Cryptosporidium Infection and CD4 Counts Timothy Flanigan, MD; Christopher Whalen, MD; John Turner, MD; Rosemary Soave, MD; Joseph Toerner, MD; Diane Havlir, MD; and Donald Kotler, MD Annals of Internal Medicine. 1992;116:840-842. Cryptosporidium is a coccidian parasite that infects the gastrointestinal tract in humans and can cause severe enteritis and malabsorption. Cryptosporidiosis is selflimited in immunocompetent persons, whereas in persons with the acquired immunodeficiency syndrome (AIDS), Cryptosporidium infection causes persistent enteritis that is usually lifelong and refractory to treatment (1). In our clinical practices, we observed men infected with the human immunodeficiency virus (HIV) who had self-limited diarrhea due to Cryptosporidium infection. To better define the laboratory and clinical characteristics associated with self-limited compared with persistent disease, we did a retrospective chart review of HIV-seropositive patients with Cryptosporidium infection. We hypothesized that self-limited cryptosporidiosis might be associated with a more intact immune system as reflected by a higher absolute CD4 lymphocyte count. Methods The study group comprised 47 HIV-seropositive patients with cryptosporidiosis. These patients were identified by six physicians with an interest in cryptosporidiosis who reviewed their patient records at referral centers in Cleveland, New York, Atlanta, San Diego, and Philadelphia. Seropositivity to human immunodeficiency virus was defined as a positive result on an enzyme-linked immunosorbent assay (ELISA) with Western blot confirmation. Cryptosporidiosis was defined as diarrhea (more than three unformed bowel movements per day) for at least 7 days with Cryptosporidium oocysts present on acid fast smear and no evidence of bacterial pathogens, pseudomembranous colitis, or other parasitic pathogens on stool examination and culture. Endoscopy was not routinely done. Self-limited Cryptosporidium infection was defined as normalization of bowel movements (three or fewer formed bowel movements per day) without the use of antimotility agents for at least 2 months and all stool examinations (with a minimum of two) negative for Cryptosporidium oocysts by both modified acid fast smear and concentration techniques. Patients were subsequently followed from 1 to 24 months without evidence of relapse. Persistent Cryptosporidium infection was defined as ongoing diarrhea in the absence of use of antimotility agents for a minimum of 2 months and continued presence of oocysts on modified acid fast smear. Most patients had had cryptosporidiosis for more than 6 months. Data were collected for each patient using a standard For current author affiliations and addresses, see end of text.
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data collection form that included age, gender, race, hematocrit, CD4 and CD8 lymphocyte counts, total lymphocyte counts, AIDS-defining opportunistic infections (2), and the outcome of treatment. If test results were not available at the time of diagnosis, then the most recent laboratory data (within 3 months) were recorded. Data were analyzed using the chi-square test and the Student Mest, and multiple logistic regression analysis was used to determine independent predictors of selflimited infection (3). To calculate the odds ratio for self-limited infection, we formed two groups based on CD4 lymphocyte counts: one group with CD4 count of less than 150 cells/mm 3 and the other with CD4 counts of 150 cells/mm 3 or more. A threshold of 150 cells/mm 3 was used because of the low mean and narrow distribution of CD4 counts in the patients with persistent infection. Results Thirteen HIV-seropositive patients who had self-limited Cryptosporidium infection were compared with 34 HIV-seropositive persons with persistent cryptosporidiosis. Ninety-four percent were men, the predominant risk factor for HIV infection in each group was homosexuality, and the mean age was 36 ± 6 (SD) years. The mean CD4 count was significantly greater in patients with self-limited infection (312 cells/mm 3 ; range, 14 to 651 cells/mm3) than in patients with persistent infection (57 cells/mm 3 [± 42]; range, 4 to 150 cells/ mm 3 ; P = 0.001) (Figure 1). A similar relationship was found in patients with self-limited disease compared with persistent disease for the CD8 count (859 ± 662 cells/mm 3 compared with 481 ± 407 cells/mm 3 ; P = 0.03), the mean ratio of CD4 to CD8 count (0.33 ± 0.18 compared with 0.19 ± 0.18, P = 0.03), and the mean hematocrit (0.40 ± 0.04 compared with 0.35 ± 0.06, P = 0.01). Of these laboratory measures, only the absolute CD4 count was an independent predictor of selflimited infection as determined in a stepwise logistic regression analysis (P = 0.03). According to this analysis, the odds of self-limited Cryptosporidium infection were 53 times greater (95% CI, 5.4 to 512) in patients with CD4 counts of 150 cells/mm 3 or more compared with patients with CD4 counts of less than 150 cells/ mm 3 . The mean total lymphocyte count was not significantly different in patients with self-limited and persistent disease (1147 cells/mm 3 compared with 806 cells/ mm 3 , respectively; P > 0.2). Other factors such as age, sex, and risk behavior were not associated with selflimited disease. All patients with CD4 counts of 180 cells/mm 3 or more (n = 8) cleared the infection spontaneously without antiretroviral therapy within 7 days to 1 month. Of 39 patients with CD4 counts of less than 180 cells/mm 3 , 5 (13%) had self-limited disease and 34 (87%) had persistent disease. Of note, four of the five patients with low CD4 counts and self-limited disease were started on treatment with zidovudine in doses of 600 to 1200 mg per day at the time cryptosporidiosis was diagnosed. Despite weight gain associated with clinical resolution of disease, their CD4 counts did not rise significantly.
