diarrhea.5,28, 39 Aeromonas also has been isolated from healthy individuals, raising the question of the pathogenic nature of these organisms. With enteric illness secondary to Aeromonus, there is often watery diarrhea (which occasionally contains blood), vomiting, and mild fever. Symptoms usually resolve within 1 week but can become chronic, lasting more than 1 year in some patients. Diagnosis is made by stool culture. Treatment is primarily symptomatic. The role of antibiotics is unclear; their use has not shown significantbenefit. Aerornonus species tend to be resistant to p-lactams and first-generation and second-generation cephalosporins. Chloramphenicol, ciprofloxacin, aminoglycosides,third-generation cephalosporins, aztreonam, and imipenem are highly active against Aeromonas.
Plesiomonas
Plesiomonas shigelloides is a non-lactose-fermenting, facultatively anaerobic, gram-negative rod. Similar to Aeromonas, P. shigelloides is found in brackish and fresh water and can cause diarrheal disease in children and adults. Most cases in the United States are associated with foreign travel or ingestion of raw shellfish, untreated water, or The exact pathogenic properties by which P. shigelloides causes diarrhea are unclear. Although some species invade intestinal mucosa, others produce a c y t o t ~ x i nMost . ~ ~ patients have evidence of colitis and bloody diarrhea.= The most common symptoms are abdominal pain, vomiting, and fever. Symptoms can last for 2 weeks. Diagnosis is made by stool culture. Cases of chronic colitis resulting from P. shigelloides have been reported. Antibiotics can shorten the duration of symptoms. I? shigelloides is uniformly resistant to ampicillin, gentamicin, erythromycin, kanamycin, and streptomycin. It is sensitive to chloramphenicol, aminoglycosides, trimethoprim-sulfamethoxazole, fluoroquinolones, tetracycline, third-generation cephalosporins, and imipenem.
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Yersinia
Yersinia are gram-negative, non-lactose-fermenting coccobacilli that are motile at 25°C. They are classified by their somatic (0)and flagellar (H) antigens. The pathogenesis of disease is related to the adhesion of the organism to the epithelium and subsequent invasion. The production of a heat-labile enterotoxin, which is elaborated at 25°C but not at 37"C, plays a role in the pathogenesis. The terminal ileum is the area of attack. The colon is involved less frequently.& Yersinia can be found in stream and lake water. Yersinia has been isolated from many animals, which are an important reservoir and source of transmission. Epidemics have been linked to contaminated milk or ice cream. Disease tends to occur most frequently in children younger than 5 years old. The predominant serotype varies with location: the United States has primarily 08 isolates and Canada has 03 serotypes. In Scandinavia and Europe, where Yersinia disease is more frequent, serotypes 03 and 09 are most common. Diarrhea and abdominal pain are the commonest Fever and bloody diarrhea are less frequent. Mesenteric adenitis has been described in children older than 5. These patients often have nausea, vomiting, and aphthous ulcers in the mouth. Adults tend to have acute diarrhea, which can be followed by joint symptoms followed by a rash (erythema nodosum or erythema multiforme). Reactive polyarthropathy occurs in 2% of patients with yersiniosis and usually is associated with the major histocompatibility antigen HLA-B27. The clinical symptoms last 1 to 3 weeks but can last longer. Although findings on radiologic or endoscopic studies can resemble inflammatory bowel disease, most patients have normal findings on these studies.4z, 48, 49 Bacteremia is rare but can occur when the patient is immunocompromised or is debilitated. The diagnosis is made by stool culture. Treatment is primarily supportive for dehydration. There is no evidence that antibiotics alter the clinical course of disease induced by Y. enterocolitica. Antibiotics can be used in severe cases or with bacteremia. Salmonella
Salmonella are gram-negative bacilli with a wide range of hosts, which can be found in sewage, river water and seawater, and certain foods. Most Salmonella are flagellated. Of Salmonella that cause disease in humans, 90% fall into groups A to E, which contain 40 serotypes. Salmonella is a major cause of large food-borne outbreaks. Poultry, meats, eggs, and dairy products are the most frequently implicated sources. It is transmitted through personal contact or the fecal-oral route. The attack rate varies with age. Children younger than 1 year old have the highest attack rate, especially in the 3- to 5-month range. Elderly or debilitated individuals have a high attack rate and increased mortality. With lo7 organisms, there is a 50% attack rate; this rises to 90% with lo9 organisms. Many conditions are associated with an increase in the risk of salmonellosis. The association of sickle cell disease and Salmonella osteomyelitis has been well documented. In humans, recent use of antibiotics appears to increase the attack rate of Salmonella.12This increase is possibly secondary to disruption of the normal colonic flora, which results in decreased resistance to colonization by Salmonella. Other risk factors for salmonellosis are gastric surgery (presumably secondary to decreased gastric acidity), neoplasm, hemolytic anemia, and any condition giving rise to immunosuppression (chemotherapy, radiation therapy,
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corticosteroid therapy). There also has been an associationbetween schistosomiasis and salmonellosis.8,36 The commonest syndrome is gastroenteritis. The usual incubation period is 6 to 48 hours, but it has been reported to be 12 days. Initially the predominant symptoms are nausea and vomiting, followed by abdominal cramps and diarrhea. The diarrhea can range from mild watery diarrhea to severe dysentery. Fever is present in 50%. Typically, symptoms last 3 to 4 days. Diagnosis is made by stool culture. Blood cultures can be positive because bacteremia occurs in 5% to 10% of cases. After acute infection, a chronic carrier state of nontyphoidal Salmonella occurs at a rate of about 4 per 1000, most frequently in newborns and the elderly. Structural abnormalities in the biliary or urinary tract are risk factors. Clostridium difficile
C. dificile is the most frequent nosocomial pathogen of the gastrointestinal tract. It is an anaerobic gram-positive bacillus that is ubiquitous in the environment. Most people acquire C. dificile when their normal colonic flora is perturbed by antibiotics or chemotherapy, but sporadic cases can occur. The altered fecal flora permits C. difficile to grow, producing 2 toxins, toxin A and B. It was thought that both toxins were necessary for disease, but strains that produce toxin B but not toxin A have been described in symptomatic individuals. Typical symptoms are watery diarrhea and abdominal cramps. Symptoms in severe cases are bloody diarrhea, fever, and abdominal pain. Diagnosis rests on detection of C. difficile toxin B in stools. Many hospitals now use enzyme immunoassay tests for toxin A or B. Mild cases respond when antibiotics are discontinued, if this is possible. Most cases are treated with metronidazole, 500 mg 4 times a day for 10 days, or vancomycin, 125 to 500 mg 4 times a day for 10 days. Metronidazole is recommended as first-line therapy because it is much less expensive; vancomycin use must be restricted because of risk of developing vancomycin-resistantorganisms, such as enterococci. Most patients respond to treatment with improvement in diarrhea within 3 to 4 days and resolution by 2 weeks, but 20% of patients relapse; these patients are more likely to have continued further relapses. Risk factors for recurrent C. difficile disease include intercurrent antibiotics, renal failure, and female sex? Some patients are reinfected with new strains; in others, the same strain can be isolated from stool, suggesting that alterations in fecal flora allow C. difficile to proliferate. This is a challenging clinical problem. Therapeutic approaches to relapsing C. difficile colitis include repeating the same or an alternate antibiotic, giving vancomycin in tapered or pulsed doses or longer (several weeks) courses, and adding toxin-binding resins such as cholestyramine or colestipol. Two cases of C. dificile were treated successfully with oral administration of nontoxigenic strains of C. dificile.41 About one quarter of C. difficile isolates do not produce toxin and do not cause disease. This approach may be associated with a decrease in relapse, but only a few patients have been treated. Rectal bacteriotherapy has been reported to treat relapsing pseudomembranous colitis. Specifically, fecal enemas have been given to patients, using rectal infusion of homologous feces donated from healthy donors, such as relatives.4oThis approach is not advisable, however, because it is impossible to ensure the safety of homologous feces, and other pathogens could be introduced inadvertently. More esthetically appealing is the use of rectal installation of mixtures of anaerobes that may result in clearing of C. dificile. Five patients with relapsing pseudomembranous colitis were treated with rectal instillation of 10 different facultatively aerobic and
