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Cryptosporidiosis, Cyclosporiasis, and Isosporiasis in the Setting of HIV Infection
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Introduction
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Cryptosporidiosis
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transparent imageEpidemiology
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transparent imageMicrobiology and Pathophysiology
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transparent imageAnimal Models, Cell Culture, and Basic Science Advances
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transparent imageClinical Presentation
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transparent imageDiagnosis
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transparent imageTreatment
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transparent imageSpecific Treatment Recommendations
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transparent imagePrevention
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Cyclosporiasis
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transparent imageEpidemiology
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transparent imageMicrobiology and Pathophysiology
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transparent imageClinical Presentation
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transparent imageDiagnosis
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transparent imageTreatment
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transparent imagePrevention
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Isosporiasis
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transparent imageIntroduction
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transparent imageEpidemiology
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transparent imageMicrobiology and Pathophysiology
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transparent imageClinical Features
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transparent imageDiagnosis
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transparent imageTreatment
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transparent imageSpecific Treatment Recommendations
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transparent imagePrevention
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References
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Introduction
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The coccidia are Apicomplexan protozoa with subcellular organelles and a life cycle that is similar to that of T. gondii. Toxoplasma has a sexual stage in the intestinal epithelium of the definitive feline host and an asexual stage in the gastrointestinal tract or the tissues of the human host. The intestinal coccidia (Cryptosporidium, Cyclospora, and Isospora) have both sexual and asexual stages confined to the intestinal mucosa of a single host. The intestinal coccidians and the Microsporidia appear to account for at least 50% of persistent diarrhea in HIV-infected persons in the developed world.(1,2)

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Cryptosporidiosis
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Cryptosporidium parvum causes self-limited disease in immunocompetent hosts.(3,4) In immunocompromised persons, including patients with advanced HIV disease, chronic watery diarrhea develops and leads to malabsorption, malnutrition, dehydration, and cachexia.(5) Cryptosporidiosis that persists for 4 weeks in an HIV-positive person confers a CDC-defined diagnosis of AIDS.

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Epidemiology
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Cryptosporidium is a zoonotic pathogen first noted to cause disease of turkeys in 1955(6) and of calves in 1971.(7) Cryptosporidium infects the respiratory or gastrointestinal tracts of a large number of hosts including fish, birds, reptiles, and mammals.(8)The first reports of human cases of cryptosporidiosis were in 1976,(9,10) followed over the next few years by reports of disease in immunosuppressed hosts. The Centers for Disease Control (CDC) documented the importance of C. parvum as a major human pathogen in 1982 in reporting outbreaks of cryptosporidial diarrhea in 21 patients with advanced HIV disease(11) and in 12 immunologically normal hosts who had been exposed to Cryptosporidium from infected calves.(12) Animal-to-human transmission, particularly from calves to veterinarians or persons living in a rural setting, and also from rabbits in the research laboratory to researchers was observed.(12-14) Cross-transmission studies indicated that human isolates are easily transmitted to a variety of mammals.(15)Whether humans can be infected by nonmammalian species has not been thoroughly investigated. Subsequent reports have described cryptosporidiosis from contaminated food and water in domestic settings, in travelers to developing nations, in transplant patients, in health care workers and hospitalized patients, in animal care workers, and in staff and children at day care centers.(13-23)

Due to a number of factors, C. parvum is easily transmitted by oral ingestion of oocysts (e.g., from contaminated hands). First, Cryptosporidium infects and preferentially causes disease in the young of many species who excrete large numbers of organisms into the environment. Second, the oocyst is immediately infectious on ingestion because it is fully sporulated when shed by the prior host. Third, the inoculum required to establish infection is very low. The ID50 for humans without prior serologic evidence of disease is 132 oocysts.(24) Lastly, the oocyst can survive in the environment under harsh conditions for more than 3 months.(25)Common home or hospital disinfectants do not neutralize the oocysts at usual strengths nor do the standard levels of chlorine and ozonation used in water purification plants.(26-30)

Cryptosporidium has become the most important contaminant found in drinking water and is an emerging cause of food-borne disease. There have been 12 documented waterborne outbreaks in North America since 1985; in two of these (Milwaukee and Las Vegas), mortality rates in the immunocompromised population ranged from 52 to 68%.(17,31-33) To date, the largest public water outbreaks have occurred in Carrollton, Georgia, in 1987(34) (13,000 symptomatic cases) and in Milwaukee, Wisconsin, in April 1993 (403,000 symptomatic cases).(31,35) Point of use water filters reduce transmission during epidemics due to contaminated potable water.(36) Outbreaks have also been associated with contaminated recreational water.(37-40) Except in large epidemics like the Milwaukee outbreak of 1993,(35) the importance of waterborne transmission to the establishment of chronic cryptosporidiosis in HIV-infected persons has not been documented because of the absence of markers with which to follow the transmission of C. parvum. Transmission of C. parvum through a variety of foods,(41) including apple cider(42) and milk products, has been reported.

