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Microsporidiosis
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Epidemiology

Microsporidia are protists related to fungi, defined by the presence of a unique invasive organelle consisting of a single polar tube that coils around the interior of the spore (255Wittner M, Weiss L. The microsporidia and microsporidiosis. Washington DC: ASM Press, 1999., 256Mathis A. Microsporidia: emerging advances in understanding the basic biology of these unique organisms. Int J Parasitol 2000;30:795-804.). They are ubiquitous organisms and are likely zoonotic and/or waterborne in origin (257Deplazes P, Mathis A, Weber R. Epidemiology and zoonotic aspects of microsporidia of mammals and birds. Contrib Microbiol 2000:6:236-60., 258Didier ES, Weiss LM. Microsporidiosis: current status. Curr Opin Infect Dis 2006;19:485-92.). The microsporidia reported as pathogens in humans include Encephalitozoon cuniculi, Encephalitozoon hellem, Encephalitozoon (syn Septata) intestinalis, Enterocytozoon bieneusi, Trachipleistophora hominis, Trachipleistophora anthropophthera, Pleistophora species, P. ronneafiei, Vittaforma (syn Nosema) corneae, Microsporidium sp., Nosema ocularum, Anncaliia (syns Brachiola/Nosema) connori, Anncaliia (syn Brachiola) vesicularum, and Anncaliia (syns Brachiola/Nosema) algerae (255Wittner M, Weiss L. The microsporidia and microsporidiosis. Washington DC: ASM Press, 1999., 256Mathis A. Microsporidia: emerging advances in understanding the basic biology of these unique organisms. Int J Parasitol 2000;30:795-804., 257Deplazes P, Mathis A, Weber R. Epidemiology and zoonotic aspects of microsporidia of mammals and birds. Contrib Microbiol 2000:6:236-60., 259Kotler DP, Orenstein JM. Clinical syndromes associated with microsporidiosis. Adv Parasitol 1998:40:321-49., 260Weber R, Bryan RT, Owen RL, et al. Improved light-microscopical detection of microsporidia spores in stool and duodenal aspirates. N Engl J Med 1992;326:161-6., 261Beauvais B, Sarfati C, Molina JM, et al. Comparative evaluation of five diagnostic methods for demonstrating microsporidia in stool and intestinal biopsy specimens. Ann Trop Med Parasitol 1993;87:99-102., 262Weiss LM, Vossbrinck CR. Microsporidiosis: molecular and diagnostic aspects. Adv Parasitol 1998:40:351-95.). In the pre-ART era, reported prevalence rates of microsporidiosis varied between 2% and 70% among HIV-infected patients with diarrhea, depending on the diagnostic techniques employed and the patient population described (255Wittner M, Weiss L. The microsporidia and microsporidiosis. Washington DC: ASM Press, 1999., 256Mathis A. Microsporidia: emerging advances in understanding the basic biology of these unique organisms. Int J Parasitol 2000;30:795-804., 257Deplazes P, Mathis A, Weber R. Epidemiology and zoonotic aspects of microsporidia of mammals and birds. Contrib Microbiol 2000:6:236-60., 259Kotler DP, Orenstein JM. Clinical syndromes associated with microsporidiosis. Adv Parasitol 1998:40:321-49.). The incidence of microsporidiosis has declined with the widespread use of effective ART, but is still being detected in HIV-infected persons unable to access or continue with ART. Among non-HIV-infected persons, microsporidiosis is being increasingly recognized in children, travelers, organ transplant recipients, and the elderly. In the immunosuppressed host, clinical signs related to microsporidiosis are most commonly observed when the CD4+ count is <100 cells/µL (255Wittner M, Weiss L. The microsporidia and microsporidiosis. Washington DC: ASM Press, 1999., 256Mathis A. Microsporidia: emerging advances in understanding the basic biology of these unique organisms. Int J Parasitol 2000;30:795-804., 257Deplazes P, Mathis A, Weber R. Epidemiology and zoonotic aspects of microsporidia of mammals and birds. Contrib Microbiol 2000:6:236-60., 259Kotler DP, Orenstein JM. Clinical syndromes associated with microsporidiosis. Adv Parasitol 1998:40:321-49.).

Clinical Manifestations

The most common manifestation of microsporidiosis is gastrointestinal tract infection with diarrhea; however, encephalitis, ocular infection, sinusitis, myositis, and disseminated infection also are described (255Wittner M, Weiss L. The microsporidia and microsporidiosis. Washington DC: ASM Press, 1999., 256Mathis A. Microsporidia: emerging advances in understanding the basic biology of these unique organisms. Int J Parasitol 2000;30:795-804., 257Deplazes P, Mathis A, Weber R. Epidemiology and zoonotic aspects of microsporidia of mammals and birds. Contrib Microbiol 2000:6:236-60., 259Kotler DP, Orenstein JM. Clinical syndromes associated with microsporidiosis. Adv Parasitol 1998:40:321-49.).

