Newer Enteric Protozoan and Bacterial Pathogens David Kramer, M.D. I. Cyclosporiasis A. The infectious agent is Cyclospora cayetanensis. Newly recognized as a protozoan parasite causing illness in humans, although earlier reports had suggested other identities for this pathogen, including blue-green algae (eg, Cyanobacteria-like bodies) or other protozoan forms. B. Epidemiology. 1. Parasite is widely distributed geographically, including the U.S., Latin America and Asia. 2. Waterborne transmission and food-borne transmission occur; whether other modes of transmission exist remains to be defined. Oocysts when passed in stool are not immediately infectious and require sporulation over days to weeks. Consequently, direct person-to-person spread of infection is not likely. In US associated with widespread outbreaks of diarrheal illness due to contaminated raspberries imported from Guatemala. C. Pathophysiology 1. Parasite invades epithelial cells as detectable in small bowel biopsies. 2. Mechanism of pathogenesis not understood, but the absence of fecal leukocytes and blood suggests that disease is due to a noninvasive mechanism. D. Clinical 1. Immunocompetent hosts: Incubation period is usually about seven days. Patients experience diarrhea, flu-like symptoms and symptoms common to other small bowel pathogens, such as flatulence and burping. May have a single self-limited episode, but prolonged diarrhea, anorexia and upper GI symptoms often occur. Pronounced fatigue and malaise have been frequent symptoms with weight loss experienced by some. 2. Immunocompromised hosts: Recognized in ADS, but nature of intestinal illness due to Cyclospora in immunocompromised hosts not yet defined. E. Diagnosis 1. Oocysts in stool (8-10 µm in diameter) are acid-fast and can be detected with acid-fast stains of stool. Thus, must be distinguished from Cryptosporidium, Cyclospora oocysts are not found on routine stool O + P exams; rather specific acid- fast stains must be requested. F. Treatment 1. Trimethoprim-sulfamethoxazole 1 double strength tablet bid for 7 days is effective. Alternative therapies for those unable to take TMP-SMX are not defined. II. Cryptosporidiosis A. Agent - Cryptosporidium parvum B. Epidemiology 1. Parasite infects humans and a variety of veterinary animals. Oocysts passed in human or animal feces are infectious and ingestion leads to acquisition of infection. 2. Infection may spread via: • waterborne transmission: both drinking water and recreational water (pools, slides, etc) • food-borne spread - oocyst contamination after any cooking • direct person-to-person transmission (amongst male homosexuals, within day-care centers, within hospitals) • animal to person spread (from calves, lambs, ?dogs/cats) C. Pathophysiology 1. Parasite invades epithelial cells and exists within a parasitophorous vacuole, which is intracellular but extra-cytoplasmic. Parasite replicates. 2. Mechanism of pathogenesis not understood. Diarrhea appears to be a secretory process and infection does not cause disruption of bowel epithelium. In addition to small bowel, parasites may be found in colon, rectum and esophagus in some patients. Oocysts have been recovered from pulmonary secretions: ? 20 to aspiration or due to infection of bronchial epithelium. Also may spread into biliary tract to cause disease. D. Clinical 1. Immunocompetent hosts: Incubation period of about 6 days (3-12 days range). Watery, non-bloody diarrhea; less commonly, abdominal discomfort, anorexia, fever, nausea and weight loss. Usually self-limited, lasting 3-14 days, only occasionally for months. Malabsorption can develop. Asymptomatic carriage is recognized. 2. Immunocompromised hosts: Chronic, unremitting, profuse, watery diarrhea. In AIDS, worse with CD4 count < 180/ul. E. Diagnosis 1. Oocysts in stool are small (4-5 µm diameter) and may be missed on conventional stool O + P exams. Oocysts, however, are acid-fast and can be detected with acid-fast stains of stool or more sensitively with a specific fluorescent antibody stain. For low numbers of oocysts, can use modified sucrose flotation method. Parasites may also be found along luminal surface of biopsied intestinal epithelium. F. Treatment 1. For immunocompetent, illness is self-limited and no therapy, other than possible supportive fluid and electrolyte replacement, is needed. 2. For immunocompromised, therapy is needed, but none has been found to be effective. Limited and not uniform successes with paromomycin. III. Isoporosis A. Agent - lsospora belli B. Epidemiology 1. Modes of transmission and sources of human infections not defined. C. Pathophysiology 1. Parasite infects the intestinal tract, but underlying pathogenic mechanisms uncertain. D. Clinical 1. Immunocompetent hosts: Usually abrupt in onset with fever and malaise followed by abdominal pain, diarrhea and weight loss. Most infections self-limited, although some may last for weeks to months. 