Fifteen of 34 patients (44%) with persistent infection and low CD4 counts were on zidovudine therapy when they developed cryptosporidiosis. Two of 13 persons (15%) with self-limited cryptosporidiosis had had a previous opportunistic infection compared with 21 of 34 persons (62%) with persistent cryptosporidiosis (P = 0.003). Discussion The results of our study suggest that the duration of the disease during HIV infection is related to the degree of immunocompetence of the host. Self-limited cryptosporidiosis was associated with a higher CD4 count, CD8 count, CD4 to CD8 ratio, and hematocrit although only the CD4 count was an independent predictor of self-limited disease. In our study group, all patients with CD4 counts of 180 cells/mm 3 or more had self-limited Cryptosporidium infection. In fact, the course of their illness was not markedly different from Cryptosporidium enteritis in immunocompetent HIVseronegative persons. We did not formally evaluate the clinical characteristics of Cryptosporidium infection at presentation. Yet, patients with both self-limited and persistent disease presented with the full range of symptoms, which varied from mild diarrhea of fewer than five stools a day to explosive diarrhea with dehydration. There is presently no well-established effective therapy for cryptosporidial enteritis (4). A few case series in the literature have reported that treatment with zidovudine resulted in clearance of Cryptosporidium infection, even in patients with markedly depressed CD4 counts (5, 6). In this study, a small number of patients with CD4 counts under 140 cells/mm 3 were able to eradicate
Figure 1. CD4 counts. Comparison of CD4 counts in human immunodeficiency virus (HlV)-positive persons with self-limited (n = 13) compared with persistent (n = 34) cryptosporidiosis. The horizontal lines indicates the mean value.
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infection after being started on zidovudine at the time they developed cryptosporidiosis. On the other hand, zidovudine did not prevent the development of Cryptosporidium infection in patients with CD4 counts of less than 140 cells/mm3. These findings have a direct clinical effect on the management of cryptosporidiosis in HIV-infected patients. The CD4 count is useful in predicting the course of Cryptosporidium infection as it is with many other opportunistic infections (7). In this study, all HIV-infected patients with cryptosporidiosis and CD4 counts of 180 cells/mm3 or more spontaneously cleared the infection within 4 weeks. In contrast, in patients with CD4 counts of less than 140 cells/mm3 who develop cryptosporidiosis, 87% develop persistent disease. These data provide important prognostic information to both the physician and patient. If patients with depressed CD4 counts and cryptosporidiosis are not on antiretroviral therapy, they should be begun immediately on zidovudine both for the drug's anti-HIV activity and because a few of these patients (10% in our experience) will clear Cryptosporidium infection while on zidovudine therapy. Past clinical trials of Cryptosporidium therapy have not all prospectively stratified patients according to CD4 count (8). Future clinical trials of Cryptosporidium therapy must be designed in such a way that they account for the immunocompetence of subjects by stratifying according to CD4 lymphocyte count.
Grant Support: By the National Institutes of Health grants AI-25879 and AI-01038. Requests for Reprints: Timothy P. Flanigan, MD, Department of Geographic Medicine, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906. Current Author Addresses: Dr. Flanigan, Department of Geographic Medicine, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906. Dr. Whalen: University Hospitals, Cleveland, OH 44106. Dr. Turner: Graduate Hospital, Philadelphia, PA 19146. Dr. Soave: New York Hospital-Cornell Medical Center, New York, NY 10021. Dr. Toerner: Whitman Walker Clinic, Washington, DC 20009. Dr. Havlir: University of California at San Diego, UCSD Treatment Center, San Diego, CA 92103. Dr. Kotler: St. Luke's-Roosevelt Medical Center, New York, NY 10025.
Presented in part at the VI International Conference on AIDS, San Francisco, 1990.
