Epidemiologic Notes and Reports Cryptosporidiosis: Assessment of Chemotherapy of Males with Acquired Immune Deficiency Syndrome (AIDS)

Since December 1979, 21 males with severe, protracted diarrhea caused by the parasite, Cryptosporidium, have been reported to CDC by physicians in Boston, Los Angeles, Newark, New York, Philadelphia, and San Fransisco. All 21 have acquired immune deficiency syndrome (AIDS); 20 are homosexual; and one is a heterosexual Haitian. Their ages range from 23 to 62 years with a mean of 35.7 years. Most had other opportunistic infections or Kaposi's sarcoma in addition to cryptosporidiosis. Eleven had Pneumocystis carinii pneumonia (PCP); nine had Candida esophagitis; two had a disseminated Mycobacterium avium-intracellulare infection; one had a disseminated cytomegalovirus infection; and two had Kaposi's sarcoma. T-lymphocyte helper-to-suppressor ratios were decreased ( 0.9) in all 18 patients on whom this test was performed. Fourteen patients have died.

The illness attributed to Cryptosporidium was characterized by chronic, profuse, watery diarrhea. The mean duration of diarrhea was 4 months, often continuing until the patient's death. Bowel movement frequency ranged from six to 25 per day. The estimated maximum volume of stool during illness ranged from 1 to 17 liters per day with a mean of 3.6 liters per day. Diagnosis of cryptosporidiosis was made by histologic examination of small bowel biopsies (13 patients) or large bowel biopsies (four patients), or by stool examination using a sucrose concentration technique (16 patients) (1). More than one type of diagnostic method was positive for several patients.

Table 1 shows the drugs given to the 21 patients while they had diarrhea attributed to Cryptosporidium. Only two patients (9.5%) have had sustained resolution of their diarrhea with negative follow-up stool examinations. The first was being treated with prednisone (60 mg daily) for chronic active hepatitis at the time his diarrhea began. When cryptosporidiosis was diagnosed, he was started on diloxanide furoate (500 mg three times daily for 10 days), and the prednisone was tapered over 2 weeks and then stopped. Two weeks later, his diarrhea was improving; in another 2 weeks, his diarrhea had completely resolved. He has had no diarrhea for 8 months. Follow-up stool examinations 2 weeks and 6 weeks after discontinuation of diloxanide furoate were negative for Cryptosporidium.

The second patient, who also had a clinical and parasitologic response, subsequently died of PCP. In early February 1982, 6 months before his death, he had onset of watery diarrhea, and a small bowel biopsy showed Cryptosporidium. Treatment with furazolidone (100 mg four times a day) was initiated on May 5, and within 6 days, the patient had gained 1.1 kilograms (2.4 pounds); parenteral nutrition was discontinued, although he continued to produce a liter of watery stool each day. Ten days after treatment was started, his stools became formed for the first time in 4 months, but Cryptosporidium oocysts were still present. Furazolidone was increased to 150 mg four times daily. Twenty days after therapy was started (10 days after the higher dose of furazolidone was begun), the patient had one bowel movement a day, but his stool was still positive for Cryptosporidium and remained positive despite continued use of furazolidone at 150 mg four times daily for a total of 2 months. At that time, two stool examinations failed to detect oocysts, and the furazolidone was stopped. One week later, the patient developed PCP; despite treatment with trimethoprim-sulfamethoxazole, he died 2 weeks later on July 22. An autopsy was not permitted.

After various treatment regimens, seven patients have had partial or transitory decreases in their diarrhea. Two received no anti-parasitic drugs. A third patient temporarily improved after treatment with furazolidone (100 mg orally four times a day for 7 days), although 2 weeks elapsed between the end of treatment with furazolidone and the onset of clinical improvement. The patient's diarrhea abated, but follow-up stool examinations remained positive for Cryptosporidium. Three months after furazolidone therapy, he again developed diarrhea, and his stools were positive for Cryptosporidium. Two patients had less diarrhea when given tetracycline. The first received tetracycline 500 mg orally four times a day for 4 months. His diarrhea decreased from 12 watery stools to three loose stools per day, but stool examination after 4 months of therapy still showed Cryptosporidium. The second patient, given the same treatment, also had a reduction in the number of stools. When the drug was discontinued, his diarrhea again increased.

Two patients' diarrhea stopped following treatment with opiates and metronidazole, given orally in one case and intravenously in the other. Neither patient had diarrhea after a few days of treatment, but both died within 1 week, and autopsies were not allowed. The first patient died from suspected peritonitis; the second died with disseminated Kaposi's sarcoma and pneumonia.

The remaining 12 patients have had continuous, severe diarrhea. In addition to the drugs listed in Table 1, bovine-transfer factor has been given to one patient and intravenous gamma globulin to two patients; neither was effective. At present, 14 (66.7%) of the 21 individuals have died, and six are alive with persistent diarrhea. In no instance was cryptosporidiosis thought to be the direct cause of death, but the associated severe malnutrition was often considered a contributing factor.