2. Immunocompromised hosts: Chronic, unremitting, profuse, watery diarrhea, indistinguishable for cryptosporidiosis. E. Diagnosis 1. Oocysts are acid-fast and can be detected with acid-fast stains of stool. For low numbers of oocysts, can use zinc sulfate concentration method. Parasites may also be found along luminal surface of biopsied intestinal epithelium. F. Treatment 1. Trimethoprim-sulfamethoxazole double-strength tablets qid for 10 days and then bid for 3 weeks. For those with AIDS, relapses are frequent and maintenance therapy is needed with one double strength trimethoprim-sulfamethoxazole tablet three times/week. IV. Escherichia coli O157 A. Escherichia coli O157 produces amounts of two types of Shiga toxins. A cause of diarrheal illness and the hemolytic- uremic syndrome. B. Epidemiology O157 is a non-pathogenic gut bacterium in cattle. 1. Beef is the food source most likely to harbor O 157. 2. Milk, fruit, vegetables that have contacted bovine feces may also become contaminated. 3. Heating (70EC for 2 mins) kills O157; thus undercooked meat or non-pasteurized cider may efficiently spread infection. C. Pathophysiology 1. O157 adheres to intestinal epithelial cells. Shiga-like toxins I and II, encoded by a bacteriophage, may be elaborated and act: • locally to cause intestinal epithelial ulceration and diarrhea, and • systemically to damage small blood vessels, eg in the kidney, causing acute renal failure, hemolytic anemia and thrombocytopenia (hemolytic uremic syndrome). D. Clinical Diarrhea, bloody diarrhea and abdominal cramps are common. E. Diagnosis 1. A history of bloody diarrhea and/or having visible blood in stools is very common, but one third of isolates are from non-bloody samples. Fecal leukocytes may be present. 2. Culture; toxin immunoassay and gene probes. F. Treatment 1. Fluoroquinolones, eg ciprofloxacin 500 mg bid or norfloxacin 400 mg bid, for 3- 5 days. 2. TMP/SMX double strength tabs bid for 3-5 days. References I. Cyclospora 1. Herwaldt BL, Ackers ML. An outbreak in 1996 of cyclosporiasis associated with imported raspberries. The Cyclospora Working Group. N Engl J Med. 336:1548, 1997. 2. Ortega YR, Sterling CR, Gilman RH, Cama VA, Diaz F. Cyclospora species - a new protozoan pathogen of humans. N Engl J Med. 328:1308, 1993. 3. Huang P, Weber JT, Sosin DM et al. The first reported outbreak of diarrheal illness associated with Cyclospora in the United States. Ann Intern Med 123:409, 1995. 4. Pape JW, Verdier RI, Boncy M, Boncy J, Johnson WD Jr. Cyclospora infection in adults infected with HIV. Clinical manifestations, treatment, and prophylaxis. Ann Intern Med 121:654, 1994. 5. Hoge CW, Shlim DR, Ghimire Met al. Placebo-controlled trial of co-trimoxazole for Cyclospora infections among travelers and foreign residents in Nepal. Lancet 345:691, 1995. 6. Outbreaks of pseudo-infection with Cyclospora and Cryptosporidium - Florida and New York City, 1995. MMWR Morb Mortal Wkly Rep 46:354, 1997. 7. Gascon J Corachan M Bombi JA Valls ME Bordes JM. Cyclospora in patients with traveller's diarrhea. Scand J Infect Dis 27:511, 1995. II. Cryptosporidiosis 1. Goldstein ST, Juranek DD, Ravenholt O, et al. Cryptosporidiosis: an outbreak associated with drinking water despite state-of-the-art water treatment. Ann Intern Med 124:459, 1996. 2. Chappell CL, Okhuysen PC, Sterling CR, DuPont HL. Cryptosporidium parrum: intensity of infection and oocyst excretion patterns in healthy volunteers. J Infect Dis 173:232, 1996. 3. McAnulty JM, Fleming DW, Gonzalez AH. A community-wide outbreak of cryptosporidiosis associated with swimming at a wave pool. JAMA 272:1597, 1994. 4. Millard PS, Gensheimer KF, Addiss DG, et al. An outbreak of cryptosporidiosis from fresh-pressed apple cider. JAMA 272:1592, 1994. 5. Vakil NB, Schwartz SM, Buggy BP, et al. Biliary cryptosporidiosis in HIV-infected people after the waterborne outbreak of cryptosporidiosis in Milwaukee. N Engl J Med 334:19, 1996. 6. Addiss DG, Pond RS, Remshak M, et al. Reduction of risk of watery diarrhea with point-of-use water filters during a massive outbreak of waterborne Cryptosporidium infection in Milwaukee, Wisconsin, 1993. Am J Trop Med Hyg 54:549, 1996. 7. Hashmey R, Smith NH, Cron S, Graviss EA, Chappell CL. White AC Jr. Cryptosporidiosis in Houston, Texas. A report of 95 cases. Medicine (Baltimore) 76:118, 1997. III. Isospora 1. DeHovitz JA, Pape JW, Boncy Met al. Clinical manifestations and therapy of lsopsora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med 315:87, 1986. 2. Pape JW, Verdier R-I, Johnson WD Jr. Treatment and prophylaxis of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med 320:1044, 1989. 3. Sorvillo FJ, Lieb LE, Seidel J, Kerndt P, Turner J, Ash LR. Epidemiology of isosporiasis among persons with acquired immunodeficiency syndrome in Los Angeles County. Am J Trop Med Hyg 53:656, 1995. IV. Escherichia coli 0157 1. Outbreaks of Escherichia coli O157:H7 infection and cryptosporidiosis associated with drinking unpasteurized apple cider--Connecticut and New York, October 1996. MMWR Morb Mortal Wkly Rep 46:4, 1997. 2. Slutsker L, Ries AA, Greene KD, Wells JG, Hutwagner L, Griffin PM. Eschereicha coli 0157:H7 diarrhea in the United States: Clinical and epidemiologic features. Ann Int Med 126:505, 1997.