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anaerobic bacteria, with prompt clearing of C. dificile and its toxin from the stool. An additional patient in this study was treated with an enema of fresh feces from a healthy relative. This study showed that Bacteroides had been absent during the patient’s illness and was present after recovery, suggesting that colonization with Bacteroides appears to be especially important in maintaining normal bowel function and strengthening the resistance to gastrointestinal infecti0ns.4~The ability of Bacteroides to aid in restoration of intestinal homeostasis may be related to its production of p-lactamase. Lactobacillus GG is a species with unusual characteristics.It is resistant to gastric acid and to bile and survives in the human gastrointestinal tract for 4 to 7 days. In a published letter, 5 patients with relapsing C. dificile (2 to 5 prior relapses) had no further relapses after oral therapy with Lactobacillus GG.” One of the authors (C.M.S.) and her colleagues have been treating patients with Saccharomyces boulardii as a part of a research protocol. S. boulardii is a nonpathogenic yeast with an unusual growth optimum temperature of 37°C. The yeast was isolated originally from the lychee fruit in South East Asia in the 1920s after observations of folkloric use as an antidiarrheal. Since 1962, S. boulardii has been used in Europe and many other countries as an antidiarrheal agent. Animal studies using the hamster model of clindamycin colitis showed a significant decrease in mortality when animals were treated with S. boulardii compared with placebo.46When S. boulardii was used to treat relapse in the same animal model, it was also highly efficacious. In an open trial, 85% of 13 patients responded to combined therapy with vancomycin and S. boulardii with no subsequent symptoms.44A placebo-controlled trial of S. boulardii as an adjunct to antibiotic therapy for recurrent C. dificile infection showed efficacy of S. boulardii (i.e., no further recurrences) of 50%.25 A later clinical trial showed efficacy of S . boulardii (no further recurrence) only in patients treated with highdose vancomycin (2 g/d) but not with low-dose vancomycin or metr~nidazole.~~ It is not known how S. boulardii exerts its prophylactic or therapeutic effects. S. boulardii does have antagonistic activity against several pathogens in vitro and in vivo in animal models. Other mechanisms of action include inactivation of C. difficle toxin or its receptor in vitro, stimulation of secretory IgA in rat small intestine, and normalization of fecal flora. S. boulardii is not killed by antibiotics. Other advantages include ease of oral administration and lack of side effects because the yeast is not absorbed. Mycobacterium tuberculosis
M . tuberculosis is the causative agent in most intestinal tuberculosis. Intestinal tuberculosis is a relatively rare disease in the United States and Europe. It is far more common in underdeveloped countries. Pulmonary involvement is found in less than 50% of cases.18,26 The organisms reach the bowel through 1 of 4 routes: (1) hematogenous spread from active pulmonary or miliary tuberculosis, (2) swallowing of infected sputum, (3) ingestion of contaminated milk or food, or (4) contiguous spread from other organs. When in the intestinal tract, the organisms invade the submucosa, resulting in an inflammatory reaction and granuloma formation. This reaction can result in fibrosis, scarring, and mass lesions or ulceration of the intestinal mucosa. Granulomas are the histologically distinguishing feature. Patients most commonly complain of abdominal pain. They also may have symptoms of weight loss, fever, change in bowel habits, malaise, night sweats, anorexia, nausea, vomiting, melena, and rectal bleeding.I8Abdominal tenderness
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is present in most, and a right lower quadrant mass may be found in 25% to 50%. Complications include obstruction, hemorrhage, perforation, fistula formation, and malabsorption. Although all areas of the intestinal tract may be involved, the most frequent area of involvement in the intestine is the distal ileum and cecum. The next most common areas are the ileum and jejunum followed by the colon (other than the cecum). Ileocecal involvement may mimic Crohn's disease. An elevated erythrocyte sedimentation rate can be found in 90% of patients. Radiologic studies may be abnormal but are not specific for intestinal tuberculosis. The diagnosis can be confirmed with histology, smear, and culture. Currently, polymerase chain reaction testing is not widely available, but it has high sensitivity and specificity. The results can be obtained within 48 hours, in contrast to cultures, which can take 4 weeksz6 Treatment is primarily medical. Triple-drug therapy is recommended for 12 months. Standard therapy includes isoniazid, 300 mg/d; pyrazinamide, 2000 mg/d; and rifampin, 600 mg/d. Surgical intervention rarely is needed even for fistulous disease, which usually resolves with medical therapy. Surgery is indicated if perforation, obstruction, or massive hemorrhage occurs. PARASITES
Chronic symptoms more often are due to parasitic infection than bacteria. Parasites that can cause chronic diarrhea include Cryptosporidium, Cyclospora, Entamoeba histolytica, Giardia lamblia, lsospora belli, Schistosomiasis, Strongyloides, and Trichuris. Blastocystis horninis can be seen, but its pathogenicity is debatable. Risk factors for parasitic infection include travel to endemic areas, including Russia (Giardia) and Nepal (Cyclospora),and day care centers (Giardia and Cryptosporidium). Protozoal infections are the most common small intestinal pathogens, of which Giardia larnblia is the most common in the United States. Cryptosporidium
Cryptosporidium has caused U.S. epidemics secondary to contaminated water. The organism resists chlorine, and the epidemic occurred in a city in the western United States despite state-of-the-art water treatment facilities.'O Other outbreaks have been reported in day care centers and among livestock and veterinary workers. The illness causes prolonged diarrhea (4 to 6 weeks), usually without fever. Diarrhea can last several months and can be associated with fatigue, flatulence, and abdominal pain. Diagnosis is made by stool examination. There is no more uniformly effective treatment, but paromomycin often is used for immunosuppressed patients. Cydospora
Cyclospora cayetanensis is a protozoan that causes prolonged watery diarrhea. It formerly was classified as blue-green algae. Organisms resemble cryptosporidia but are larger (8 to 10 mm) compared with cryptosporidia (4 to 6 mm), and have a blue autofluorescence when examined by UV epifluorescence microscopy-hence the names cyanobacter and blue-green algae. Initial reported cases from travelers to Nepal and an outbreak among hospital workers in Chicago
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likely were due to contaminated water. Highly publicized outbreaks associated with raspberries from Guatemala have been reported during 2 summers. Raspberries probably were contaminated at sites of harvest.14 Typically, there is a 1-day prodrome of malaise and low-grade fever. Watery diarrhea follows the prodrome and can last for weeks. Other symptoms include abdominal cramps, nausea, and muscle aches. Identification of the organism can be made on microscopic examination of the stool. Treatment with trimethoprimsulfamethoxazole for 1 week usually clears the infection. Amebiasis
Enfamoeba hisfolyfica is the only ameba that is pathogenic in humans. E. hisfolyficacan be found worldwide with an overall prevalence estimated at 10%. In developing countries, the prevalence is much higher. Transmission occurs primarily through the fecal-oral route by contaminated water or food.Z3E. histolyfica can cause outbreaks in day care centers or mental health institutions. Poor sanitary conditions and hygiene play an important role in the spread of E. hisfolyfica. E. histolytica exists in humans in 2 forms: the nonmotile cyst and the motile trophozoite. The cyst form is infective. When the cyst is ingested, it colonizes the host. Asymptomatic carriers or carriers with only mild symptoms primarily have the cyst form in their stool as opposed to the trophozoite. When the cysts transform into motile trophozoites, they can be found with red blood cells within their cytoplasm. This is the pathognomonic histologic finding for amebiasis in humans. The trophozoite subsequently invades intestinal mucosa, resulting in ulcers. Clinical symptoms vary from asymptomatic carriage to severe bloody diarrhea that can be indistinguishable from ulcerative c01itis.~Other common symptoms include abdominal cramping, diarrhea with blood or mucus, and malaise. In severe cases, patients may develop colonic dilation or perforation. Other patients may have massive bleeding or obstruction from inflammatory mass or ameboma. Systemic spread may lead to involvement of other organs, the commonest of which is the liver, which can cause liver abscess. Endoscopic evaluation of the colon may reveal changes ranging from mild hyperemia to severe ulceration that resembles ulcerative colitis. Ulcers usually are scattered throughout the large intestine, but the most frequently involved areas are the cecum and ascending colon. Although the diagnosis of E. hisfolyfica can be made with routine microscopic stool examination, it often can be missed if only a single sample is sent.15 This organism is indistinguishable by light microscopy from the nonpathogenic Enfamoeba dispar strains. Serology is positive with E. hisfolyfica but not E. dispar infection, but currently no other readily available methods distinguish these 2 organisms. A reasonable approach is to treat patients with positive stool samples who are symptomatic. Currently, enzyme immunoassay tests are available commercially and have been shown to have a higher sensitivity and specificity than 2o Biopsies can be useful to differentiate acute microscopic stool e~amination.'~, severe amebiasis from ulcerative colitis. It is important to evaluate patients with presumed ulcerative colitis for E. hisfolyfica before institution of corticosteroids because this may result in dissemination of disease. Metronidazole is the drug of choice for amebiasis. Iodoquinol and paromomycin are luminally active agents that are not absorbed and have been advocated as treatment adjuncts with metronidazole.