Shortly before cryptosporidiosis was recognized in AIDS patients, investigators at the U.S Department of Agriculture National Animal Disease Center (NADC) began testing drugs for efficacy against Cryptosporidium in animals; results of these initial studies were published in February, 1982 (2). More recently, five additional drugs have been evaluated at the NADC. Calves or pigs up to 14 days old without infection were given the drugs orally twice daily. One day after the drugs were started, each animal received a single oral inoculation of Cryptosporidium. The following drugs (with doses in mg/kg/day) were tested: amprolium (10.7), difluoromethylornithine (1250) plus bleomycin (6 IM), diloxanide furoate (125.0), dimetridazole (19.0), ipronidazole (23.8), lasalocid (0.7), metronidazole (23.8), monensin (4.8), oxytetracycline (50.0), pentamidine (10.0), quinacrine (11.9), salinomycin (6.0), sulfaquinoxaline (200.0), sulfadimidine (119.0), and trimethoprim (4.8) plus sulfadiazine (23.8). Although small numbers of animals were tested in each treatment group, no drugs prevented fecal shedding of oocysts or reduced the number of Cryptosporidium seen on intestinal biopsies. Reported by J Goldfarb, MD, H Tanowitz, MD, Albert Einstein College of Medicine, Bronx, R Grossman, MD, Medical Arts Center Hospital, C Bonanno, MD, D Kaufman, MD, P Ma, PhD, St. Vincent's Medical Center, R Soave, MD, New York Hospital-Cornell Medical Center, D Armstrong, MD, J Gold, MD, Memorial Sloan-Kettering Cancer Center, S Dikman, MD, M Finkel, MD, H Sacks, MD, Mt. Sinai Medical Center, R Press, MD, New York University Medical Center, D William, MD, St. Luke's-Roosevelt Hospital, S Friedman, MD, New York City Dept of Health, R Rothenberg, MD, State Epidemiolgist, New York State Dept of Health; S Brown, MD, United Hospitals, Newark, WE Parkin, DVM, State Epidemiologist, New Jersey State Dept of Health; EJ Bergquist, MD, Thomas Jefferson University Hospital, Philadelphia, CW Hays, MD, State Epidemiologist, Pennsylvania State Dept of Health; P Forgacs, MD, Lahey Clinic Medical Center, Burlington, L Weinstein, MD, Brigham and Women's Hospital, Boston, NJ Fiumara, MD, State Epidemiologist, Massachusetts State Dept of Public Health; D Busch, MD, San Francisco, M Derezin, MD, M Gottlieb, MD, J Matthew, MD, W Weinstein, MD, UCLA Center for Health Sciences, J Chin, MD, State Epidemiologist, California Dept of Health Svcs; H Moon, PhD, National Animal Disease Center, Ames, Iowa; AIDS Activity, Div of Parasitic Diseases, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: Cryptosporidium is a protozoan parasite; it is a well recognized cause of diarrhea in animals, especially calves, but has only rarely been associated with diarrhea in humans (3). Individuals with normal immune function who have developed cryptosporidiosis have self-limited diarrhea lasting 1-2 weeks, but immunosuppressed individuals have developed chronic diarrhea. An effective drug to treat cryptosporidiosis has not been identified, and the above reports are equally discouraging. Of seven patients who are still living, only one has no diarrhea at present. His recovery coincided with treatment with diloxanide furoate and discontinuation of prednisone. It seems unlikely that diloxanide furoate was responsible for his recovery, since three other patients who received the drug did not respond, and the drug was ineffective in experimentally infected pigs given nearly six times the recommended human dose. It is similarly difficult to be certain that improvement reported in other patients was due to the drugs they received because only a few patients receiving a drug responded, responses were brief, and the same or similar drugs were ineffective in preventing infection in experimental animals. The difficulty in interpreting isolated responses is underscored by the two patients who improved before any specific therapy began.

Since none of the drugs reported above appears clearly efficacious, additional tests of other anti-parasitic drugs in animals are needed. Until an effective drug for cryptosporidiosis is identified or the underlying immune deficiency in patients with AIDS becomes correctable, management of diarrhea due to cryptosporidiosis will continue to focus on supportive care.

References

1. Anderson BC. Patterns of shedding of cryptosporidial oocysts in Idaho calves. J Am Vet Med Assoc 1981; 178:982-4.

2. Moon HW, Woode GN, Ahrens FA. Attempted chemoprophylaxis of cryptosporidiosis in calves. Vet Rec 1982; 110:181.

3. CDC. Human cryptosporidiosis--Alabama. MMWR 1982; 31:252-4.

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