References 1. Fayer R, Ungar LP. Cryptosporidium spp. and cryptosporidiosis. Microbiol Rev. 1986;50:458-83. 2. Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR. 1987; 36(Suppl 1S):3S-15S. 3. SUGI Supplemental Library User's Guide, Version 5. Cary, North Carolina: SAS Institute Inc.; 1986:270-94. 4. Soave R, Johnson WD Jr. Cryptosporidium and Isospora belli infections. J Infect Dis. 1988;157:225-9. 5. Greenberg RE, Mir R, Bank S, Siegal FP. Resolution of intestinal cryptosporidiosis after treatment of AIDS with AZT. Qastroenterology. 1989;97:1327-30. 6. Connolly GM, Dryden MS, Shanson DC, Gazzard BG. Cryptosporidia! diarrhoea in AIDS and its treatment. Gut. 1988;29:593-7. 7. Jacobson MA, Hopewell PC, Yajko DM, Hadley WK, Lazarus E, Mohanty PK, et al. Natural history of disseminated Mycobacterium avium complex infection in AIDS. J Infect Dis. 1991;164:994-8. 8. Hojlyng N, Henriksen SA, Gaub J, Hjelt K, Mathieson L, Jepson S, et al. Cryptosporidium diarrhea in AIDS patients treated with hyperimmune bovine colostrum. VI International Conference on AIDS. 20-24 June 1990. San Francisco, California. 1990;TH.B.521:253.
Acknowledgments: The authors thank Richard E. DuBois, MD, for his assistance and Maureen Lemieux for preparation of the manuscript.
© 1992 American College of Physicians
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data collection form that included age, gender, race, hematocrit, CD4 and CD8 lymphocyte counts, total lymphocyte counts, AIDS-defining opportunistic infections (2), and the outcome of treatment. If test results were not available at the time of diagnosis, then the most recent laboratory data (within 3 months) were recorded. Data were analyzed using the chi-square test and the Student Mest, and multiple logistic regression analysis was used to determine independent predictors of selflimited infection (3). To calculate the odds ratio for self-limited infection, we formed two groups based on CD4 lymphocyte counts: one group with CD4 count of less than 150 cells/mm 3 and the other with CD4 counts of 150 cells/mm 3 or more. A threshold of 150 cells/mm 3 was used because of the low mean and narrow distribution of CD4 counts in the patients with persistent infection. Results Thirteen HIV-seropositive patients who had self-limited Cryptosporidium infection were compared with 34 HIV-seropositive persons with persistent cryptosporidiosis. Ninety-four percent were men, the predominant risk factor for HIV infection in each group was homosexuality, and the mean age was 36 ± 6 (SD) years. The mean CD4 count was significantly greater in patients with self-limited infection (312 cells/mm 3 ; range, 14 to 651 cells/mm3) than in patients with persistent infection (57 cells/mm 3 [± 42]; range, 4 to 150 cells/ mm 3 ; P = 0.001) (Figure 1). A similar relationship was found in patients with self-limited disease compared with persistent disease for the CD8 count (859 ± 662 cells/mm 3 compared with 481 ± 407 cells/mm 3 ; P = 0.03), the mean ratio of CD4 to CD8 count (0.33 ± 0.18 compared with 0.19 ± 0.18, P = 0.03), and the mean hematocrit (0.40 ± 0.04 compared with 0.35 ± 0.06, P = 0.01). Of these laboratory measures, only the absolute CD4 count was an independent predictor of selflimited infection as determined in a stepwise logistic regression analysis (P = 0.03). According to this analysis, the odds of self-limited Cryptosporidium infection were 53 times greater (95% CI, 5.4 to 512) in patients with CD4 counts of 150 cells/mm 3 or more compared with patients with CD4 counts of less than 150 cells/ mm 3 . The mean total lymphocyte count was not significantly different in patients with self-limited and persistent disease (1147 cells/mm 3 compared with 806 cells/ mm 3 , respectively; P > 0.2). Other factors such as age, sex, and risk behavior were not associated with selflimited disease. All patients with CD4 counts of 180 cells/mm 3 or more (n = 8) cleared the infection spontaneously without antiretroviral therapy within 7 days to 1 month. Of 39 patients with CD4 counts of less than 180 cells/mm 3 , 5 (13%) had self-limited disease and 34 (87%) had persistent disease. Of note, four of the five patients with low CD4 counts and self-limited disease were started on treatment with zidovudine in doses of 600 to 1200 mg per day at the time cryptosporidiosis was diagnosed. Despite weight gain associated with clinical resolution of disease, their CD4 counts did not rise significantly.