In the 1980s, Cryptosporidium was recognized as a cause of a traveller's diarrhea in persons returning from Leningrad, Russia.(43) Subsequently, reports of disease acquired by travellers to Pakistan, New Guinea, Central Africa, Egypt, Mauritius, the Caribbean, and Mexico suggested that Cryptosporidium is a widespread agent of traveler's diarrhea.(44-47)Approximately 0.1% of asymptomatic persons in developed countries carry Cryptosporidium in their stools.(48) Immunocompromised asymptomatic persons may carry Cryptosporidium.(49-51)

Person-to-person transmission of Cryptosporidium, like that of Giardia, occurs frequently in day care centers.(21,22)Nosocomial transmission of Cryptosporidium infection to hospital personnel and among patients in hospitals occurs, but the magnitude of this phenomenon is unknown.(16,19,23)Person-to-person transmission is the assumed mechanism; however, contamination of the environment may also be important.(23) Inadequate disinfection of the environment would not be surprising given the hardy nature of the oocysts and their resistance to routine disinfection protocols.(26)

In San Francisco, 56% of persons with AIDS and cryptosporidiosis had cryptosporidiosis as an AIDS-defining diagnosis.(52) An estimated 10 to 15% of U.S. AIDS patients develop cryptosporidiosis during the course of HIV disease.(53) In one European study of 275 AIDS patients with chronic diarrhea, 15.6%(43) had intestinal cryptosporidiosis. The prevalence was higher in homosexual patients (33.3%) than in intravenous drug abusers (10.6%). Thirty percent of patients (13 patients) with intestinal cryptosporidiosis had extraintestinal infection; 8 of 13 had C. parvum in the bile, 7 of 13 had C. parvum in sputum.(54) In Central Africa, approximately 30% of persons with advanced HIV disease and persistent diarrhea have cryptosporidiosis.(55,56) In Lusaka, Zambia, 14% of HIV-seropositive children with diarrhea had Cryptosporidium, whereas only 6% of the HIV-seronegative children with diarrhea had C. parvum.(57) In the seropositive group, the prevalence of C. parvum rose to 21% in children with chronic diarrhea.(57)

The relative risk for a patient with advanced HIV disease of acquiring Cryptosporidium infection during exposure to asymptomatic or clinically infected humans or animals or to contaminated food or water is not known. The risk of nosocomial spread, however, is likely to increase with increasing numbers of patients with advanced HIV disease and chronic Cryptosporidium infection being admitted to hospitals and dedicated HIV disease care units. Because there is currently no treatment for cryptosporidiosis, epidemiologic investigation to define these risks is extremely important.

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Microbiology and Pathophysiology
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Cryptosporidium is phylogenetically related to Toxoplasma gondii, Isospora belli, and Sarcocystis species. Infection is initiated when oocysts are ingested and excyst in the small bowel. Four sporozoites are released from each oocyst and initiate the asexual cycle by invading the microvillous border of enterocytes, where they develop into meronts. Meronts release eight merozoites, the second form that invades enterocytes. Both sexual and asexual cycles occur in the gut, resulting in the production of fully sporulated, infectious oocysts. Disease in humans is primarily localized to the jejunum, but in immunocompromised patients, organisms may be found throughout the epithelium of the gastrointestinal and respiratory tracts from the pharynx, sinuses, and lungs to the rectum.(46)

The pathogenetic mechanism by which Cryptosporidium causes diarrhea is not known. Histologic reports describe villous atrophy and blunting, epithelial flattening, and inflammation of the lamina propria characterized by infiltration of plasma cells, lymphocytes, and macrophages.(58) These findings are nonspecific and can occur with other intestinal infections. Absorption is frequently abnormal, suggesting that Cryptosporidium causes an osmotic diarrhea.(59)High-volume diarrhea, however, occurs in many patients, leading to the speculation that cyclic adenosine monophosphate (cAMP) production in proximal small-bowel epithelial cells with subsequent hypersecretion of fluids and electrolytes might be triggered by a cholera-like cryptosporidial enterotoxin.(3) Electrolyte transport was investigated during chronic cryptosporidiosis in adult anti-interferon-gamma-treated SCID mice by means of Ussing chamber techniques. This study suggests that long-term cryptosporidiosis in immunocompromised animals leads to a reduction in net ion exchanges, decreased paracellular shunting, and impaired Na+-glucose cotransport in the ileum, without prostanoid- or enterotoxin-mediated electrogenic Cl- secretion.(60) In vitro studies also indicate that C. parvum infection causes cell death in Caco-2 cells.(61)

Gamma-interferon, intraepithelial CD4+ lymphocytes, and secretory IgA appear to be important factors in the host's control of cryptosporidiosis.(62-66) IL-12 prevents or ameliorates C. parvum infection in immunocompetent and immunocompromised animals when given before C. parvum challenge by increasing gamma-interferon production.(67) Upregulation of C-X-C chemokine (IL-8 and GRO-alpha) production from the basolateral surface of C. parvum-infected epithelial cells in in vitro culture suggests that these chemokines may contribute to the mucosal inflammatory cell infiltrate in the underlying intestinal mucosa in vivo.(68)

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Animal Models, Cell Culture, and Basic Science Advances
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Intense efforts to develop suitable animal models for evaluation of the treatment and pathophysiology of cryptosporidiosis in the immunocompromised host have been made.(69) Cryptosporidium cell culture systems have been developed with a wide variety of cells, including fibroblast L929 cells, human embryonic intestine cells, Madin Darby canine kidney cells, human enterocyte HT29.74 cells, and Caco-2 cells.(69)These in vitro systems successfully support the invasion and differentiation of sporozoites and in some cases the growth of sexual as well as asexual stages. They are facilitating the evaluation of therapeutic agents and pathogenic processes. Unfortunately, none of the culture systems has resulted in the propagation of Cryptosporidium, so they are not yet useful for the preparation of large numbers of parasites for research.