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Giardia duodenalis Giardia duodenalis is an important cause of diarrhea worldwide and is a major cause of traveler’s diarrhea. Its prevalence may be 40% in some areas. In the United States, it is typically acquired by drinking water from lakes or streams contaminated by feces from an infected host. Boiling is an effective way of disinfecting water. Giardia can be spread by person-to-person contact, and outbreaks can occur in day care centers or nursing homes.35Patients with dysgammaglobulinemias are at high risk for giardiasis. G. duodenalis is ingested in the cyst form and subsequently excysts and multiplies in the duodenum. It then colonizes the small bowel. The exact mechanism by which G. duodenalis causes diarrhea is unclear. Giardiasis occurs with varying degrees of invasion.*,38 The degree of invasion seems to correlate with the number of trophozoites in the lumen and often correlates with the degree of diarrhea and steatorrhea. The clinical symptoms vary from asymptomatic carriage to chronic watery diarrhea. Stools are loose and often contain mucus but rarely blood. Other symptoms include nausea, abdominal cramping, flatulence, steatorrhea, and weight loss. Sigmoidoscopic examination may be normal or may show hyperemic mucosa. Eosinophilia is not present in giardiasis. Duodenal biopsy specimens often reveal reduced numbers of plasma cells and flattened mucosa. If organisms are not present, the lack of plasma cells is the primary distinguishing feature between giardiasis and celiac sprue. Cysts and trophozoites can be found on microscopic examination of the stool, but the sensitivity may be only 50%. Commercially available enzyme immunoassays have a sensitivity of 96% and specificity of Metronidazole in dosages of 250 mg 3 times daily for 5 days usually is effective. Alternative medications include furazolidone, 100 mg 4 times a day for 7 days, and albendazole, 400 mg/d for 5 days. Paromomycin, 500 mg 3 times daily for 7 days, is effective and is the drug of choice for pregnant women because it is not absorbed from the intestinal tract. Drug resistance is rare, but if patients have recurrence or treatment failures, they should be treated with an alternate drug.
lsospora bellj
lsospora most commonly is a cause of disease in immunocompromised individuals, especially those living in tropical areas.3zSporadic outbreaks have occurred in day care centers and mental institutions. In immunocompetent individuals, disease is rare but does occur sporadically. Transmission occurs through the fecal-oral route. Infections are acquired by ingestion of infective oocysts in contaminated water or food. When in the small intestine, they excyst and invade the epithelium. The exact mechanism of virulence is not clearly understood. Typical clinical symptoms include watery diarrhea, steatorrhea, headache, fever, malaise, abdominal pain, and vomiting. The symptoms can be chronic, and recurrences are common. The diagnosis can be made by identifying the cysts in stool or by finding the organism in a small bowel mucosal biopsy specimen. Treatment of I. belli with trimethoprim-sulfamethoxazole usually results in rapid response of clinical symptoms. Pyrimethamine can be substituted if patients are allergic to trimethoprim-sulfamethoxazole.
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Schistosomiasis
Schistosomiasis is a disease produced by trematodes. The most common species that affect humans are S. mansoni, S. japonicum, and S . haematobium. It has been estimated that the worldwide prevalence exceeds 200 million. The prevalence is highest in tropical and subtropical areas that have poor sanitation. Humans acquire the infection by exposure to water contaminated with the infective form of the organism. The organisms penetrate the skin and enter the circulation and mature in the portal venous system. The mature forms migrate to the mesenteric venous system, where the female produces eggs. The eggs erode through the gut wall into the lumen and can be excreted in the feces. Because of preferential migration into different mesenteric vessels, S. japonicum tends to involve the small intestine, descending colon, and rectum; S. mansoni, the descending colon; and S. huematobiurn, the rectum as well as the bladder. Pathologic changes occur secondary to the erosion of the eggs into the bowel wall. This erosion causes an inflammatory response that can result in punctate hemorrhages and ulcerations, and in later stages of the disease, polypoid lesions and fistulas may develop.27With more severe infestation, the bowel wall becomes damaged, which results in lower abdominal cramping and diarrhea with occasional passage of bloody stools. Fever often is present, and patients may have allergic-type responses with urticaria, cough, and swelling. The diagnosis is made by finding ova in the patient's stool. Praziquantel, 20 mg/kg 3 times a day for 1 day, is the treatment of choice for all 3 species. Strongyloides stercoralis
Strongyloides stercoralis exists in warm moist climates. Groups at increased risk include residents and emigrants from any developing country as well as southern, eastern, and central Europe; travelers and veterans returning from endemic areas; natives and residents of the Appalachian region in the United States; and institutionalized persons? Immunocompromised patients also are at increased risk. The organisms usually are swallowed and invade the small bowel mucosa. Infestation is most common in the small intestine but can occur in other areas of the intestinal tract. Clinical symptoms are a result of the mucosal destruction or migration of the worm to other organ sites. Mild infections may be asymptomatic. More severe infections result in diarrhea and steatorrhea, abdominal pain, nausea, vomiting, and fever. Chronic infections may occur secondary to autoinfection. Peripheral eosinophila is present in 50%. Identifying the larvae and occasionally the eggs in the stool can make the diagnosis. Aspiration of duodenal fluid provides the diagnosis because it has a higher concentration of organisms. Enzyme-linked immunoassays have been shown to be highly sensitive and specific but are not widely available." The therapy of choice is thiabendazole, 25 mg/kg twice daily for 2 days or 5 days for disseminated stongyloides. Ivermectin and mebendazole are alternative therapies for patients who do not tolerate thiabendazole. Patients with strongyloidiasis should never receive corticosteroids because this may result in dissemination of the organism. Trichuris trichiura
Trichuris trichiura, the whipworm, is found throughout the world. It is more common in warmer climates and areas of poor sanitation. Transmission is
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through the fecal-oral route. The larvae initially reside in the small intestinal mucosa, but the adults migrate to the colon, where they invade the mucosa. Most patients are asymptomatic. Patients with moderate-to-severe infestations have right lower quadrant abdominal pain, diarrhea, and occasionally blood in the stools. The diagnosis is made by identifymg the organisms in the stool. The treatment of choice is mebendazole, 100 mg twice daily for 3 days. This therapy should be avoided during pregnancy because of teratogenicity. Blastocystis horninis
Blastocystis kominis is seen in stools from patients with diarrhea, but it can be seen in stools from asymptomatic individuals as well. It is not clear whether B. kominis is a pathogenF1, If no other cause for diarrhea is obvious, a course of treatment (metronidazole) is reasonable. FUNGI
Yeast and fungal infections usually occur in immunosuppressed patients. Reports of elderly individuals with chronic diarrhea and copious yeast in their stool who respond to nystatin therapy suggest that Candida may be a pathogen in some situations.lZ CHRONIC EPIDEMIC DIARRHEAS
Chronic watery diarrhea outbreaks in epidemics were reported in Brainerd, Minnesota; San Antonio, Texas; and rural Henderson County, Illinois.lg,31, 33 Although organisms were not identified, the implicated vehicles were raw milk or well water. In all cases, an infectious cause was likely. Some patients had microscopic colitis on colonoscopic biopsy when evaluated for chronic diarrhea.3 BACTERIAL OVERGROWTH
Bacterial overgrowth can occur in areas of bowel stasis, such as in a bypassed loop, or when motility is decreased, as in diabetes mellitus. Diagnosis is difficult because small bowel aspirate and culture usually cannot be done with sterile equipment so that results may not be meaningful. Quantitative culture of luminal fluid yielding greater than lo6 organisms per milliliter may indicate bacterial overgrowth. Serum vitamin B,, and folate levels can be decreased but are nonspecific. Some centers have breath hydrogen testing available to diagnose bacterial overgrowth-these include lactose or glucose breath H, tests, 14C D xylose test, and14 C-glycocholate breath tests. The tests rely on the ability of bacteria to deconjugate bile salts or sugars. Most clinicians make the diagnosis indirectly using a trial of empirical broad-spectrum antibiotics. POSTINFECTION DIARRHEAL SYNDROMES
Postinfectious diarrhea may be due to irritable bowel syndrome or inflammatory bowel disease, both of which can develop after acute dysentery or can
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be due to lingering infection. Evaluation may require stool analysis and upper or lower endoscopy with biopsy. Persistent traveler’s diarrhea may be caused by parasites (Giardia, Cyptosporidium, I. belli, and Cyclospora) or bacteria (much less likely but can include enteropathogenic or enteroadherent E. coli, Shigella, C. jejuni, or Aeromonas). A reasonable therapeutic approach is empirical antibiotics and antigiardial therapy, with further evaluation if symptoms persist. EVALUATION OF CHRONIC DIARRHEA
Clues to an infectious cause include abrupt onset, travel to endemic areas, or an epidemic situation. The presence of white blood cells in the stool can indicate infection, but their absence does not exclude infection. White blood cells can be seen in the stools of patients with inflammatory bowel disease. Some investigators use a rapid fecal latex agglutination test to detect the neutrophil protein lactoferrin’; the most common cause of a positive test in chronic diarrhea patients was inflammatory bowel disease. It also can be positive in acute infectious diarrhea as well as C. difficile colitis. A reasonable evaluation includes stool for occult blood, white blood cell examination, ova and parasites (amebic trophozoites, Giardia cysts, or ova of other parasites such as Cyptosporidium and Microsporida), and bacterial culture. Diagnosis of parasites traditionally has depended on microscopic detection. Improved methods for detection of some parasites are available. Monoclonal anti-C. lamblia antibody stains detect cysts in stool and may double the yield of standard microscopy. Giardia antigen in stool can be detected with commercial enzyme immunoassay kits with a sensitivity of 95% and specificity of 100%. Similar tests are available for Cyptosporidium. A string test (Enterotest [HDC Corporation, San Jose, CAI) can be used to detect Giardia, Cyptosporidium, and occasionally S . stercoralis. Amebic serology can be useful to diagnose occult amebiasis. Endoscopy can be helpful in diagnosis; upper endoscopy allows detection of small bowel mucosal disease, such as celiac sprue and tropical sprue as well as many parasites, such as Giardia. Colonoscopy or flexible sigmoidoscopy with biopsy can detect other parasites, such as amebae and schistosomiasis. Empirical therapy for presumed bacterial diarrhea lasting longer than 2 weeks is reasonable (Table 2). A fluoroquinolone is a reasonable choice. If diarrhea persists, empirical therapy for possible Giardia is reasonable, especially because stool evaluation often is negative. Table 2. EMPIRICAL THERAPY OF CHRONIC INFECTIOUS DIARRHEA Organism
Therapy
Giardia Gastrointestinal bacterial overgrowth or possible bacterial cause (i.e., persistent traveler’s diarrhea) Intestinal amebiasis
Metronidazole, 250 mg qid X 7 days Quinolone (e.g., ciprofloxacin, 500 mg bid for 1-5 days)
lsospora Cyclospora bid = twice a day; qid sulfamethoxazole.
