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Microsporidiosis and HIV
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Introduction
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Epidemiology
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Microbiology and Pathophysiology
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Clinical Presentation
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Diagnosis
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Treatment
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References
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Introduction
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Microsporidia are small, sporeforming, obligate intracellular protozoan parasites that are found in the intestine, liver, kidney, cornea, brain, nerves, and muscles of a variety of wild and domesticated animals.(1) Microsporidiosis is recognized as a cause of gastrointestinal disease, renal disease, sinusitis, and keratitis in AIDS patients.(2,3) Some genera are associated with dissemination. Microsporidia have not been studied extensively as agents of disease because they are small, stain poorly, evoke little inflammation, and are difficult to diagnose in the absence of electron microscopy.(1) Since the advent of AIDS, investigation had markedly increased, leading to the identification of new species and the reclassification of old ones. Microsporidiosis should be considered in AIDS patients with chronic diarrhea, sinusitis, keratitis, or renal failure.

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Epidemiology
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Both vertebrates and invertebrates may serve as reservoirs of infection depending on the genus. For example, Encephalitozoon infects birds and mammals; Nosema infects insects. Spores, ingested after release from the gastrointestinal tract or in the urine of other infected animals, are thought to be the mode of transmission of disease.(4) Serologic studies suggest that antibodies to Encephalitozoon cuniculi are widespread in animals and humans and are more frequently found in persons who have traveled to the tropics.

The reported prevalence of microsporidiosis in AIDS patients in one select population that was referred for gastrointestinal symptoms was 39%.(5) Enterocytozoon bieneusi infection of AIDS patients may be as common as Cryptosporidium as a cause of diarrhea in AIDS patients.(1,6,7) Encephalitozooan intestinalis, formerly called Septata intestinalis, also causes severe enteritis in AIDS patients and may disseminate to kidney.

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Microbiology and Pathophysiology
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Microsporidia multiply in the cytoplasm of host cells. At least five genera -- Vittaforma, Nosema, Enterocytozoon, Encephalitozoon, and Pleistophora -- have been associated with human disease.(1) New genera that cause disease are being identified or renamed.(8) Members of the different genera have variable and complex structural relationships with the host cell cytoplasm. All are ultimately released into a cell from a spore by ejection from a long coiled polar tubule, a characteristic microsporidian feature. Within the host cell, schizonts (meronts), sporonts, sporoblasts, and spores develop.(1,4)

Enterocytozoon bieneusi infection of the intestinal epithelium is confined to enterocytes covering the villi, especially those at the tip, and is associated with villous atrophy, cell degeneration, necrosis, and sloughing. The jejunum appears to be the preferred site of infection, the duodenum is less frequently infected, and the large intestine is relatively spared.(6,9) Encephalitozooan intestinalis causes severe diarrhea and a granulomatous tubulointerstitial enteritis and may disseminate to lungs and sinuses.(10) Encephalitozoon cuniculi infection may involve the kidneys and CNS in a wide range of mammals, including humans.

Microsporidial parasites may not evoke an inflammatory response in tissues, especially in immunocompromised patients, or may elicit moderate granulomatous inflammation with a mononuclear cell infiltrate. It is not known whether microsporidiosis in immunocompromised patients reflects activation of a latent infection.

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Clinical Presentation
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Although microsporidiosis is reported in immunocompetent patients, disease caused by microsporidiosis is much more common in the immunocompromised host.(4) Infection of the intestinal epithelium with Enterocytozoon bieneusi or Encephalitozoon intestinalis is the most common manifestation of microsporidiosis in AIDS patients.(1,2,6,9,11-15) E. bieneusi was found to be the cause of unexplained diarrhea in 27 to 30% of HIV-infected patients.(6,16) Clinical manifestations of disease include wasting, chronic diarrhea, and cholangiopathy and are indistinguishable from the manifestations of isosporiasis and cryptosporidiosis in AIDS patients.(17) Diarrheal stools are watery and are not accompanied by blood or fever.(6) Routine laboratory tests are normal, with occasional hypokalemia and hypomagnesemia. Carbohydrate and fat malabsorption are present.

E. bieneusi has been identified in bronchioalveolar lavage fluid and transbronchial lung biopsies in an AIDS patient with chronic diarrhea, cough, dyspnea, and chest radiographic findings of a pulmonary infiltrate and pleural effusion.(18) Microsporidial species may be found in pulmonary cavitary lesions of AIDS patients infected with Rhodococcus equi and in respiratory secretions or lung biopsy specimens. Microsporidium in the lungs usually represents colonization; however, it is not known if microsporidia cause significant clinical pulmonary disease.(18-21) Encephalitozoon intestinalis is associated with hematuria, renal failure, cystitis, and bowel perforation.(15,22) Encephalitozoon intestinalis and Encephalitozoon cuniculi and other less well-described microsporidia may disseminate and may cause CNS symptoms.(10,15,23-26) Pancreatic abnormalities, AIDS- related cholangitis, and sinusitis/otitis in patients with advanced immunosuppression of HIV may be due to Cryptosporidium or microsporidium species.(27-31) Pleistophora and Trachipleistophora have been reported in skeletal muscle.(8,32) Two types of microsporidial ocular infection have been reported in AIDS patients. The first, corneal infection by organisms of the genus Vittaforma corneae following trauma, is seen in immunocompetent patients and may result in corneal perforation and blindness.(33) The second type of infection, keratoconjunctivitis in AIDS patients, is caused by Encephalitozoon hellem, which can also disseminate.(21,34)