Attempts to investigate the biochemical pathways and molecular interactions that may be exploited in developing effective therapeutic intervention have advanced in the past 5 years with the identification and analysis of important enzymes and structural proteins of Cryptosporidium. For example, polyamine biosynthesis in Cryptosporidium parvum occurs via a pathway chiefly found in plants and some bacteria. The lead enzyme of this pathway, arginine decarboxylase (ADC), is sensitive to the specific, irreversible inhibitor DL-alpha-difluoromethyl-arginine (IC50 30 microM), and intracellular growth of C. parvum is significantly reduced by inhibitors of ADC. C. parvum differs fundamentally in its polyamine metabolism from the majority of eukaryotes, including humans, rendering this pathway a chemotherapeutic target.(70) In addition, resistance of C. parvum to clinically available anti-folates directed at dihydrofolate reductase has been investigated and found to be due to genotypic variation in the TS-DHFR bifunctional gene in regions that confer susceptibility to known anti-folates.(71) Understanding of the structure of the gene and its cognate protein may allow identification of better anti-folate drugs for cryptosporidiosis.

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Clinical Presentation
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In immunocompetent hosts, Cryptosporidium infection results in a self-limited diarrheal illness that lasts from 4 to 20 days and is associated with abdominal cramping, nausea, vomiting, low-grade fever, and anorexia.(3,4,72) The disease has an incubation period of 2 to 14 days. Oocysts may be excreted for 1 to 2 weeks after clinical improvement.(73)

In any given patient with advanced HIV disease, cryptosporidiosis may present as persistent, profuse watery diarrhea, may wax and wane, or may be asymptomatic.(5,49,51)Stool volume (1 to 17 liters per day) and frequency (6 to 26 bowel movements per day) are variable. This variability appears to be multifactorial. The role and contribution of individual factors, such as CD4 cell levels, pre-existing mucosal B-cell immunity and differences in the virulence of Cryptosporidium isolates, is not known. Goodgame et al. reported that stool oocyst excretion rates correlate with the intensity of infection as assessed histologically in biopsy specimens of the duodenum; however, the relationship of oocyst excretion to symptomatology has not been evaluated.(74)In some HIV-positive patients, the infection appears to resolve spontaneously(75,76); in others, it improves with the initiation of antiretroviral therapy (AZT)(77,78) or highly active antiretroviral therapy (HAART),(79) and in still others, it progresses to severe and unremitting diarrhea.(3)A review of 47 HIV-seropositive patients with cryptosporidiosis(80) indicated that all patients with a CD4 count higher than 180 cells per microliter (17%) cleared the infection spontaneously without antiretroviral therapy within 7 days to 1 month. In addition, 13% of patients with a CD4 count less than 180 cells per microliter, including one with a CD4 count of 14, also cleared Cryptosporidium. Four of the five patients with a low CD4 count and self-limited disease were started a regimen of AZT at the time of diagnosis of cryptosporidiosis, but improvement in cryptosporidiosis did not correlate with significant changes in CD4 count.

Nausea, vomiting, abdominal pain, cramping, anorexia, weight loss, and marked wasting commonly accompany the diarrhea of cryptosporidiosis. Low-grade fever may be present, but high-grade fever is not a component of this illness and its presence necessitates a more thorough evaluation for other infectious diseases. Malabsorption, documented by abnormal d-xylose and abnormalities of 72-hour fecal fat, frequently occurs.(81-83)

The most serious extraintestinal complications of cryptosporidiosis are secondary to involvement of the gallbladder, biliary tree, and pancreatic ducts.(84-87) Although the true incidence of biliary tract involvement is difficult to ascertain as it requires invasive diagnostic measures, the New York Hospital experience suggests that it is approximately 15% of Cryptosporidia-infected AIDS patients.(88)Right upper quadrant pain, nausea, vomiting, and elevated alkaline phosphatase and gamma-glutamyl transpeptidase levels in the absence of elevated bilirubin and transaminase levels are features of this complication.(88)Imaging studies often reveal intrahepatic strictures and irregular beading of the ducts. The common bile duct may be dilated with or without stenosis of the papilla of Vater.(89) Alkaline phosphatase levels are usually elevated. Biliary cryptosporidiosis is diagnosed by finding the organism in bile or on histologic examination of tissue from the biliary tree.(85)Concomitant cytomegalovirus infection may play a role in symptomatology.(90)The value of papillotomy is controversial.(89,91) Cryptosporidium may appear to cause symptomatic interstitial pulmonary infection,(92-95) but the importance of it as a pulmonary pathogen as opposed to a colonizer is unknown.(54,96) Cryptosporidium also causes chronic sinusitis and otitis.(97)