=
Metronidazole, 750 mg tid for 5-10 days plus a drug to treat cysts (prevent relapses) (e.g., iodoquinol; 650 mg tid X 20 days) TMP-SMX, 160 mg/800 mg bid X 7 days TMP-SMX, 160 mg/800 mg bid X 7 days
four times a day; tid
=
three times a day; TMP-SMX = trimethoprim-
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ACKNOWLEDGMENTS The authors thank Rebecca Rudolph, MD, for expert manuscript evaluation, and Susan Sperline, for expert manuscript preparation.
References 1. Anand B, Schneider F, El-Zaatari F, et a1 Diagnosis of intestinal tuberculosis by polymerase chain reaction on endoscopic biopsy specimens. Am J Gastroenterol 892248-2249,1994 2. Brandborg L, Tankersley C, Gottieb S, et al: Histological demonstration of mucosal invasion by Giurdiu lurnbliu in man. Gastroenterology 52143-150, 1967 3. Bryant DA, Mintz ED, Puhr ND, et al: Colonic epithelial lymphocytosis associated with an epidemic of chronic diarrhea. Am J Surg Patho1201102-1109,1996 4. Ciftci A, Karnak I, Senocak M, et al: Spectrum of complicated intestinal amebiasis through resected specimens: Incidence and outcome. J Pediatr Surg 341369-1373,1999 5. Deodhar L, Saraswathi K, Varudkar A. Aeromonas spp. and their association with human diarrheal disease. J Clin Microbiol29:853-856, 1991 6. Do AN, Fridkin SK, Yechouron A, et al: Risk factors for early recurrent Clostridium difficile-associated diarrhea. Clin Infect Dis 263954959, 1998 7. Fine KD, Ogunji F, George J, et a1 Utility of a rapid fecal latex agglutination test ' detecting the neutrophil protein, lactoferrin, for diagnosing inflammatory causes of chronic diarrhea. Am J Gastroenerol931300-1305, 1998 8. Gendrel D, Kombila M, Beaudoin-Leblevec G, et al: Nontyphoidal salmonella1septicemia in Gabonese children infected with Schistosoma interculutum. Clin Infect Dis 18:103105, 1994 9. Genta R Global prevalence of strongyloidiasis: Critical review with epidemiologic insights into the prevention of disseminated disease. Rev Infect Dis 11:755-767, 1989 10. Goldstein ST, Juranek DD, Ravenholt 0, et a1 Cryptosporikiosis: An outbreak associated with drinking water despite state-of-the-art water treatment. Ann Intern Med 124459468, 1996 11. Gorbach SL, Chang TW, Goldin B Successful treatment of relapsing Clostridium diJJlcile colitis with Lactobacillus GG [letter]. Lancet 2:1519, 1987 12. Gupta TP, Ehrinpreis M N Candidu-associateddiarrhea in hospitalized patients. Gastroenterology 98:780-785, 1990 13. Haque R, Neville L, Hahn P, et al: Rapid diagnosis of Entumoebu infection by using Entarnoebu and Entarnoebu histolyticu stool antigen detection kits. J Clin Microbiol 33:2558-2561,1995 14. Henvaldt BL, Beach MJ: The return of cyclospora in 1997 Another outbreak of cyclosporiasis in North America associated with imported raspberries. Cyclospora Working Group. Ann Intern Med 130:210-220, 1999 15. Hiatt R, Markell E, Ng E How many stool examinations are necessary to detect pathogenic intestinal protozoa? Am J Trop Med Hyg 533639,1995 16. Holmberg S, Schell W, Fanning G, et al: Aeromonas intestinal infections in the United States. Ann Intern Med 105:683-689, 1986 17. Holmberg S, Wachsmuth I, Hickman-Brenner F, et al: Plesiornonus enteric infections in the United States. Ann Intern Med 105:690-694, 1986 18. Horvath K, Whelan R Intestinal tuberculosis: Return of an old disease. Am J Gastroenterol93692-696, 1998 19. Janda RC, Conklin JL, Mitros FA, et al: Multifocal colitis associated with an epidemic of chronic diarrhea. Gastroenterology 100:458-564, 1991 20. Jelinek T, Peyerl G, Loscher T, et a1 Evaluation of an antigen-capture enzyme immunoassay for detection of Entumoebu histolyticu in stool samples. Eur J Clin Microbiol Infect Dis 15752-755, 1996 21. Jelinek T, Peyerl G, Loscher T, et al: The role of blastocystis hominis as a possible intestinal pathogen in travelers. J Infect 35:63-66, 1997
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22. Kain K, Kelly M: Clinical features, epidemiology, and treatment of Plesiomonas shigelloides diarrhea. J Clin Microbiol 27998-1001, 1989 23. Leber A: Intestinal amebae. Clin Lab Med 19:601419,1999 24. Lindo J, Conway D, Atkins N, et al: Prospective evaluation of enzyme-linked immunosorbent assay and immunoblot methods for the diagnosis of endemic Strongyloides stercoralis infection. Am J Trop Med Hyg 51:175-179, 1994 25. McFarland LV, Surawicz CM, Greenberg RN, et al: A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium dificile disease. JAMA 271:1913-1918, 1994 26. Misra S, Misra V, Dwivedi M, et al: Colonic tuberculosis: Clinical features, endoscopic appearance and management. J Gastroenterol Hepatol 14:723-729, 1999 27. Mohamed A, a1 Karawi M, Yasawy M: Schistosomal colonic disease. Gut 31:439442, 1990 28. Namdari H, Bottone E: Microbiologic and clinical evidence supporting the role of Aeromonas caviae as a pediatric enteric pathogen. J Clin Microbiol 28:837-840, 1990 29. Nostrant T, Kumar N, Appelman H: Histopathology differentiates acute self-limited colitis from ulcerative colitis. Gastroenterology 92:312-318, 1987 30. Olsvik 0, Wachsmuth K, Kay B, et al: Laboratory observations on Plesiomonas shigelloides strains isolated from children with diarrhea in Peru. J Clin Microbiol 28:886889, 1990 31. Osterholm MT, MacDonald KL, White KE, et a1 An outbreak of a newly recognized chronic diarrhea syndrome associated with raw milk consumption. JAMA 256:484,1986 32. Pape J, Johnson WJ: lsospora belli infections. Prog Clin Parasitol 2:119-127, 1991 33. Parsonnet J, Trock SC, Bopp CA, et al: Chronic diarrhea associated with drinking untreated water. Ann Intern Med 110:985-991, 1989 34. Pavia A, Shipman L, Wells J, et a1 Epidemiologic evidence that prior antimicrobial exposure decreases resistance to infection by antimicrobial-sensitive Salmonella. J Infect Dis 161:255-260, 1990 35. Rauch A, Van R, Bartlett A, et al: Longitudinal study of Giardia larnblia infection in a day care center population. Pediatr Infect Dis J 9:186-189, 1990 36. Rocha H, Kirk J, Hearey CJ: Prolonged Salmonella bacteremia in patients with Schistosoma mansoni infection. Arch Intern Med 128:245-247, 1971 37. Rosoff J, Sanders C, Sonnad S, et al: Stool diagnosis of giardiasis using a commercially available enzyme immunoassay to detect Giardia-specific antigen 65 (GSA 65). J Clin Microbiol 271997-2002, 