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Diagnosis
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Encephalitozoon spores are gram positive and some are acid fast, but spores of other genera stain unpredictably with these stains. Enterocytozoon bieneusi may be identified on light microscopy of plastic sections of intestinal biopsy material stained with methylene blue-azure II, basic fuchsin hematoxylin-eosin, toluidine blue, chromotrope 2R modified-trichrome, Warthin-Starry or Brown-Brenn stains.(6,35-38)

Several groups have reported success with the use of Giemsa-stained stool specimens for diagnosis of Enterocytozoon bieneusi diarrhea.(16) Giemsa-stained spores in the stool are oval, with the cytoplasm staining light gray-blue and the nucleus staining intensely purple. The modified trichrome stain stains the spore wall bright pinkish red.(16) Fluorescence techniques utilizing fluorescent chitin stains like Fungifluor, Calcofluor White, and Fungiqual A are sensitive and rapid methods for detecting microsporidia spores in stool, intestinal fluid, biopsy imprints, and tissue specimens.(39) Weber's modified trichrome and fluorescent stains (the fluorochrome Uvitex 2B and chitin fluorochrome stains) have been reported to be equally useful for detecting microsporidia in stool specimens.(40,41) A new acid fast trichrome stain is comparable to Kinyoun and modified trichrome methods for the diagnosis of stool microsporidium and Cryptosporidium and is advantageous as it detects both parasites.(42) Methods of stool concentration (Ritchie formalin-ethyl acetate stool concentration, sodium chloride floatation, sucrose, and Percoll gradients) did not improve the rate of detection when compared to concentrated stool smears.(16) Consultation with your local AIDS referral laboratory is necessary to determine which stool examination is in current use.

Electron microscopy is required for detection of the polar filament that identifies a member of the phylum Microsporidia and for speciation.(6,38) Ocular infection may be suspected on the basis of corneal scrapings and may be confirmed by electron microscopy.

Genetic probes specific for Encephalitozoon cuniculi, E. hellem, Encephalitozoon intestinalis, Enterocytozoon bieneusi, and Nosema have been developed.(43-46) In vitro culture of Enterocytozoon bieneusi, Encephalitozoon intestinalis, Vittaforma corneae, and Trachipleistophora hominis have been achieved.(8,44,47,48) Neither PCR nor culture is available for diagnosis in a non-research setting yet. The development of propagation techniques will be crucial for testing antimicrosporidial drugs in the future. PCR diagnosis appears to be superior to standard fluorescent chitin spore staining techniques for speciation of microsporidium and may ultimately allow selection of appropriate therapy without invasive biopsy.(49)

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Treatment
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Albendazole (400 mg PO bid) may be useful for the treatment of Encephalitozoon intestinalis,(14,22,24,25,50-53) but is variable in its effect on Enterocytozoan bieneusi.(54) Therapy for microsporidiosis must be continued, because relapse is common in patients who have responded to albendazole when therapy is stopped. No results from controlled trials are available. Albendazole is an inhibitor of tublin polymerization and is chemically related to metronidazole. Albendazole has been associated with C. difficile-mediated pseudomembranous colitis in an AIDS patient under treatment for microsporidiosis.(55) WBC counts need to be monitored in HIV-positive persons treated with albendazole, because severe pancytopenia has been noted in patients receiving the drug for Echinococcus infection.(14)

At a dose of 100 mg/day, thalidomide, an inhibitor of TNF-alpha, may be useful in the symptomatic therapy of Enterocytozoon bieneusi diarrhea that does not respond to albendazole.(56) The chronic diarrhea of microsporidiosis may be symptomatically improved with a medium chain triglyceride-based diet.(57) Preliminary evidence suggests that HAART may be the best intervention in patients with chronic microsporidiosis. Ocular lesions due to E. hellem have responded to fumagillin eyedrops. Controlled trials for the treatment of microsporidiosis have not been published.

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References

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3.   Bryan RT. Microsporidiosis as an AIDS-related opportunistic infection. Clin Infect Dis 1995;21(Suppl):S62-S65.
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5.   Kotler DP, Orenstein JM. Prevalence of intestinal microsporidiosis in HIV-infected individuals referred for gastrointestinal evaluation. Am J Gastroenterol 1994;89:1998-2002.
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6.   Orenstein JM, Chiang J, Steinberg W, et al. Intestinal microsporidiosis as a cause of diarrhea in human immunodeficiency virus-infected patients: A report of 20 cases. Hum Pathol 1990;21:475-481.
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7.   Wuhib T, Silva TM, Newman RD, et al. Cryptosporidial and microsporidial infections in human immunodeficiency virus-infected patients in northeastern Brazil. J Infect Dis 1994;170:494-497.
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