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Diagnosis
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Routine ova and parasite examination of feces is not sufficient for the detection of Cryptosporidium oocysts. The organism is the size of a yeast, 4 to 6 µm, and is easily mistaken for yeast on routine stool examination.(82,84)In most laboratories, clinicians must request specific screening for the organism. There are numerous sedimentation, flotation, and staining techniques and modifications of techniques for the identification of oocysts in feces. Several studies have compared desirable attributes of some of these techniques. Garcia et al. highly recommended the modified Ziehl-Neelsen carbolfuchsin stain in a study of 15 detection methods.(98) Comparison of six techniques, namely, Giemsa staining, Ziehl-Neelsen staining, auramine and rhodamine staining, Sheather's sucrose flotation, indirect immunofluorescence (Merifluor Cryptosporidium kit; Meridian Diagnostics), and a modified concentration-sugar flotation method, on stool specimens fixed with sodium acetate-acetic acid-formalin (SAF) was performed using multiattribute evaluation.(99)Variables included diagnostic yield, cost of performing the test, ease of handling, and ability to process large numbers of specimens for screening purposes by batching. The authors correctly pointed out that the value of each of these attributes will vary depending on the health care setting. The auramine-rhodamine and indirect immunofluorescence techniques required investment in a fluorescence microscope. In the Ziehl-Neelsen technique specimens were easy to handle and to batch. The technique was relatively inexpensive, but was not as sensitive as three of the other techniques. Giemsa stain was the least sensitive, but was relatively easy to handle and lent itself to the processing of large numbers of samples. No single staining technique identified all of the positive stools, although the combination of Sheather's sucrose flotation and auramine and rhodamine staining did. SAF or formalin fixation of stool specimens did not interfere with staining or fluorescence.(99)The mainstay of Cryptosporidium diagnosis in many laboratories has been modified acid-fast stain (cold Kinyoun stain(100)) of freshly excreted feces or feces fixed with formaldehyde or SAF. This technique stains oocysts red and counterstains yeast blue green.

Two enzyme immunoassay kits (Alexon ProSpecT Cryptosporidium Microplate Assay and Meridian Premier Cryptosporidium) were tested for sensitivity and specificity with respect to the Meridian Merifluor Cryptosporidium IF reference assay. The sensitivities and specificities for these three methods were equivalent. Fluorescent detection procedures offer both increased sensitivity and specificity compared to conventional staining methods and may be particularly helpful in screening large numbers of patients in an outbreak situation or when screening patients with minimal symptoms.(101)

As clinicians have become familiar with cryptosporidiosis and laboratories have gained diagnostic experience, fewer patients have required biopsy of the bowel for diagnosis. Biopsy may still be necessary, however, in some cases.(11,81-84) The yield is highest in terminal ileal biopsies.(102) Hematoxylin and eosin-stained bowel biopsy specimens reveal the small round intracellular forms, which appear to be applied to the microvillous border but are actually inside the cell.(4,72,82,84)

Serum antibodies are currently of no value in the diagnosis of acute disease. These studies, however, may be of great benefit in tracking nosocomial and occupational transmission (veterinarians, day care workers, health care workers) as well as spread among other special groups at risk (children at day care centers). Results of routine laboratory tests, including liver function tests and studies of malabsorption, as well as radiographic studies, may be abnormal but are not helpful in establishing a diagnosis of cryptosporidiosis.

PCR primers for the detection of cryptosporidiosis have been identified and used largely for the detection of environmental contamination. PCR has not come into usage for diagnosis of C. parvum in stool except in a research setting.(103,104)

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Treatment
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Researchers have tried a large number of drugs and immune modulators for treatment of cryptosporidiosis, often in uncontrolled small series. More than 100 drugs have been assayed in vitro and 40 were reported to have some anticryptosporidial activity,(105) but none has been shown to be unequivocally effective in human trials with AIDS patients. Antiparasitic drugs, like quinine, chloroquine, difluoromethyl ornithine (DFMO), pyrimethamine, diclazuril, spiramycin, and trimethoprim-sulfa, do not treat cryptosporidiosis. In some cases, the refractoriness of Cryptosporidium to a given chemotherapeutic agent may be due to a block in delivery of the drug to the intracellular, extracytoplasmic form of the parasite, to structural variation of the drug's molecular target, or to unusual metabolic pathways that circumvent the drug's effect.

