Cryptosporidiosis in Patients with HIV Disease
Is It Safe to Drink the Water?
Cryptosporidiosis is a relatively uncommon, but nonetheless worrisome, opportunistic infection in patients with HIV disease. It is the chief AIDS-defining infection in no more than 2% of reported cases, but it is seen with considerably greater frequency in patients living with AIDS, particularly in those with advanced disease.
The incidence of cryptosporidiosis in AIDS patients with diarrhea varies geographically -- from 10% to 20% in the United States and Western Europe to as high as 50% in developing countries in Africa and Latin America.(1) Some studies have shown a higher incidence of cryptosporidiosis in patients with sexually-acquired HIV infection than in those with IV drug-related HIV infection, most likely due to contact with feces during anal-oral sex.(2)
Although most reported cases of cryptosporidiosis have occurred in immunodeficient patients, it is a common cause of self-limited gastroenteritis in immunocompetent individuals. Outbreaks have been attributed to contamination in municipal water supplies, both surface and underground,(3, 4) in swimming pools,(5) and even in a hospital ice-machine.(6)
A waterborne outbreak led to 400,000 cases of cryptosporidiosis in Milwaukee, Wisconsin, in 1993, and resulted in at least 100 deaths in patients with AIDS.(3) This was the largest outbreak of waterborne illness in American history, and it occurred despite the fact that the water quality met all existing federal and local standards. Another waterborne outbreak -- this one is Las Vegas, Nevada, in 1994 -- led to the deaths of 41 AIDS patients.(4) Experts were not able to identify the reason that water from the Lake Mead reservoir had become contaminated.
Clinical manifestations of cryptosporidiosis
Although cryptosporidiosis can be acquired at any time during the course of HIV infection, including primary infection,(7) major morbidity and mortality occur almost exclusively in patients with CD4 counts below 180 cells/mm3; above this level, spontaneous recovery generally occurs.(8) Patients with CD4 counts below 50 cells/mm3 usually experience progressive diarrhea that results in death. In the Milwaukee outbreak, mortality at one year in patients with AIDS and epidemic cryptosporidiosis was 73% when baseline CD4 count was less than 50 cells/mm3 and 36% when baseline count was between 50 and 200 cells/mm3.(9)
The most common clinical presentation of cryptosporidiosis in HIV-infected patients is an acute onset of non-bloody, watery diarrhea without fever. In patients with CD4 counts greater than 180 cells/mm3, as in immunocompetent HIV-negative individuals, cryptosporidiosis is a self-limiting condition that lasts from 5 to 14 days, although transient relapses may occur in up to 30% of cases.(10) In patients with AIDS, cryptosporidiosis is, commonly, a permanent diarrheal illness that leads to chronic malabsorption of fluids, nutrients, vitamins, and electrolytes -- with resulting wasting and hypokalemic metabolic acidosis.(11) In patients who fail to respond to therapy, death usually occurs in three to six months.(12)
Biliary involvement is seen in up to 25% of cryptosporidiosis cases, and it usually presents as right upper-quadrant pain and elevated alkaline phosphatase.(13) Two distinct presentations are seen: 1) papillary stenosis with extrahepatic ductal dilatation and sclerosing cholangitis, and 2) acalculous cholecystitis. Gastric involvement may present as nausea and vomiting, with or without diarrhea.(14) Respiratory cryptosporidiosis has been reported, occasionally with cryptosporidial pneumonitis,(15) with the likely mechanism of infection being the aspiration of organisms from the GI tract. As a rule, cryptosporidial colitis is associated with less severe wasting than is seen with enteritis. Extraintestinal manifestations of cryptosporidiosis are unique to HIV infection and have not been reported in immunocompetent hosts.
In HIV-infected individuals, a lack of cell-mediated immunity leads to heavy infestations of cryptosporidia oocysts on the intestinal mucosa, and these infestations correlate with an intense inflammatory response and impaired absorptive function.(16, 17) Small-bowel morphology may be normal or abnormal. Although specific serum IgA levels are high in infected patients, specific secretory IgA is absent.(18) There is no clear evidence that an enterotoxin is involved. Inflammatory changes may be seen in the biliary sphincter and on the gall bladder wall, with or without cryptosporidia oocysts.