Fifteen of 34 patients (44%) with persistent infection and low CD4 counts were on zidovudine therapy when they developed cryptosporidiosis. Two of 13 persons (15%) with self-limited cryptosporidiosis had had a previous opportunistic infection compared with 21 of 34 persons (62%) with persistent cryptosporidiosis (P = 0.003). Discussion The results of our study suggest that the duration of the disease during HIV infection is related to the degree of immunocompetence of the host. Self-limited cryptosporidiosis was associated with a higher CD4 count, CD8 count, CD4 to CD8 ratio, and hematocrit although only the CD4 count was an independent predictor of self-limited disease. In our study group, all patients with CD4 counts of 180 cells/mm 3 or more had self-limited Cryptosporidium infection. In fact, the course of their illness was not markedly different from Cryptosporidium enteritis in immunocompetent HIVseronegative persons. We did not formally evaluate the clinical characteristics of Cryptosporidium infection at presentation. Yet, patients with both self-limited and persistent disease presented with the full range of symptoms, which varied from mild diarrhea of fewer than five stools a day to explosive diarrhea with dehydration. There is presently no well-established effective therapy for cryptosporidial enteritis (4). A few case series in the literature have reported that treatment with zidovudine resulted in clearance of Cryptosporidium infection, even in patients with markedly depressed CD4 counts (5, 6). In this study, a small number of patients with CD4 counts under 140 cells/mm 3 were able to eradicate
Figure 1. CD4 counts. Comparison of CD4 counts in human immunodeficiency virus (HlV)-positive persons with self-limited (n = 13) compared with persistent (n = 34) cryptosporidiosis. The horizontal lines indicates the mean value.
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infection after being started on zidovudine at the time they developed cryptosporidiosis. On the other hand, zidovudine did not prevent the development of Cryptosporidium infection in patients with CD4 counts of less than 140 cells/mm3. These findings have a direct clinical effect on the management of cryptosporidiosis in HIV-infected patients. The CD4 count is useful in predicting the course of Cryptosporidium infection as it is with many other opportunistic infections (7). In this study, all HIV-infected patients with cryptosporidiosis and CD4 counts of 180 cells/mm3 or more spontaneously cleared the infection within 4 weeks. In contrast, in patients with CD4 counts of less than 140 cells/mm3 who develop cryptosporidiosis, 87% develop persistent disease. These data provide important prognostic information to both the physician and patient. If patients with depressed CD4 counts and cryptosporidiosis are not on antiretroviral therapy, they should be begun immediately on zidovudine both for the drug's anti-HIV activity and because a few of these patients (10% in our experience) will clear Cryptosporidium infection while on zidovudine therapy. Past clinical trials of Cryptosporidium therapy have not all prospectively stratified patients according to CD4 count (8). Future clinical trials of Cryptosporidium therapy must be designed in such a way that they account for the immunocompetence of subjects by stratifying according to CD4 lymphocyte count.
Grant Support: By the National Institutes of Health grants AI-25879 and AI-01038. Requests for Reprints: Timothy P. Flanigan, MD, Department of Geographic Medicine, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906. Current Author Addresses: Dr. Flanigan, Department of Geographic Medicine, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906. Dr. Whalen: University Hospitals, Cleveland, OH 44106. Dr. Turner: Graduate Hospital, Philadelphia, PA 19146. Dr. Soave: New York Hospital-Cornell Medical Center, New York, NY 10021. Dr. Toerner: Whitman Walker Clinic, Washington, DC 20009. Dr. Havlir: University of California at San Diego, UCSD Treatment Center, San Diego, CA 92103. Dr. Kotler: St. Luke's-Roosevelt Medical Center, New York, NY 10025.
Presented in part at the VI International Conference on AIDS, San Francisco, 1990.
References 1. Fayer R, Ungar LP. Cryptosporidium spp. and cryptosporidiosis. Microbiol Rev. 1986;50:458-83. 2. Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR. 1987; 36(Suppl 1S):3S-15S. 3. SUGI Supplemental Library User's Guide, Version 5. Cary, North Carolina: SAS Institute Inc.; 1986:270-94. 4. Soave R, Johnson WD Jr. Cryptosporidium and Isospora belli infections. J Infect Dis. 1988;157:225-9. 5. Greenberg RE, Mir R, Bank S, Siegal FP. Resolution of intestinal cryptosporidiosis after treatment of AIDS with AZT. Qastroenterology. 1989;97:1327-30. 6. Connolly GM, Dryden MS, Shanson DC, Gazzard BG. Cryptosporidia! diarrhoea in AIDS and its treatment. Gut. 1988;29:593-7. 7. Jacobson MA, Hopewell PC, Yajko DM, Hadley WK, Lazarus E, Mohanty PK, et al. Natural history of disseminated Mycobacterium avium complex infection in AIDS. J Infect Dis. 1991;164:994-8. 8. Hojlyng N, Henriksen SA, Gaub J, Hjelt K, Mathieson L, Jepson S, et al. Cryptosporidium diarrhea in AIDS patients treated with hyperimmune bovine colostrum. VI International Conference on AIDS. 20-24 June 1990. San Francisco, California. 1990;TH.B.521:253.
Acknowledgments: The authors thank Richard E. DuBois, MD, for his assistance and Maureen Lemieux for preparation of the manuscript.
© 1992 American College of Physicians
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