The first drug believed to be effective in cryptosporidiosis was spiramycin, a macrolide antibiotic used to treat toxoplasmosis in pregnant women in Europe. In spite of early promising reports,(106) neither oral spiramycin nor a later trial of intravenous spiramycin have proved effective (R. Soave, unpublished data). Subsequently, three other macrolide antibiotics (azithromycin, clarithromycin, and roxithromycin) became available. Reports have described azithromycin as an effective suppressive therapy for cryptosporidiosis in steroid immunosuppressed rodents.(107,108)High-dose azithromycin has been described in the treatment of some cases of cryptosporidiosis in children with AIDS(109) or leukemia,(110) but a study in adults with AIDS who received 500 mg/day showed no effect.(111) No controlled or dose-escalation studies have been performed. Researchers have not been able to reproduce initial encouraging results of an antimalarial drug, atovaquone, in animals with cryptosporidiosis.(112) Some studies suggested that paromomycin, a nonabsorbable aminoglycoside that is an effective luminal agent for Entamoeba histolytica, may be effective against cryptosporidiosis in vivo and in vitro.(113,114) In one study, five patients with advanced HIV disease and cryptosporidiosis, identified at five different hospitals, responded to paromomycin treatment; however, the report did not include the number of nonresponders.(113) In another study, seven patients with HIV disease with cryptosporidiosis initially responded to paromomycin but recurrences and relapses were common.(115)Both studies used divided doses of 1,500 to 2,000 mg per day. Duration of therapy varied from 10 days to longer than 4 months. Doses of more than 3 g per day have been associated with nausea, abdominal discomfort, and diarrhea. As significant amounts of paromomycin may be absorbed in the presence of intestinal damage, patients given long courses of paromomycin should be monitored for nephrotoxicity. C. parvum contains serine proteinases, at least one of which appears to be involved in excystation of oocysts. Serine proteinase inhibitors inhibit parasite invasion in vitro in cell culture.(116) The combination of paromomycin and alpha1-antitrypsin, a serine proteinase inhibitor, has been reported to be more efficacious than paromomycin alone for the treatment of C. parvum.(117) Diclazuril, a static drug effective against the animal gastrointestinal pathogen Eimeria, was shown to be poorly absorbed and ineffective in human cryptosporidiosis in a small controlled trial. Letrazuril, an analogue of diclazuril with greater bioavailability, is under study. Octretide, a synthetic cyclic octapeptide with somatostatin activity, may be effective in controlling the secretory diarrhea of some patients with advanced HIV disease. A prospective, multicenter clinical trial concluded that octretide was not useful for treating the diarrhea of patients with advanced HIV disease and cryptosporidiosis.(118) Passive oral transfer of protective antibody in hyperimmune bovine colostrum (HBC) has led to marked improvement in symptoms in some immunocompromised patients(119-122) and in animals with severe cryptosporidiosis, but antibody preparations have not become clinically available.

A marked decrease in the number of cases of chronic cryptosporidiosis in AIDS patients in the United States since the widespread introduction of HAART in 1996 has rendered further testing of the efficacy of all agents under study difficult. In particular, studies of nitrozoxanide and hyperimmune bovine colostral antibodies for their efficacy in treating cryptosporidiosis in AIDS patients have languished.

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Specific Treatment Recommendations
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There are no proven regimens for treatment of cryptosporidiosis, although paromomycin,(123,124) 500 mg qid until symptoms have decreased followed by 500 mg bid, may be efficacious. Nitazoxanide,(125) azithromycin,(109) or anticryptosporidial hyperimmune bovine colostral antibodies(122) may aid some patients,(126) but optimal dosages have not been determined. The most reliable intervention for symptomatic cryptosporidiosis appears to be treatment of the underlying retroviral infection, with AZT or HAART regimens including protease inhibitors, resulting in improvement in immune parameters.(79) Inhaled paromomycin has been used for the treatment of symptomatic pulmonary infection.(127)

Nonspecific treatment for cryptosporidiosis is empiric and depends on the judicious use of antidiarrheal agents (opiates, diphenoxylate, and loperamide) and fluid and nutrition management. Although infectious complications are frequent, placement of a central intravenous line for maintenance of fluid and electrolyte balance and nutrition may be beneficial when it is initiated before the patient has lost a large amount of weight.

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Prevention
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As there are no effective therapies for cryptosporidiosis, prevention depends on intervening in transmission by avoiding contaminated water and preventing direct contact with persons or animals with cryptosporidiosis.(128) As these sources may not be apparent, prudence suggests that immunocompromised persons drink distilled or boiled water where the risk of Cryptosporidium in the water is significant (for example, in developing countries) and avoid contact with persons with diarrhea secondary to Cryptosporidium or with diarrhea for which an etiologic agent has not been established. Guidelines for pet ownership are difficult to formulate at this time as there is not sufficient evidence that this is a significant route of transmission.

Swimming pools and recreational water use as well as tap water in the United States have been associated with sporadic outbreaks of cryptosporidiosis. Use of a submicron filter will prevent ingestion of Cryptosporidia from tap water.(129) At-risk persons should be cautioned concerning the potential for transmission in recreational waters.