Diagnosis of cryptosporidiosis
Cryptosporidiosis is one of the most common causes of prolonged diarrhea in HIV-infected patients. The differential diagnosis includes other protozoans, enteric bacteria, viruses, drug side effects, and HIV enteropathy (Table).(19) Multiple pathogens may be present. A single stool specimen, treated with modified acid-fast (Kinyoun) stain, is usually adequate for diagnosis, but occasionally a repeat specimen, or even a duodenal aspirate or biopsy, is necessary.(20)
Elevated alkaline phosphatase is the hallmark of biliary cryptosporidiosis; dilation of the common bile duct is often seen on ultrasound or retrograde cholangiography. Significantly, cryptosporidia oocysts have been found in the bile, papilla, and gall bladder wall in the presence of typical symptoms and absence of radiographic findings.(13) In respiratory cryptosporidiosis, oocysts may be identified in expectorated sputum or material obtained at bronchoscopy.
Since cryptosporidiosis resolves within 14 days in HIV-infected patients with CD4 counts above 200 cells/mm3, no treatment is required for these patients.(8) There is increasing anecdotal evidence that colonization during the early stages of HIV infection may lead to active disease as immune function diminishes, and if future research confirms this observation, treatment may be indicated before CD4 counts drop below 200 cells/mm3.(21, 22)
For patients with CD4 counts less than 200 CD4 cells/mm3, paromomycin (Humatin®), a nonabsorbable aminoglycoside, is the treatment of choice.(23-25) The recommended dosage is 500 mg q.i.d. for 14 to 28 days. Chronic maintenance therapy is often required for patients with heavy infestations, those with CD4 counts below 50 cells/mm3, and those who relapse after initial treatment.
With treatment, most patients experience a reduction or cessation of diarrhea and regain lost weight. Clearance of oocysts from the stool is less frequent, occuring in 27% by four weeks.(26) The side effects of paromomycin therapy are usually limited to mild GI symptoms, but enhanced systemic absorption due to small-bowel injury with vestibular toxicity has been reported.(25) There is no evidence that paromomycin is effective in biliary cryptosporidiosis.
Azithromycin (Zithromax®) has shown some clinical activity against cryptosporidial enteritis and can be tried if paromomycin fails. Nitazoxanide has demonstrated efficacy against cryptosporidiosis in a small Mexican study,(27) and U.S. trials are currently under way. (The drug has been made available by its manufacturer, Unimed Pharmaceuticals, under a compassionate-access program. For further details call 1-800-864-6330, ext. 3032.) Other drugs, among them hyperimmune bovine colostrum and letrazuril,(28) have shown only sporadic efficacy against cryptosporidial enteritis.
Supportive measures are essential for patients with intractable diarrhea. These measures include both prescription and over-the-counter antimotility agents, antiemetics, narcotics, octreotide,(29) and enteral replacement of caloric, electrolyte, and fluid losses (see "Management of Wasting Syndrome in Late-Stage HIV Infection," Vol. 1, No. 5, pages 91-97). Total parenteral nutrition may have to be considered for refractory cases, but it is unclear if the benefit of TPN outweighs the complications and expense, and this approach should be highly individualized.(30) Resolution of cryptosporidiosis after a response to antiretroviral therapy has been reported.(21, 31)
Biliary cryptosporidiosis occurs in the most profoundly immunocompromised patients, those with CD4 counts below 50 cells/mm3, and as was seen in the Milwaukee outbreak, it carries a dismal prognosis. Cholecystectomy and endoscopic sphincterotomy may provide short-term palliative relief but they are not likely to affect overall outcome.(13) Parenteral narcotics are often required for end-stage palliation. Aerosolized paromomycin has been used successfully in a patients with respiratory cryptosporidiosis.(30)
Prevention of cryptosporidiosis
The potential for waterborne transmission of cryptosporidiosis to AIDS patients, the "canaries in the cage," has been dramatically demonstrated by the recent outbreaks in Milwaukee(3) and Las Vegas,(4) which led to at least 140 deaths in this highly vulnerable population. Because cryptosporidia oocysts are present even in the treated surface water supplies in most American cities, there is speculation that many if not most cases of sporadic cryptosporidiosis are due to contaminated drinking water.(33) Indeed, only a few ingested oocysts are required to establish infection.(34) In the Las Vegas outbreak, 70% of the cases that occurred in HIV-infected patients -- and 87% in those with CD4 counts below 100 cells/mm3 -- would have been prevented if those individuals had avoided tap water completely.