1989 38. Saha T, Ghosh T Invasion of small intestinal mucosa by Giardia larnblia in man. Gastroenterology 72:402-405, 1977 39. San Joaquin V, Pickett D: Aeromonas-associated gastroenteritis in children. Pediatr Infect Dis J 753-57, 1988 40. Schwaan A, Sjolin S, Trottestam U, et al: Relapsing C. dzficile enterocolitis cured by rectal infusion of normal feces. Sand J Infect Dis 16:211-215, 1984 41. Seal DV, Borriello SP, Barclasy F, et al: Treatment of relapsing Clostridium dificile diarrhoea by administration of non-toxigenic strain. Eur J Clin Microbiol6751-53,1987 42. Simmonds S, Noble M, Freeman H: Gastrointestinal features of culture-positive Yersinia enterocolitica infection. Gastroenterology 92112-117, 1987 43. Shlim DR, Hoge CW, Rajah R, et al: Is blastocystis hominis a cause of diarrhea in travelers? A prospective controlled study in Nepal. Clin Infect Dis 21:97-101, 1995 44. Surawicz CM, McFarland LV, Elmer G, et al: Treatment of recurrent Clostridiurn dzficile colitis with vancomycin and Saccharomyces boulardii. Am J Gastroenterol 841285-1287, 1989 45. Surawicz CM, McFarland LV, Greenberg RN, et al: The search for a better treatment for recurrent Clostridium dzficile disease: The use of high dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 31:1012-1017, 2000 46. Toothaker RD, Elmer G W Prevention of clindamycin-induced mortality in hamsters by Saccharomyces boulardii. Antimicrob Agents Chemother 26~552-556,1984 47. Tvede M, Rask-Madsen J: Bacteriotherapy for chronic relapsing Clostridium dzficile diarrhea in six patients. Lancet 1:1156-1160, 1989
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48. Vantrappen G, Geboes K, Ponette E: Yersiniu enteritis. Med Clin North Am 66639653, 1982 49. Vantrappen G, Ponette E, Geboes K, et a1 Yersiniu enteritis and enterocolitis: Gastroenterological aspects. Gastroenterology 72:220-227, 1977
Address reprint requests to Christina M. Surawicz, MD University of Washington Harborview Medical Center 325 Ninth Avenue, Box 359773 Seattle, WA 98104 e-mail: [email protected]
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INFECTIOUS CAUSES OF CHRONIC DIARRHEA Scott D. Lee, MD, and Christina M. Surawicz, MD
Most infectious diarrhea is acute. Chronic diarrhea can occur as a result of infections in several situations, as follows: 1. Some pathogens cause chronic symptoms, usually parasites, but sometimes bacteria. 2. Immunosuppressed individuals, such as those with human immunodeficiency virus (HIV) infection or on steroids or other immunosuppressants, cannot clear pathogens effectively and can develop chronic diarrhea. Campylobacter and Salmonella can cause persistent diarrhea in patients with HIV infection. 3. Some infections clear, but persons develop chronic symptoms, such as irritable bowel syndrome with diarrhea. Occasionally, ulcerative colitis develops after an acute infection.
This article focuses on the pathogens that can cause chronic diarrhea in immunocompetent individuals (Table 1). BACTERIA
Bacterial causes of chronic diarrhea are uncommon, but include Aeromonas, Plesiomonas, Campylobacter jejuni, Yersinia enterocolitica, Clostridium dificile, Salmonella, and Mycobacterium tuberculosis. Aeromonas
Aeromonas species are non-lactose-fermenting, facultative anaerobic, gramnegative rods found in fresh or brackish water. Three major species have been From the Department of Medicine (SDL, CMS), Section of Gastroenterology; and the Harborview Medical Center (CMS), University of Washington, Seattle, Washington
GASTROENTEROLOGY CLINICS OF NORTH AMERICA VOLUME 30 * NLTMBER 3 * SEPTEMBER 2001
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Table 1. INFECTIONS CAUSING CHRONIC DIARRHEA Colonic
Small Intestinal
Bacteria Aeromonas Plesiomonas Campylobactw Recurrent Clostridium difFcile Salmonella Mycobacterium tuberculosis Parasites Amoeba Trichuris Schis tosoma
Parasites Cryptosporidium Cyclospora Giardia lamblia lsospora belli Strongyloides
implicated as being pathogenic in humans: A. hydrophila, A. caviae, and A. sobria. The virulence of the organism is related to its ability to produce several toxins: enterotoxin, hemolysin, and cytotoxin. Aeromonas infections usually are associated with ingestion of untreated water.16 Infections tend to occur during warm months. Several studies have found that Aeromonas can be isolated in symptomatic children, implicating it as a pathogenic cause of diarrhea.5,28, 39 Aeromonas also has been isolated from healthy individuals, raising the question of the pathogenic nature of these organisms. With enteric illness secondary to Aeromonus, there is often watery diarrhea (which occasionally contains blood), vomiting, and mild fever. Symptoms usually resolve within 1 week but can become chronic, lasting more than 1 year in some patients. Diagnosis is made by stool culture. Treatment is primarily symptomatic. The role of antibiotics is unclear; their use has not shown significantbenefit. Aerornonus species tend to be resistant to p-lactams and first-generation and second-generation cephalosporins. Chloramphenicol, ciprofloxacin, aminoglycosides,third-generation cephalosporins, aztreonam, and imipenem are highly active against Aeromonas.
Plesiomonas
Plesiomonas shigelloides is a non-lactose-fermenting, facultatively anaerobic, gram-negative rod. Similar to Aeromonas, P. shigelloides is found in brackish and fresh water and can cause diarrheal disease in children and adults. Most cases in the United States are associated with foreign travel or ingestion of raw shellfish, untreated water, or The exact pathogenic properties by which P. shigelloides causes diarrhea are unclear. Although some species invade intestinal mucosa, others produce a c y t o t ~ x i nMost . ~ ~ patients have evidence of colitis and bloody diarrhea.= The most common symptoms are abdominal pain, vomiting, and fever. Symptoms can last for 2 weeks. Diagnosis is made by stool culture. Cases of chronic colitis resulting from P. shigelloides have been reported. Antibiotics can shorten the duration of symptoms. I? shigelloides is uniformly resistant to ampicillin, gentamicin, erythromycin, kanamycin, and streptomycin. It is sensitive to chloramphenicol, aminoglycosides, trimethoprim-sulfamethoxazole, fluoroquinolones, tetracycline, third-generation cephalosporins, and imipenem.