The nosocomial transmission of Cryptosporidium infection to hospital personnel and to hospitalized patients is a public health concern. Universal body substance precautions are in use in most hospitals; however, it is not known whether these precautions as currently practiced are sufficient to prevent spread of cryptosporidiosis. With the low inoculum required to initiate disease and the hardy nature of oocysts, small numbers of oocysts on the skin of patients or in the environment may be sufficient to transmit disease. Oocysts are very resistant to the usual antiseptic techniques. Their infectivity is destroyed, however, by 5 to 10% ammonium, 10% formaldehyde, freeze drying, and exposure to temperatures below freezing and above 65°F for 30 minutes.(130) Some commercial products also inactivate oocysts, such as Oocide, which produces ammonia, and Expor, a chlorine-dioxide sterilant.(131)

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Cyclosporiasis
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Cyclospora cayetanensis is an emerging worldwide cause of diarrhea in immunocompetent persons and AIDS patients.(132,133)

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Epidemiology
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Cyclospora infections have been identified in otherwise healthy travellers to developing countries,(132,134-137) consumers of perishable food products and water contaminated with Cyclospora,(29,30,138-141) infants and children in developing countries,(132) children in child care centers in the United States, and AIDS patients.(142) The magnitude of cyclosporiasis as a form of community-acquired diarrhea in the United States is unknown.(143) Epidemics in the United States have been associated with fecal-oral transmission through contaminated water and food.(138)

A large outbreak of cyclosporiasis in 1996, totaling 1465 cases in 20 states, the District of Columbia, and 2 provinces of Canada, was associated with contaminated raspberries from Guatemala, revealing the importance of point source contamination of perishable foodstuffs in widespread epidemics of cyclosporiasis.(140)

The incidence of Cyclospora as a cause of diarrhea in AIDS patients in the United States is unknown. In Haiti, the prevalence of Cyclospora cayetanensis (11%) in stools of AIDS patients with diarrhea approximates the incidence of Isospora belli (12%).

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Microbiology and Pathophysiology
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Previously designated "big Cryptosporidium" or thought to be a blue-green algae ("cyanobacterium-like bodies"), Cyclospora were recognized as a separate coccidian species in 1993.(132,133) Although the morphology of the oocyst resembles C. parvum, morphology of intracellular intestinal forms is more similar to Isospora.(144) Phylogenetically, Cyclospora belongs within the Eimeria clade and may be a mammalian Eimeria species.(145,146)

Jejunal biopsies of Peruvian patients with cyclosporiasis showed an altered mucosal architecture with shortening and widening of the intestinal villi due to diffuse edema and infiltration by mixed inflammatory cell infiltrate. Dilatation and congestion of villous capillaries was present.(147)

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Clinical Presentation
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Illness caused by Cyclospora is characterized by watery diarrhea, abdominal cramping, flatulence, weight loss, and nausea.(133,147,148) Symptoms typically wax and wane for several weeks and may persist for several months.(148) Cyclospora may be associated with prolonged diarrhea in immunocompetent as well as immunocompromised populations.(149)

Symptoms in the Haitian study of AIDS patients were indistinguishable from those reported in AIDS patients with isosporiasis or cryptosporidiosis. Cyclospora, like Cryptosporidium, Isospora, and microsporidial species, may cause biliary tract disease in AIDS patients.(1,150)

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Diagnosis
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Microscopic examination of stool specimens using a modified Ziehl Neelsen technique reveals abundant spherical bodies, 8 to 10 microns in diameter, that are morphologically similar to, but larger than, Cryptosporidium oocysts.(133) The modified Ziehl Neelsen technique, however, stains Cyclospora variably.(151) Recent assessment of six different procedures that included Giemsa, trichrome, chromotrope, Gram-chromotrope, acid-fast, and safranin stains indicated that heating of fecal smears prior to safranin-based staining yielded a uniform, fast, reliable and easy to perform procedure that was superior to acid-fast staining.(152) Cyclospora oocysts autofluoresce, rendering fluorescent microscopy a rapid, sensitive, and inexpensive method of diagnosis.(153) Recommendations regarding stool examination for Cyclospora change frequently with reporting of new data. Consult your hospital or local health department for current laboratory examinations performed in your area. Three stool examinations usually are ordered, but the yield with this regimen has not been reported.

Detection of tissue stages of Cyclospora by light rather than electron microscopy may be accomplished using hematoxylin stain alone for 15 minutes on biopsy specimens.(154)

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Treatment
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Immunocompetent adult patients have been successfully treated with trimethoprim-sulfamethoxazole (160 mg and 800 mg PO twice a day for 7 days).(1,133,135,155) Children treated in Peru with a 3-day course of trimethoprim-sulfamethoxazole had a significant decrease in the duration of oocyst excretion from 12 to 5 days.(156) Patients with AIDS should be treated with higher doses of trimethoprim-sulfamethoxazole (160 mg and 800 mg PO four times a day for 10 days) followed by trimethoprim-sulfamethoxazole prophylaxis three times a week to prevent relapse.(142)

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Prevention
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Little is known about prevention of Cyclospora at this point. Because Cyclospora is much larger than Cryptosporidia, it may be less of a risk in U.S. filtered water supplies than is Cryptosporidia. Precautions exercised to avoid C. parvum while travelling in developed areas (i.e., submicron filtered water, eating of cooked foods, avoidance of recreational water use) would appear to be prudent measures to avoid cyclosporiasis.