Many American cities -- including New York, Boston, San Francisco, and other cities with a high incidence of HIV infection -- do not filter municipal drinking water from the surface source. Although oocysts have been found in these water supplies, there is no conclusive evidence that this has led to cryptosporidium infection in AIDS patients.(33) Chlorination is not effective in preventing cryptosporidiosis, but ozonation may possibly be effective.(33)
To reduce the likelihood that HIV-positive individuals will become infected with cryptosporidium, the Centers for Disease Control have made these recommendations:(33, 35)
HIV-positive individuals should not drink directly from lakes or rivers, and they should avoid ingesting even small amounts of swimming pool water.
Persons with cryptosporidiosis should not use swimming pools (except for private pools not used by others).
Patients with advanced HIV disease should consider measures that should decrease the likelihood that they will be exposed to waterborne cryptosporidiosis -- by boiling tap water or filtering it through an "absolute" one-micron filter, or by using bottled water exclusively.
Because substantial variation in purity exists among bottled waters, patients should select bottled water that comes from underground springs and is free of coliforms, or water that has been distilled or filtered through a NSF Standard #53 filter that will remove all oocysts.
Although additional precautions are not formally recommended by the C.D.C., many clinicians are advising all HIV-positive patients who live in areas where tap water is derived from surface water supplies to use only boiled or adequately filtered tap water or high-quality bottled water that meets C.D.C. criteria. For specific recommendations regarding precautions against cryptosporidium infection, see the Pull Out and Save feature in this issue, "Avoiding Cryptosporidiosis: What the HIV-Positive Patient Needs to Know."
As more cities take up regular monitoring of finished tap water for the presence of oocysts, it will be increasingly possible to issue a selective "boil advisory" for individuals with impaired immune systems whenever oocysts are found or the turbidity of the city's water supply reaches a level known to be associated with cryptosporidial contamination. These advisories should be handled proactively by advocates of people with HIV infection, members of the medical community, and public health authorities.
In the Milwaukee outbreak, cryptosporidiosis was acquired by 45% of a studied cohort of 73 AIDS patients. Treatment of this local epidemic accounted for approximately $800,000 in excess medical expenses over the first six months of the outbreak, by which time 40% of the affected patients had died (9). Nearly all of the inpatient hospital days in the entire cohort were attributed to patients with cryptosporidiosis.
Assuming an annual excess expenditure of $38,000 per case, a 2% rate of cryptosporidiosis among AIDS patients in the United States, and 300,000 individuals with AIDS, approximately $200,000,000 in direct medical expenditures could potentially be saved annually by instituting and enforcing water purity standards. Uniform enforcement could reduce the incidence of cryptosporidiosis by as much as 90%. This figure must be kept in mind as the national political debate on clean water standards continues. Those of us who witness the unnecessary suffering of our patients must make ourselves heard on this crucial subject.
1. Petersen C. Cryptosporidiosis in patients infected with the human immunodeficiency virus. Clin Infect Dis 1992; 15: 903-9.
2. Lopez-Velez R, et al. Intestinal and extraintestinal cryptosporidiosis in AIDS patients. Eur J Clin Micro Infect Dis 1995; 14: 677-81.
3. MacKenzie WR, Hoxie NJ, Proctor ME, et al. A massive outbreak in Milwaukee of Cryptosporidium infection transmitted through the public water supply. N Engl J Med 1994; 331: 161-7.
4. 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 1996; 124: 459-68.
5. Centers for Disease Control and Prevention. Cryptosporidium infections associated with swimming pools: Dane County, Wisconsin, 1993. MMWR 1994; 43: 561-3.
6. Ravn P, Lundgren JD, Kjaldgaard P, et al. Nosocomial outbreak of cryptosporidiosis in AIDS patients. Br Med J 1991; 302: 277-280.
7. Moss PJ, et al. Prolonged cryptosporidiosis during primary HIV infection. J Infection 1995; 30: 51-3.
8. Flanigan T, et al. Cryptosporidium infection and CD4 counts. Ann Intern Med 1992; 116: 840-2.
9. Gilson I, Buggy B, Brummitt CF, et al. Impact of a community-wide outbreak of cryptosporidiosis in patients with AIDS. Tenth International Conference on AIDS, Yokohama, Japan, 1994. Abstract 390B.