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Yersinia
Yersinia are gram-negative, non-lactose-fermenting coccobacilli that are motile at 25°C. They are classified by their somatic (0)and flagellar (H) antigens. The pathogenesis of disease is related to the adhesion of the organism to the epithelium and subsequent invasion. The production of a heat-labile enterotoxin, which is elaborated at 25°C but not at 37"C, plays a role in the pathogenesis. The terminal ileum is the area of attack. The colon is involved less frequently.& Yersinia can be found in stream and lake water. Yersinia has been isolated from many animals, which are an important reservoir and source of transmission. Epidemics have been linked to contaminated milk or ice cream. Disease tends to occur most frequently in children younger than 5 years old. The predominant serotype varies with location: the United States has primarily 08 isolates and Canada has 03 serotypes. In Scandinavia and Europe, where Yersinia disease is more frequent, serotypes 03 and 09 are most common. Diarrhea and abdominal pain are the commonest Fever and bloody diarrhea are less frequent. Mesenteric adenitis has been described in children older than 5. These patients often have nausea, vomiting, and aphthous ulcers in the mouth. Adults tend to have acute diarrhea, which can be followed by joint symptoms followed by a rash (erythema nodosum or erythema multiforme). Reactive polyarthropathy occurs in 2% of patients with yersiniosis and usually is associated with the major histocompatibility antigen HLA-B27. The clinical symptoms last 1 to 3 weeks but can last longer. Although findings on radiologic or endoscopic studies can resemble inflammatory bowel disease, most patients have normal findings on these studies.4z, 48, 49 Bacteremia is rare but can occur when the patient is immunocompromised or is debilitated. The diagnosis is made by stool culture. Treatment is primarily supportive for dehydration. There is no evidence that antibiotics alter the clinical course of disease induced by Y. enterocolitica. Antibiotics can be used in severe cases or with bacteremia. Salmonella
Salmonella are gram-negative bacilli with a wide range of hosts, which can be found in sewage, river water and seawater, and certain foods. Most Salmonella are flagellated. Of Salmonella that cause disease in humans, 90% fall into groups A to E, which contain 40 serotypes. Salmonella is a major cause of large food-borne outbreaks. Poultry, meats, eggs, and dairy products are the most frequently implicated sources. It is transmitted through personal contact or the fecal-oral route. The attack rate varies with age. Children younger than 1 year old have the highest attack rate, especially in the 3- to 5-month range. Elderly or debilitated individuals have a high attack rate and increased mortality. With lo7 organisms, there is a 50% attack rate; this rises to 90% with lo9 organisms. Many conditions are associated with an increase in the risk of salmonellosis. The association of sickle cell disease and Salmonella osteomyelitis has been well documented. In humans, recent use of antibiotics appears to increase the attack rate of Salmonella.12This increase is possibly secondary to disruption of the normal colonic flora, which results in decreased resistance to colonization by Salmonella. Other risk factors for salmonellosis are gastric surgery (presumably secondary to decreased gastric acidity), neoplasm, hemolytic anemia, and any condition giving rise to immunosuppression (chemotherapy, radiation therapy,
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corticosteroid therapy). There also has been an associationbetween schistosomiasis and salmonellosis.8,36 The commonest syndrome is gastroenteritis. The usual incubation period is 6 to 48 hours, but it has been reported to be 12 days. Initially the predominant symptoms are nausea and vomiting, followed by abdominal cramps and diarrhea. The diarrhea can range from mild watery diarrhea to severe dysentery. Fever is present in 50%. Typically, symptoms last 3 to 4 days. Diagnosis is made by stool culture. Blood cultures can be positive because bacteremia occurs in 5% to 10% of cases. After acute infection, a chronic carrier state of nontyphoidal Salmonella occurs at a rate of about 4 per 1000, most frequently in newborns and the elderly. Structural abnormalities in the biliary or urinary tract are risk factors. Clostridium difficile
C. dificile is the most frequent nosocomial pathogen of the gastrointestinal tract. It is an anaerobic gram-positive bacillus that is ubiquitous in the environment. Most people acquire C. dificile when their normal colonic flora is perturbed by antibiotics or chemotherapy, but sporadic cases can occur. The altered fecal flora permits C. difficile to grow, producing 2 toxins, toxin A and B. It was thought that both toxins were necessary for disease, but strains that produce toxin B but not toxin A have been described in symptomatic individuals. Typical symptoms are watery diarrhea and abdominal cramps. Symptoms in severe cases are bloody diarrhea, fever, and abdominal pain. Diagnosis rests on detection of C. difficile toxin B in stools. Many hospitals now use enzyme immunoassay tests for toxin A or B. Mild cases respond when antibiotics are discontinued, if this is possible. Most cases are treated with metronidazole, 500 mg 4 times a day for 10 days, or vancomycin, 125 to 500 mg 4 times a day for 10 days. Metronidazole is recommended as first-line therapy because it is much less expensive; vancomycin use must be restricted because of risk of developing vancomycin-resistantorganisms, such as enterococci. Most patients respond to treatment with improvement in diarrhea within 3 to 4 days and resolution by 2 weeks, but 20% of patients relapse; these patients are more likely to have continued further relapses. Risk factors for recurrent C. difficile disease include intercurrent antibiotics, renal failure, and female sex? Some patients are reinfected with new strains; in others, the same strain can be isolated from stool, suggesting that alterations in fecal flora allow C. difficile to proliferate. This is a challenging clinical problem. Therapeutic approaches to relapsing C. difficile colitis include repeating the same or an alternate antibiotic, giving vancomycin in tapered or pulsed doses or longer (several weeks) courses, and adding toxin-binding resins such as cholestyramine or colestipol. Two cases of C. dificile were treated successfully with oral administration of nontoxigenic strains of C. dificile.41 About one quarter of C. difficile isolates do not produce toxin and do not cause disease. This approach may be associated with a decrease in relapse, but only a few patients have been treated. Rectal bacteriotherapy has been reported to treat relapsing pseudomembranous colitis. Specifically, fecal enemas have been given to patients, using rectal infusion of homologous feces donated from healthy donors, such as relatives.4oThis approach is not advisable, however, because it is impossible to ensure the safety of homologous feces, and other pathogens could be introduced inadvertently. More esthetically appealing is the use of rectal installation of mixtures of anaerobes that may result in clearing of C. dificile. Five patients with relapsing pseudomembranous colitis were treated with rectal instillation of 10 different facultatively aerobic and
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anaerobic bacteria, with prompt clearing of C. dificile and its toxin from the stool. An additional patient in this study was treated with an enema of fresh feces from a healthy relative. This study showed that Bacteroides had been absent during the patient’s illness and was present after recovery, suggesting that colonization with Bacteroides appears to be especially important in maintaining normal bowel function and strengthening the resistance to gastrointestinal infecti0ns.4~The ability of Bacteroides to aid in restoration of intestinal homeostasis may be related to its production of p-lactamase. Lactobacillus GG is a species with unusual characteristics.It is resistant to gastric acid and to bile and survives in the human gastrointestinal tract for 4 to 7 days. In a published letter, 5 patients with relapsing C. dificile (2 to 5 prior relapses) had no further relapses after oral therapy with Lactobacillus GG.” One of the authors (C.M.S.) and her colleagues have been treating patients with Saccharomyces boulardii as a part of a research protocol. S. boulardii is a nonpathogenic yeast with an unusual growth optimum temperature of 37°C. The yeast was isolated originally from the lychee fruit in South East Asia in the 1920s after observations of folkloric use as an antidiarrheal. Since 1962, S. boulardii has been used in Europe and many other countries as an antidiarrheal agent. Animal studies using the hamster model of clindamycin colitis showed a significant decrease in mortality when animals were treated with S. boulardii compared with placebo.46When S. boulardii was used to treat relapse in the same animal model, it was also highly efficacious. In an open trial, 85% of 13 patients responded to combined therapy with vancomycin and S. boulardii with no subsequent symptoms.44A placebo-controlled trial of S. boulardii as an adjunct to antibiotic therapy for recurrent C. dificile infection showed efficacy of S. boulardii (i.e., no further recurrences) of 50%.25 A later clinical trial showed efficacy of S . boulardii (no further recurrence) only in patients treated with highdose vancomycin (2 g/d) but not with low-dose vancomycin or metr~nidazole.~~ It is not known how S. boulardii exerts its prophylactic or therapeutic effects. S. boulardii does have antagonistic activity against several pathogens in vitro and in vivo in animal models. Other mechanisms of action include inactivation of C. difficle toxin or its receptor in vitro, stimulation of secretory IgA in rat small intestine, and normalization of fecal flora. S. boulardii is not killed by antibiotics. Other advantages include ease of oral administration and lack of side effects because the yeast is not absorbed. Mycobacterium tuberculosis