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Isosporiasis
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Introduction
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Human isosporiasis is caused by Isospora belli. Infection is acquired by the ingestion of oocysts in food or water contaminated with the feces of infected humans.(157) In the United States, Isospora belli is an infrequent cause of watery diarrhea in travelers, immigrants from endemic areas, and immunocompromised persons, especially patients with advanced HIV disease. Endemic areas for Isospora belli included some areas of Indochina, South America, and the islands of the southwestern Pacific. In developing nations where the organism is much more prevalent in the general population, it is also seen more frequently in patients with advanced HIV disease. Chronic Isospora diarrhea is a qualifying diagnosis for CDC-defined AIDS in persons with HIV infection. Diagnosis can be made using acid-fast staining of feces and may be improved by examination of duodenal contents; ultimately, however, intestinal biopsy may be required. Patients usually respond to treatment with high doses of trimethoprim-sulfamethoxazole or pyrimethamine-sulfadiazine. Long-term suppression is necessary to prevent relapse.

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Epidemiology
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I. belli, a coccidian parasite phylogenetically related to Toxoplasma, Cryptosporidium, and Sarcocystis, was rarely reported as a cause of human disease prior to the HIV epidemic and those cases were generally from South America or Africa.(90) In patients with advanced HIV disease, I. belli is a cause of debilitating diarrhea with wasting and malabsorption. It has been reported in less than 0.2% of patients with advanced HIV disease in the United States(53,82,83,158) and in 15% of patients with advanced HIV disease in Haiti.(159) Reports describe Isospora occurring in 10%, 12%, and 16%, respectively, of patients with HIV disease and diarrhea in Brazil, Zaire, and Zambia.(55,56,160)Rates of infection in the United States may be high in groups immigrating from areas of greater endemicity.(161)In Los Angeles, Hispanic patients, who accounted for 17% of patients with advanced HIV disease, represented 81% of HIV-related isosporiasis. Eight percent of patients with advanced HIV disease in Los Angeles County who came from Latin America had isosporiasis. The high rate of isosporiasis in HIV-infected Latin Americans raised the rate of isosporiasis to 1% of all AIDS patients in Los Angeles.(161) Isosporiasis was more likely to occur in foreign-born patients than in those born in the United States. A prior history of Pneumocystis carinii pneumonia (PCP) was negatively associated with isosporiasis presumably due to the prevention of primary isosporiasis or expression of latent isosporiasis by TMP-SMX prophylaxis for PCP.(162)

Reports describe chronic Isospora diarrhea in immunocompetent travelers, but the organism's importance as a cause of chronic traveller's diarrhea is not known.(163,164)Nonetheless, Isospora should be considered a hazard to the immunocompromised traveller.

Person-to-person transmission via direct oral-anal contact has been suggested(158); however, several lines of evidence suggest that sexual contact and direct fecal-oral contact are not usual routes of transmission. First, I. belli oocysts, unlike Cryptosporidium oocysts, are released unsporulated and usually require 48 hours in the environment for the oocyst to sporulate and become infectious.(165,166) Second, heterosexual partners of Haitian bisexual men with advanced HIV disease and isosporiasis did not show evidence of isosporiasis.(159)It appears likely that fecal contamination of food, water, or the environment is the usual source of transmission, but definitive epidemiologic studies have not been undertaken.

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Microbiology and Pathophysiology
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Sporulated oocysts of Isospora are ingested and release sporozoites, which invade the villous epithelium of the gastrointestinal tract to initiate the asexual cycle. On light microscopy, hematoxylin and eosin staining demonstrates intracellular forms of Isospora deep within the cytoplasm of the villous epithelium, whereas cryptosporidial intracellular forms lie immediately below the host-cell membrane and appear to be outside of the cell. The sexual cycle also occurs in the human host and culminates when the unsporulated oocyst sheds into the gut lumen and is released to the environment. Electron microscopy reveals all phases of the sexual and asexual life cycle within the enterocyte.

The pathophysiology of the isosporiasis disease process and the immune perturbations that lead to prolonged disease have not been reported. Some studies, however, did reveal various architectural and functional features of the infected intestinal epithelium. Electron microscopy reveals mucosal alterations, including shortened villi, and eosinophilic infiltration of the lamina propria, particularly in the proximal part of the small intestine.(167)Villus architecture may return to normal with treatment. Several reports described malabsorption.(82,83,167) Infected watery feces lack red blood cells or leukocytes.

