Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Cryptosporidiosis Epidemiology       Cryptosporidiosis is caused by Cryptosporidium species, a group of protozoan parasites that infect the small bowel mucosa, and in immunosuppressed persons, the large bowel and extraintestinal sites. Those at greatest risk for disease are patients with advanced immunosuppression (i.e., CD4+ T lymphocyte counts generally <100 cells/µL The three most common species infecting humans are C. hominis (formerly C. parvum genotype 1 or human genotype), C. parvum (formerly C. parvum genotype 2 or bovine genotype), and C. meleagridis. In addition, infections with C. canis, C. felis, C. muris, and Cryptosporidium pig genotype have been reported in immunocompromised patients. Preliminary analyses indicate that some zoonotic species might have a stronger association with chronic diarrhea than C. hominis. However, whether the different Cryptosporidium species are associated with differences in severity of disease or response to therapy is unknown. In developed countries with low rates of environmental contamination where potent ART is widely available, cryptosporidiosis occurs at an incidence rate of <1 per 100 person-years among persons with AIDS. Transmission occurs through ingestion of Cryptosporidium oocysts. C. hominis infects only humans, and C. parvum infects humans and other large mammals (e.g., cows and sheep). C. meleagridis infects avians (e.g., turkeys and chickens) and humans. Feces from infected animals, including humans, can contaminate water supplies and recreational water with viable oocysts despite standard chlorination (90). Person-to-person transmission, primarily among men who engage in oral-anal sex, also has been observed. Young children with cryptosporidial diarrhea also might infect adults, especially during diapering. Scrupulous handwashing, use of barriers during anal sex, and other hygiene measures might help prevent person-to-person transmission. Clinical Manifestations The most common presentation of cryptosporidiosis is the acute or subacute onset of profuse, nonbloody watery diarrhea, frequently accompanied by nausea, vomiting, and lower abdominal cramping (151). Fever is present in approximately one third of patients. Malabsorption is often present. The epithelium of both the biliary tract and the pancreatic duct can be infected with Cryptosporidium. Cholangitis and pancreatitis occur among patients with prolonged disease (152). Diagnosis Cryptosporidium species cannot be cultivated in vitro. Diagnosis of cryptosporidiosis is primarily based on microscopic identification of the oocysts in stool or tissue. Oocysts stain red with varying intensities with a modified acid-fast technique; this technique allows for differentiation of the Cryptosporidium oocysts from yeasts that are similar in size and shape but are not acid fast. Oocysts also can be detected by direct immunofluorescent or enzyme-linked immunosorbent assays (153). No consensus exists on the optimal oocyst detection method in fecal samples. The modified acid-fast stain and a fluorescein labeled monoclonal antibody technique indicate comparability for diarrheal samples, but the immunofluorescent method is probably preferable for formed stool specimens. Cryptosporidium species and genotype identification requires molecular methods (e.g., PCR followed by sequencing). Cryptosporidial enteritis can be diagnosed on small intestinal biopsy sections by identification of developmental stages of Cryptosporidium organisms, found individually or in clusters, on the brush border of the mucosal epithelial surfaces. Organisms project into the lumen because of their intracellar but extracytoplasmic characteristics and appear basophilic with hematoxylin and eosin staining. Electron microscopy allows resolution of cellular detail. Among persons with profuse diarrheal illness, a single stool specimen is usually adequate for diagnosis. Among persons with less severe disease, repeat stool sampling is recommended, although no controlled studies have demonstrated the utility of three consecutive stool samples as is the case in Giardia duodenalis infection. Treatment Recommendations ART with immune restoration (an increase of CD4+ T lymphocyte count to >100 cells/µL) is associated with complete resolution of cryptosporidiosis, and all patients with cryptosporidiosis should be offered ART as part of the initial management of their infection (AII). No consistently effective pharmacologic or immunologic therapy directed specifically against C. parvum exists. Approximately 95 interventional agents have been tried for the treatment of cryptosporidiosis with no consistent success. Paromomycin, a nonabsorbable aminoglycoside that is indicated for the treatment of intestinal amebiasis, is effective in high doses for the treatment of cryptosporidiosis in animal models . A meta-analysis of 11 published paromomycin studies in humans reported a response rate of 67%. However, relapse was common in certain studies, with long-term success rates of only 33%. Two randomized controlled trials have compared paromomycin with placebo among patients with AIDS and cryptosporidiosis; modest, but statistically significant improvement in symptoms and oocyst shedding was demonstrated in one, but no difference from placebo was observed in the other . A small open-label study suggested a substantial benefit of paromomycin when used in combination with azithromycin, but few cures were noted . Therefore, efficacy data do not support a recommendation for the use of paromomycin for therapy, although the drug appears to be safe (CIII). Nitazoxanide, an orally administered nitrothiazole benzamide, has in vivo activity against a broad range of helminths, bacteria, and protozoa, including cryptosporidia . A short-term study among patients with HIV-1 infection documented increased cure rates compared with controls (based on clearance of organisms from stool and reduced rates of diarrhea) among patients with CD4+ T lymphocyte counts >50 cells/µL, but not in those with CD4+ T lymphocyte counts <50 cells/µL . Available data do not warrant a definite recommendation for use of this agent in this setting, but the drug has been approved by the U.S. Food and Drug Administration (FDA) for use in children and is expected to be approved for use in adults (CIII). Treatment of persons with cryptosporidiosis should include symptomatic treatment of diarrhea (AIII). Rehydration and repletion of electrolyte losses by either the oral or intravenous route is important. Severe diarrhea, which might be >10 L/day among patients with AIDS, often requires intensive support. Aggressive efforts at oral rehydration should be made with oral rehydration solutions that contain glucose, sodium bicarbonate, potassium, magnesium, and phosphorus (AIII). Treatment with antimotility agents can play an important adjunctive role in therapy, but these agents are not consistently effective (BIII). Loperamide or tincture of opium will often palliate symptoms. Octreotide, a synthetic octapeptide analog of naturally occurring somatostatin that is approved for the treatment of secreting tumor induced diarrhea, is no more effective than other oral antidiarrheal agents, and is generally not recommended  (DII). Monitoring and Adverse Events Patients should be closely monitored for signs and symptoms of volume depletion, electrolyte and weight loss, and malnutrition and should receive supportive treatment. Total parenteral nutrition might be indicated in certain patients (CIII). Management of Treatment Failure Supportive treatment and optimizing ART to achieve full virologic suppression are the only feasible approaches to the management of treatment failure (CIII). Prevention of Recurrence No drug regimens are proven to be effective in preventing the recurrence of cryptosporidiosis. Special Considerations During Pregnancy As with nonpregnant woman, initial treatment efforts should rely on rehydration and initiation of ART. Pregnancy should not preclude the use of ART.