M . tuberculosis is the causative agent in most intestinal tuberculosis. Intestinal tuberculosis is a relatively rare disease in the United States and Europe. It is far more common in underdeveloped countries. Pulmonary involvement is found in less than 50% of cases.18,26 The organisms reach the bowel through 1 of 4 routes: (1) hematogenous spread from active pulmonary or miliary tuberculosis, (2) swallowing of infected sputum, (3) ingestion of contaminated milk or food, or (4) contiguous spread from other organs. When in the intestinal tract, the organisms invade the submucosa, resulting in an inflammatory reaction and granuloma formation. This reaction can result in fibrosis, scarring, and mass lesions or ulceration of the intestinal mucosa. Granulomas are the histologically distinguishing feature. Patients most commonly complain of abdominal pain. They also may have symptoms of weight loss, fever, change in bowel habits, malaise, night sweats, anorexia, nausea, vomiting, melena, and rectal bleeding.I8Abdominal tenderness
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is present in most, and a right lower quadrant mass may be found in 25% to 50%. Complications include obstruction, hemorrhage, perforation, fistula formation, and malabsorption. Although all areas of the intestinal tract may be involved, the most frequent area of involvement in the intestine is the distal ileum and cecum. The next most common areas are the ileum and jejunum followed by the colon (other than the cecum). Ileocecal involvement may mimic Crohn's disease. An elevated erythrocyte sedimentation rate can be found in 90% of patients. Radiologic studies may be abnormal but are not specific for intestinal tuberculosis. The diagnosis can be confirmed with histology, smear, and culture. Currently, polymerase chain reaction testing is not widely available, but it has high sensitivity and specificity. The results can be obtained within 48 hours, in contrast to cultures, which can take 4 weeksz6 Treatment is primarily medical. Triple-drug therapy is recommended for 12 months. Standard therapy includes isoniazid, 300 mg/d; pyrazinamide, 2000 mg/d; and rifampin, 600 mg/d. Surgical intervention rarely is needed even for fistulous disease, which usually resolves with medical therapy. Surgery is indicated if perforation, obstruction, or massive hemorrhage occurs. PARASITES
Chronic symptoms more often are due to parasitic infection than bacteria. Parasites that can cause chronic diarrhea include Cryptosporidium, Cyclospora, Entamoeba histolytica, Giardia lamblia, lsospora belli, Schistosomiasis, Strongyloides, and Trichuris. Blastocystis horninis can be seen, but its pathogenicity is debatable. Risk factors for parasitic infection include travel to endemic areas, including Russia (Giardia) and Nepal (Cyclospora),and day care centers (Giardia and Cryptosporidium). Protozoal infections are the most common small intestinal pathogens, of which Giardia larnblia is the most common in the United States. Cryptosporidium
Cryptosporidium has caused U.S. epidemics secondary to contaminated water. The organism resists chlorine, and the epidemic occurred in a city in the western United States despite state-of-the-art water treatment facilities.'O Other outbreaks have been reported in day care centers and among livestock and veterinary workers. The illness causes prolonged diarrhea (4 to 6 weeks), usually without fever. Diarrhea can last several months and can be associated with fatigue, flatulence, and abdominal pain. Diagnosis is made by stool examination. There is no more uniformly effective treatment, but paromomycin often is used for immunosuppressed patients. Cydospora
Cyclospora cayetanensis is a protozoan that causes prolonged watery diarrhea. It formerly was classified as blue-green algae. Organisms resemble cryptosporidia but are larger (8 to 10 mm) compared with cryptosporidia (4 to 6 mm), and have a blue autofluorescence when examined by UV epifluorescence microscopy-hence the names cyanobacter and blue-green algae. Initial reported cases from travelers to Nepal and an outbreak among hospital workers in Chicago
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likely were due to contaminated water. Highly publicized outbreaks associated with raspberries from Guatemala have been reported during 2 summers. Raspberries probably were contaminated at sites of harvest.14 Typically, there is a 1-day prodrome of malaise and low-grade fever. Watery diarrhea follows the prodrome and can last for weeks. Other symptoms include abdominal cramps, nausea, and muscle aches. Identification of the organism can be made on microscopic examination of the stool. Treatment with trimethoprimsulfamethoxazole for 1 week usually clears the infection. Amebiasis
Enfamoeba hisfolyfica is the only ameba that is pathogenic in humans. E. hisfolyficacan be found worldwide with an overall prevalence estimated at 10%. In developing countries, the prevalence is much higher. Transmission occurs primarily through the fecal-oral route by contaminated water or food.Z3E. histolyfica can cause outbreaks in day care centers or mental health institutions. Poor sanitary conditions and hygiene play an important role in the spread of E. hisfolyfica. E. histolytica exists in humans in 2 forms: the nonmotile cyst and the motile trophozoite. The cyst form is infective. When the cyst is ingested, it colonizes the host. Asymptomatic carriers or carriers with only mild symptoms primarily have the cyst form in their stool as opposed to the trophozoite. When the cysts transform into motile trophozoites, they can be found with red blood cells within their cytoplasm. This is the pathognomonic histologic finding for amebiasis in humans. The trophozoite subsequently invades intestinal mucosa, resulting in ulcers. Clinical symptoms vary from asymptomatic carriage to severe bloody diarrhea that can be indistinguishable from ulcerative c01itis.~Other common symptoms include abdominal cramping, diarrhea with blood or mucus, and malaise. In severe cases, patients may develop colonic dilation or perforation. Other patients may have massive bleeding or obstruction from inflammatory mass or ameboma. Systemic spread may lead to involvement of other organs, the commonest of which is the liver, which can cause liver abscess. Endoscopic evaluation of the colon may reveal changes ranging from mild hyperemia to severe ulceration that resembles ulcerative colitis. Ulcers usually are scattered throughout the large intestine, but the most frequently involved areas are the cecum and ascending colon. Although the diagnosis of E. hisfolyfica can be made with routine microscopic stool examination, it often can be missed if only a single sample is sent.15 This organism is indistinguishable by light microscopy from the nonpathogenic Enfamoeba dispar strains. Serology is positive with E. hisfolyfica but not E. dispar infection, but currently no other readily available methods distinguish these 2 organisms. A reasonable approach is to treat patients with positive stool samples who are symptomatic. Currently, enzyme immunoassay tests are available commercially and have been shown to have a higher sensitivity and specificity than 2o Biopsies can be useful to differentiate acute microscopic stool e~amination.'~, severe amebiasis from ulcerative colitis. It is important to evaluate patients with presumed ulcerative colitis for E. hisfolyfica before institution of corticosteroids because this may result in dissemination of disease. Metronidazole is the drug of choice for amebiasis. Iodoquinol and paromomycin are luminally active agents that are not absorbed and have been advocated as treatment adjuncts with metronidazole.
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Giardia duodenalis Giardia duodenalis is an important cause of diarrhea worldwide and is a major cause of traveler’s diarrhea. Its prevalence may be 40% in some areas. In the United States, it is typically acquired by drinking water from lakes or streams contaminated by feces from an infected host. Boiling is an effective way of disinfecting water. Giardia can be spread by person-to-person contact, and outbreaks can occur in day care centers or nursing homes.35Patients with dysgammaglobulinemias are at high risk for giardiasis. G. duodenalis is ingested in the cyst form and subsequently excysts and multiplies in the duodenum. It then colonizes the small bowel. The exact mechanism by which G. duodenalis causes diarrhea is unclear. Giardiasis occurs with varying degrees of invasion.*,38 The degree of invasion seems to correlate with the number of trophozoites in the lumen and often correlates with the degree of diarrhea and steatorrhea. The clinical symptoms vary from asymptomatic carriage to chronic watery diarrhea. Stools are loose and often contain mucus but rarely blood. Other symptoms include nausea, abdominal cramping, flatulence, steatorrhea, and weight loss. Sigmoidoscopic examination may be normal or may show hyperemic mucosa. Eosinophilia is not present in giardiasis. Duodenal biopsy specimens often reveal reduced numbers of plasma cells and flattened mucosa. If organisms are not present, the lack of plasma cells is the primary distinguishing feature between giardiasis and celiac sprue. Cysts and trophozoites can be found on microscopic examination of the stool, but the sensitivity may be only 50%. Commercially available enzyme immunoassays have a sensitivity of 96% and specificity of Metronidazole in dosages of 250 mg 3 times daily for 5 days usually is effective. Alternative medications include furazolidone, 100 mg 4 times a day for 7 days, and albendazole, 400 mg/d for 5 days. Paromomycin, 500 mg 3 times daily for 7 days, is effective and is the drug of choice for pregnant women because it is not absorbed from the intestinal tract. Drug resistance is rare, but if patients have recurrence or treatment failures, they should be treated with an alternate drug.
lsospora bellj
lsospora most commonly is a cause of disease in immunocompromised individuals, especially those living in tropical areas.3zSporadic outbreaks have occurred in day care centers and mental institutions. In immunocompetent individuals, disease is rare but does occur sporadically. Transmission occurs through the fecal-oral route. Infections are acquired by ingestion of infective oocysts in contaminated water or food. When in the small intestine, they excyst and invade the epithelium. The exact mechanism of virulence is not clearly understood. Typical clinical symptoms include watery diarrhea, steatorrhea, headache, fever, malaise, abdominal pain, and vomiting. The symptoms can be chronic, and recurrences are common. The diagnosis can be made by identifying the cysts in stool or by finding the organism in a small bowel mucosal biopsy specimen. Treatment of I. belli with trimethoprim-sulfamethoxazole usually results in rapid response of clinical symptoms. Pyrimethamine can be substituted if patients are allergic to trimethoprim-sulfamethoxazole.
