Cryptosporidia Cyclospora Isospora and Microsporidia

The AIDS epidemic has increased awareness and recognition of intestinal spore-forming protozoa hitherto considered rare pathogens. The many common characteristics of these four intestinal protozoa (reviewed by Goodgame 1996) justify a common review here, of their clinical presentation and demonstration in HIV-infected individuals.

About the same time as the AIDS epidemic was recognized in the USA, a very useful staining method for Cryptosporidium parvum was published in Scandinavia by veterinarians (Henriksen and Pohlenz 1981). This modified Ziehl-Neelsen acid fast stain soon became helpful to diagnose human cryptosporidiosis as well (Payne et al. 1983). The first cases of cryptosporidium enterocolitis in homosexual men with AIDS were reported in Denmark by Gerstoft et al. (1983). Cryptosporidium parvum may be fatal in AIDS patients. McGowan et al. (1993). found a median survival of 15 weeks from diagnosis. The clinical presentation in AIDS is a chronic, debilitating watery diarrhoea, with 5-10 bowel movements per day, and abdominal cramps, anorexia, and low-grade fever. Extraintestinal infection with C. parvum has been described in the biliary tract causing sclerosing cholangitis in patients with AIDS, and may also be associated with hepatitis, pancreatitis, and respiratory problems (Hojlyng and Jensen 1988).

About 1-3% of Danish AIDS patients suffered from cryptosporidiosis (Smith and Orholm 1990) before HAART was introduced. A major nosocomial outbreak of cryptosporidiosis in a department of infectious diseases implying 18 cases - infected through an ice machine contamined by an infected patient - resulted in eight patients dying (Ravn et al. 1991). This underlines that infection may only require a very small inoculum, and that C. parvum may survive at low temperature. Since there is no effective therapy, preventative measures are vital. Unfortunately, sulphonamides (used in combination with antifolates against P. carinii and T. gondii) are not helpful for preventing C. parvum (Ravn et al. 1991), while macrolides offer some hope (Fichtenbaum et al. 2001). Paromomycin (White et al. 1994), and more recently, a 5-nitrothiazole (Nitazoxamide) have been used with some success for treatment (Doumbo et al. 1997), while numerous other medicaments have been disappointing, including immunotherapy with specific antibodies from cows' colostrum (Saxon and Weinstein 1987). Fortunately, HAART can restore immunity, including mucosal, and lead to eradication of opportunistic pathogens (Schmidt et al. 2001).

The laboratory confirmation of C. parvum infection can be by light microscopy of unstained faeces with or without previous concentration. Acid-fast stains are very useful, as indicated above, and C. parvum is clearly visible at 400 x magnification (as opposed to microsporidia). Monoclonal antibody-based fluorescent stain is also helpful. Electron microscopy of biopsies from the gut will show organisms on the brush border of the mucosal surface (Goodgame 1996). PCR and PCR-ELISA may be more sensitive than light microscopy, and may also specify genotypes (Gibbons et al. 2001).

Cyclospora cayetanensis, previously referred to as 'cyanobacterium-like bodies' has now been identified worldwide in the faeces of both immunocompetent and immunocompromized patients with diarrhoea (Ortega et al. 1993). Pape et al. (1994) give four reasons for the relatively few cases observed and published initially: Cyclospora may be confused with Cryptosporidia; acid-fast stain may not be ordered by the physician; co-trimoxazole chemoprophylaxis for P. carinii and T. gondii may affect C. cayetanensis; and cyclospora may have a low prevalence in developed countries. In patients with low CD4+ counts, watery diarrhoea, abdominal cramps, and weight loss are the main symptoms - as in cryptosporidiosis, isosporiasis, and microsporidiosis (Goodgame 1996). When the CD4 + count is almost normal (>400mio./l), the patient may have no symptoms at all, and shedding of C. cayetanensis oocysts may resolve spontaneously after a couple of months (Schubach et al. 1997). A 1-week course of co-trimoxazole is effective in HIV-infected patients (Verdier et al. 2000). The laboratory diagnosis can be made by trained microscopists on formolether concentrated faeces sediments, but modified acid-fast staining is more helpful. It is very important to measure the size of the oocysts. Those of cyclospora are 8-10^m, while Cryptosporidia are 4-6 •m (Gonzalez-Ruiz and Bendall 1995). Electron microscopy and examination of biopsies are also helpful (Goodgame 1996). Isospora belli was recognized as an opportunistic enteric pathogen in AIDS in 1985-1986, in the USA (DeHovitz et al. 1986). It is most common in tropical and subtropical climates, and only single cases are observed in north European AIDS patients; in France, about 2% of chronic AIDS-related diarrhoea are associated with Isospora (Cotte et al. 1993). A negative association between isosporiasis and pneumocystosis has been related to use co-trimoxazole prophylaxis in HIV positive patients (Sorvillo et al. 1995). Disseminated isosporiasis has been described in AIDS (Bernard et al. 1997). The identification of I. belli is easy in unstained wet or acid-fast stained faeces by light microscopy. The oocysts are large, 10-20 x 20-30 •m. In small-bowel biopsy specimens, I. belli are easily seen as oval enterocyte inclusions (Goodgame 1996). Isosporiasis in patients with AIDS can be treated effectively with a 10-day course of co-trimoxazole, and prevents by prophylactic doses of co-trimoxazole (Pape et al. 1989). However, refractory cases may be encountered (Bygbjerg, unpublished). Five genera of microsporidia have been recognized in humans (Garcia and Bruckner 1993), of which two are common intestinal pathogens in patients with AIDS: Enterocytozoon bieneusi and Encephalitozoon (Septata) intestinalis; the former is by far the commonest (Goodgame 1996). Enterocytozoon bieneusi was the first hitherto completely unknown eukaryotic parasite discovered in man because of immunodeficiency (Canning and Hollister 1990). Its clinical significance has been reviewed by Schattenkerk et al. (1991). The first cases of microsporidiosis caused by E. bieneusi in Scandinavian patients with AIDS were reported by Hojlyng et al. (1993). Enterocytozoon bieneusi is found in more than 20% of AIDS patients with permanent diarrhoea. In 1995, E. (Septata) intestinalis was increasingly recognized as a cause of chronic diarrhoea in patients with AIDS (Molina et al. 1995). Besides of chronic diarrhoea it is usually associated with fever, cholangitis, sinusitis, bronchitis, or kerato-conjunctivitis. Most patients have very low CD4+ counts.

The use of light microscopy to diagnose intestinal microsporidiosis in patients with AIDS has been outlined by Rijpstra et al. (1988), for example, by Giemsa staining of smears of specimens from duodenal/jejunal biopsies. Electron microscopy confirmation of the minute organisms (1-2^m microns only) is helpful. Identification in stool is difficult (Orenstein et al. 1990). Invasive biopsy procedures may be avoided by PCR on stool specimens (Owen 1997; Liguory et al. 1997).

Albendazole - a broad-spectrum antihelmintic drug - may be a useful palliative treatment for microsporidial diarrhoea (Blanshard et al. 1992); however, only for E. intestinalis

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(Molina et al. 1995), while no specific therapy is available for E. bieneusi (Goodgame 1996). Thalidomide may be useful in intractable cases of diarrhoea (Sharpstone et al. 1995). Other genera of microsporidia, Encephalitozoon cuniculi and Encephalitozoon hellem have also been reported in AIDS patients with keratitis and sinusitis (Garcia and Bruckner 1993). HAART may effectively clear microsporidiosis (Martins et al. 2001).

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