10. MacKenzie WR, et al. Massive outbreak of waterborne Cryptosporidium infection in Milwaukee, Wisconsin: Recurrence of illness and risk of secondary transmission. Clin Infect Dis 1995; 21: 57-62.
11. Mannheimer SB, Soave R. Protozoal infections in patients with AIDS: Cryptosporidiosis, isosporiasis, cyclosporiasis, and microsporidiosis. Infect Dis Clin North Am 1994; 8: 483-98.
12. Blanshard C, et al. Cryptosporidiosis in HIV-seropositive patients. Quart J Med 1992; 85: 813-23.
13. Vakil NB, et al. Biliary cryptosporidiosis in HIV-infected people after the waterborne outbreak of cryptosporidiosis in Milwaukee. N Engl J Med 1996; 334: 19-23.
14. Garone MA, Winston BJ, Lewis JH. Cryptosporidiosis of the stomach. Am J Gastroent 1986; 81: 465-70.
15. Ma P, et al. Respiratory cryptosporidiosis in the acquired immunodeficiency syndrome. JAMA 1984; 252: 1298-1301.
16. Goodgame RW, et al. Intestinal function and injury in acquired immunodeficiency syndrome-related cryptosporidiosis. Gastroent 1995; 108: 1075-82.
17. Goodgame RW. Understanding intestinal spore-forming protozoa: Cryptosporidia, microsporidia, isospora, and cyclospora. Ann Intern Med 1996; 124: 429-41.
18. Flanigan TP. Human immunodeficiency virus infection and cryptosporidiosis: Protective immune responses. Am J Trop Med Hyg 1994; 50 (Suppl 5): 29-35.
19. Smith PD, et al. Gastrointestinal infections in AIDS. Ann Intern Med 1992; 116: 63-77.
20. Clavel A, et al. Evaluation of the optimal number of faecal specimens in the diagnosis of cryptosporidiosis in AIDS and immunocompetent patients. Eur J Clin Micro 1995; 14: 46-9.
21. Buggy BP. Unpublished observation, 1996.
22. Soave R. Waterborne cryptosporidiosis -- setting the stage for control of an emerging pathogen. Clin Infect Dis 1995; 21: 63-4.
23. Fichtenbaum CJ, Ritchie DJ, Powderly WG. Use of paromomycin for treatment of cryptosporidiosis in patients with AIDS. Clin Infect Dis 1993; 16: 298-300.
24. White AC Jr, et al. Paromomycin for cryptosporidiosis in AIDS: A prospective, double-blind trial. J Infect Dis 1994; 170: 419-24.
25. Wallace MR, Nguyen MT, Newton JA Jr. Use of paromomycin for the treatment of cryptosporidiosis in patients with AIDS. Clin Infect Dis 1993; 17: 1070-1.
26. Flanigan TP, et al. Prospective trial of paromomycin for cryptosporidiosis in AIDS. Am J Med 1996; 100: 370-2.
27. Feregrino GM, et al. Extraordinary potency of nitazoxanide, a new antiparasitary against cryptosporidium parvum infections in advanced AIDS. Eleventh International Conference on AIDS, Vancouver, B.C., Canada, 1996. Abstract B4213.
28. Harris M, et al. A phase I study of letrazuril in AIDS-related cryptosporidiosis. AIDS 1994; 8: 1109-13.
29. Liberti A, Bisogno A, Izzo E. Octreotide treatment in secretory and cryptosporidial diarrhea in patients with AIDS. J Chemotherapy 1992; 4: 303-5.
30. Knowles JB, Gilmore N. Discontinuation of total parenteral nutrition in a patients with AIDS: A Canadian perspective. Nutr Rev 1994; 52: 271-4.
31. Chandrasekar PH. "Cure" of chronic cryptosporidiosis during treatment with azidothymidine in a patient with AIDS. Am J Med 1987; 83: 187.
33. Juranek DD. Cryptosporidiosis: Sources of infection and guidelines for prevention. Clin Infect Dis 1995; 21 (Suppl 1): 57-61.
34. DuPont HL, et al. The infectivity of Cryptosporidium parvum in health volunteers. N Engl J Med 1995; 332: 855-9.
35. Assessing the public health threat associated with waterborne cryptosporidiosis: Report of a workshop. MMWR 1995; 44 (RR-6): 1-19.
Ian Gilson, M.D., and Brian P. Buggy, M.D., are with the Wisconsin AIDS Research Consortium, Milwaukee, WI.