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Schistosomiasis
Schistosomiasis is a disease produced by trematodes. The most common species that affect humans are S. mansoni, S. japonicum, and S . haematobium. It has been estimated that the worldwide prevalence exceeds 200 million. The prevalence is highest in tropical and subtropical areas that have poor sanitation. Humans acquire the infection by exposure to water contaminated with the infective form of the organism. The organisms penetrate the skin and enter the circulation and mature in the portal venous system. The mature forms migrate to the mesenteric venous system, where the female produces eggs. The eggs erode through the gut wall into the lumen and can be excreted in the feces. Because of preferential migration into different mesenteric vessels, S. japonicum tends to involve the small intestine, descending colon, and rectum; S. mansoni, the descending colon; and S. huematobiurn, the rectum as well as the bladder. Pathologic changes occur secondary to the erosion of the eggs into the bowel wall. This erosion causes an inflammatory response that can result in punctate hemorrhages and ulcerations, and in later stages of the disease, polypoid lesions and fistulas may develop.27With more severe infestation, the bowel wall becomes damaged, which results in lower abdominal cramping and diarrhea with occasional passage of bloody stools. Fever often is present, and patients may have allergic-type responses with urticaria, cough, and swelling. The diagnosis is made by finding ova in the patient's stool. Praziquantel, 20 mg/kg 3 times a day for 1 day, is the treatment of choice for all 3 species. Strongyloides stercoralis
Strongyloides stercoralis exists in warm moist climates. Groups at increased risk include residents and emigrants from any developing country as well as southern, eastern, and central Europe; travelers and veterans returning from endemic areas; natives and residents of the Appalachian region in the United States; and institutionalized persons? Immunocompromised patients also are at increased risk. The organisms usually are swallowed and invade the small bowel mucosa. Infestation is most common in the small intestine but can occur in other areas of the intestinal tract. Clinical symptoms are a result of the mucosal destruction or migration of the worm to other organ sites. Mild infections may be asymptomatic. More severe infections result in diarrhea and steatorrhea, abdominal pain, nausea, vomiting, and fever. Chronic infections may occur secondary to autoinfection. Peripheral eosinophila is present in 50%. Identifying the larvae and occasionally the eggs in the stool can make the diagnosis. Aspiration of duodenal fluid provides the diagnosis because it has a higher concentration of organisms. Enzyme-linked immunoassays have been shown to be highly sensitive and specific but are not widely available." The therapy of choice is thiabendazole, 25 mg/kg twice daily for 2 days or 5 days for disseminated stongyloides. Ivermectin and mebendazole are alternative therapies for patients who do not tolerate thiabendazole. Patients with strongyloidiasis should never receive corticosteroids because this may result in dissemination of the organism. Trichuris trichiura
Trichuris trichiura, the whipworm, is found throughout the world. It is more common in warmer climates and areas of poor sanitation. Transmission is
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through the fecal-oral route. The larvae initially reside in the small intestinal mucosa, but the adults migrate to the colon, where they invade the mucosa. Most patients are asymptomatic. Patients with moderate-to-severe infestations have right lower quadrant abdominal pain, diarrhea, and occasionally blood in the stools. The diagnosis is made by identifymg the organisms in the stool. The treatment of choice is mebendazole, 100 mg twice daily for 3 days. This therapy should be avoided during pregnancy because of teratogenicity. Blastocystis horninis
Blastocystis kominis is seen in stools from patients with diarrhea, but it can be seen in stools from asymptomatic individuals as well. It is not clear whether B. kominis is a pathogenF1, If no other cause for diarrhea is obvious, a course of treatment (metronidazole) is reasonable. FUNGI
Yeast and fungal infections usually occur in immunosuppressed patients. Reports of elderly individuals with chronic diarrhea and copious yeast in their stool who respond to nystatin therapy suggest that Candida may be a pathogen in some situations.lZ CHRONIC EPIDEMIC DIARRHEAS
Chronic watery diarrhea outbreaks in epidemics were reported in Brainerd, Minnesota; San Antonio, Texas; and rural Henderson County, Illinois.lg,31, 33 Although organisms were not identified, the implicated vehicles were raw milk or well water. In all cases, an infectious cause was likely. Some patients had microscopic colitis on colonoscopic biopsy when evaluated for chronic diarrhea.3 BACTERIAL OVERGROWTH
Bacterial overgrowth can occur in areas of bowel stasis, such as in a bypassed loop, or when motility is decreased, as in diabetes mellitus. Diagnosis is difficult because small bowel aspirate and culture usually cannot be done with sterile equipment so that results may not be meaningful. Quantitative culture of luminal fluid yielding greater than lo6 organisms per milliliter may indicate bacterial overgrowth. Serum vitamin B,, and folate levels can be decreased but are nonspecific. Some centers have breath hydrogen testing available to diagnose bacterial overgrowth-these include lactose or glucose breath H, tests, 14C D xylose test, and14 C-glycocholate breath tests. The tests rely on the ability of bacteria to deconjugate bile salts or sugars. Most clinicians make the diagnosis indirectly using a trial of empirical broad-spectrum antibiotics. POSTINFECTION DIARRHEAL SYNDROMES
Postinfectious diarrhea may be due to irritable bowel syndrome or inflammatory bowel disease, both of which can develop after acute dysentery or can
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be due to lingering infection. Evaluation may require stool analysis and upper or lower endoscopy with biopsy. Persistent traveler’s diarrhea may be caused by parasites (Giardia, Cyptosporidium, I. belli, and Cyclospora) or bacteria (much less likely but can include enteropathogenic or enteroadherent E. coli, Shigella, C. jejuni, or Aeromonas). A reasonable therapeutic approach is empirical antibiotics and antigiardial therapy, with further evaluation if symptoms persist. EVALUATION OF CHRONIC DIARRHEA
Clues to an infectious cause include abrupt onset, travel to endemic areas, or an epidemic situation. The presence of white blood cells in the stool can indicate infection, but their absence does not exclude infection. White blood cells can be seen in the stools of patients with inflammatory bowel disease. Some investigators use a rapid fecal latex agglutination test to detect the neutrophil protein lactoferrin’; the most common cause of a positive test in chronic diarrhea patients was inflammatory bowel disease. It also can be positive in acute infectious diarrhea as well as C. difficile colitis. A reasonable evaluation includes stool for occult blood, white blood cell examination, ova and parasites (amebic trophozoites, Giardia cysts, or ova of other parasites such as Cyptosporidium and Microsporida), and bacterial culture. Diagnosis of parasites traditionally has depended on microscopic detection. Improved methods for detection of some parasites are available. Monoclonal anti-C. lamblia antibody stains detect cysts in stool and may double the yield of standard microscopy. Giardia antigen in stool can be detected with commercial enzyme immunoassay kits with a sensitivity of 95% and specificity of 100%. Similar tests are available for Cyptosporidium. A string test (Enterotest [HDC Corporation, San Jose, CAI) can be used to detect Giardia, Cyptosporidium, and occasionally S . stercoralis. Amebic serology can be useful to diagnose occult amebiasis. Endoscopy can be helpful in diagnosis; upper endoscopy allows detection of small bowel mucosal disease, such as celiac sprue and tropical sprue as well as many parasites, such as Giardia. Colonoscopy or flexible sigmoidoscopy with biopsy can detect other parasites, such as amebae and schistosomiasis. Empirical therapy for presumed bacterial diarrhea lasting longer than 2 weeks is reasonable (Table 2). A fluoroquinolone is a reasonable choice. If diarrhea persists, empirical therapy for possible Giardia is reasonable, especially because stool evaluation often is negative. Table 2. EMPIRICAL THERAPY OF CHRONIC INFECTIOUS DIARRHEA Organism
Therapy
Giardia Gastrointestinal bacterial overgrowth or possible bacterial cause (i.e., persistent traveler’s diarrhea) Intestinal amebiasis
Metronidazole, 250 mg qid X 7 days Quinolone (e.g., ciprofloxacin, 500 mg bid for 1-5 days)
lsospora Cyclospora bid = twice a day; qid sulfamethoxazole.
=
Metronidazole, 750 mg tid for 5-10 days plus a drug to treat cysts (prevent relapses) (e.g., iodoquinol; 650 mg tid X 20 days) TMP-SMX, 160 mg/800 mg bid X 7 days TMP-SMX, 160 mg/800 mg bid X 7 days
four times a day; tid
=
three times a day; TMP-SMX = trimethoprim-
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ACKNOWLEDGMENTS The authors thank Rebecca Rudolph, MD, for expert manuscript evaluation, and Susan Sperline, for expert manuscript preparation.
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Address reprint requests to Christina M. Surawicz, MD University of Washington Harborview Medical Center 325 Ninth Avenue, Box 359773 Seattle, WA 98104 e-mail: [email protected]