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Clinical Features
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Clinical features of isosporiasis are indistinguishable from those of Cryptosporidium infection. Symptoms include a particularly crampy abdominal pain and profuse watery diarrhea of 8 to 10 stools per day, along with weight loss (which may be profound), weakness, anorexia, and occasional low-grade fever.(82) In immunocompetent individuals, the disease resolves spontaneously in several weeks; in immunocompromised patients, it progresses to dehydration, malnutrition, and cachexia, if not treated.(168) Isospora infection may involve the pancreas and biliary tree in AIDS patients.(169,170) Extraintestinal Isospora belli infection has been described involving the liver, spleen, and mediastinal and mesenteric lymph nodes, but is apparently rare.(167,171)

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Diagnosis
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Isospora cysts can be distinguished from cryptosporidial cysts by their larger size (25 µm in contrast to 5 µm) and their shape (elliptic rather than round). For diagnosis, a stool sample is usually stained with a modified Kinyoun stain (an acid-fast stain using carbolfuchsin and a bright-green counterstain), which colors oocysts of both Cryptosporidium parvum and Isospora belli bright red. Consult your hospital laboratory or local health department to determine which test they currently use. Characteristic Isospora oocytes can occasionally be found in concentrated stool by means of flotation or sedimentation techniques. The oocysts do not stain readily with iodine and are best seen under reduced illumination as elongated oval structures of approximately 30 by 15 µm, tapering at the end. Oocysts may be difficult to find in stool, even in persons known to be infected. In these persons, the Entero test or duodenal aspiration may be particularly helpful. In one series of three patients with strongly positive results on duodenal aspiration, two showed only rare oocytes on stool examination and one of these required a sugar flotation method for detection. The third patient, who was strongly positive on the Entero test, had negative findings on six stool examinations.(82) In another case of mixed Isospora and Cryptosporidium infection, Isospora was not identified on routine ova and parasite examination, but was readily found using the acid-fast technique for Cryptosporidium.(172)

Biopsy of the villous epithelium, particularly of the small bowel, is diagnostic, but invasive. Electron microscopy of biopsy material may be required for definitive diagnosis.(82) There are no serologic means of detection of Isospora infection.

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Treatment
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There have been very few treatment trials of Isospora infection in HIV disease. The largest treatment trial was conducted in Haiti. Thirty-two symptomatic I. belli-infected patients with advanced HIV disease were treated with trimethoprim-sulfamethoxazole (160/800 mg orally 4 times per day for 10 days) and then were randomized to receive trimethoprim-sulfamethoxazole (160/800 mg 3 times a week), sulfadoxine (500 mg) and pyrimethamine (25 mg), or placebo once a week. All 32 patients responded clinically to the initial trimethoprim-sulfamethoxazole therapy and all achieved microbiologic cure. Recurrent disease was prevented by ongoing prophylaxis with either trimethoprim-sulfamethoxazole or sulfadoxine-pyrimethamine. Five (50%) of the 10 patients given placebo after initial cure had a relapse at a mean of 1.6 months.(168)

In individual cases and series of two or three patients, the most promising response occurred after treatment with trimethoprim-sulfamethoxazole (160/800 mg 4 times per day for 10 days and then 2 times daily for 3 weeks; three out of three patients responding), furazolidone (100 mg 4 times a day for 10 days; one out of two responding), and pyrimethamine-sulfadiazine (one response out of three treated patients).(82) Twenty Haitian patients all responded to oral trimethoprim-sulfamethoxazole within 48 hours of treatment, but 47% had a relapse. In other series, after therapy ended, relapse followed within weeks to months. The patients with relapses often responded, however, to a repeat course of the same therapy.(159) One patient who failed to respond to multiple forms of therapy responded to pyrimethamine (50 mg daily) and sulfadiazine (4.5 g daily) with resolution of severe malabsorption, a weight gain of 23 kg, and elimination of I. belli from stool, duodenal aspirate, and duodenal biopsy specimens.(83) The patient relapsed, however, when taken off the medication, but responded again to a repeat course of pyrimethamine and sulfadiazine.

Twenty-one Haitian patients who received trimethoprim-sulfamethoxazole for I. belli or Cryptosporidium infection showed no evidence of hypersensitivity reaction,(173) in contrast to the 50% likelihood of severe hypersensitivity occurring in homosexual men treated with trimethoprim-sulfamethoxazole for PCP.(174) Two patients with severe hypersensitivity reactions to sulfa drugs were treated successfully with pyrimethamine alone (75 mg/day). Recurrences were prevented with daily pyrimethamine (25 mg/day).(175) Roxithromycin, a macrolide licensed in Europe, was used effectively in one French patient who failed to respond to trimethoprim-sulfamethoxazole.(176) Spiramycin was totally ineffective in one reported case.(177)

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Specific Treatment Recommendations
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For treatment of I. belli in HIV-positive individuals, I recommend trimethoprim-sulfamethoxazole (160/800 mg orally 4 times per day for 10 days) followed by longtime suppression. The suppressive drug dosage and interval must be individualized, depending on symptoms and toleration of trimethoprim-sulfamethoxazole. A dosage of 160/800 mg 3 times per week is recommended for initiation of suppression.

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Prevention
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Although no reports describe nosocomial transmission, knowledge of the transmission mechanisms suggests that it could occur. In addition, there are no report of animal transmission to humans.(178)Immunocompromised persons traveling to Latin America, Africa, or other developing regions should exercise precautions when ingesting food and water, in order to avoid infection with multiple gastrointestinal pathogens including Isospora, Cyclospora, microsporidium, and Cryptosporidium. These precautions include the use of submicron filters for purifying water, eating cooked foods, and avoiding recreational water activities.

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