Clinical syndromes can vary by infecting species. E. bieneusi is associated with malabsorption, diarrhea, and cholangitis. E. cuniculi is associated with hepatitis, encephalitis, and disseminated disease. E. intestinalis is associated with diarrhea, disseminated infection, and superficial keratoconjunctivitis. E. hellem is associated with superficial keratoconjunctivitis, sinusitis, respiratory disease, prostatic abscesses, and disseminated infection. Nosema, Vittaforma, and Microsporidium are associated with stromal keratitis following trauma in immunocompetent hosts. Pleistophora, Anncaliia, and Trachipleistophora are associated with myositis. Trachipleistophora is associated with encephalitis and disseminated disease.

Diagnosis

Although microsporidia belonging to the genera Encephalitozoon, Anncaliia, Vittaforma, and Trachipleistophora have been cultivated in vitro, E. bieneusi has not been successfully cultivated in vitro. Effective morphologic demonstration of microsporidia by light microscopy can be accomplished by staining methods that produce differential contrast between the spores of the microsporidia and the cells and debris in clinical samples (e.g., stool). In addition, because of the small size of the spores (1-5 mm), adequate magnification (e.g., 1,000X) is required for visualization. Chromotrope 2R, calcofluor white (a fluorescent brightener), and Uvitex 2B (a fluorescent brightener) are useful as selective stains for microsporidia in stool and other body fluids (262Weiss LM, Vossbrinck CR. Microsporidiosis: molecular and diagnostic aspects. Adv Parasitol 1998:40:351-95.).

In biopsy specimens, microsporidia can be visualized with Giemsa, tissue Gram stains (Brown-Hopps Gram stain), calcofluor white or Uvitex 2B (fluorescent brighteners) staining, Warthin-Starry silver staining, hematoxylin and eosin, or Chromotrope 2A (262Weiss LM, Vossbrinck CR. Microsporidiosis: molecular and diagnostic aspects. Adv Parasitol 1998:40:351-95.). In gastrointestinal disease, examination of three stools with chromotrope and chemofluorescent stains is often sufficient for diagnosis. If stool examination is negative and microsporidiosis is suspected, a small bowel biopsy should be performed. If the etiologic agent is Encephalitozoon or Trachipleistophora spp., examination of urine often also reveals the organism. Determination of the species of microsporidia causing disease can be made by the morphology of the organism demonstrated by transmission electron microscopy, by staining with species-specific antibodies, or by PCR using species- or genus-specific primers (262Weiss LM, Vossbrinck CR. Microsporidiosis: molecular and diagnostic aspects. Adv Parasitol 1998:40:351-95.). Assistance of specialists familiar with the species differentiation of microsporidia should be sought.

Preventing Exposure

Patients with AIDS (e.g., CD4+ count <200 cells/µL) should avoid untreated water sources (AIII). Otherwise, other than general attention to handwashing and other personal hygiene measures, no precautions to reduce exposure to microsporidia are recommended.

Preventing Disease

No chemoprophylactic regimens are known to be effective in preventing microsporidiosis.

Treatment of Disease

ART with immune restoration (an increase of CD4+ count to >100 cells/µL) is associated with resolution of symptoms of enteric microsporidiosis, including that caused by E. bieneusi (245Miao YM, Awad-El-Kariem FM, Franzen C, et al. Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy. J Acquir Immune Defic Syndr 2000;25:124-9., 263Maggi P, Larocca AM, Quarto M, et al. Effect of antiretroviral therapy on cryptosporidiosis and microsporidiosis in patients infected with human immunodeficiency virus type 1. Eur J Clin Microbiol Infect Dis 2000;19:213-7., 264Goguel J, Katlama C, Sarfati C,et al. Remission of AIDS-associated intestinal microsporidiosis with highly active antiretroviral therapy. AIDS 1997;11:1658-9., 265Conteas CN, Berlin OG, Speck CE, et al. Modification of the clinical course of intestinal microsporidiosis in acquired immunodeficiency syndrome patients by immune status and anti-human immunodeficiency virus therapy. Am J Trop Med Hyg 1998;58:555-8.). All patients should be offered ART as part of the initial management of microsporidial infection (AII). Data suggest that following successful ART, immune reconstitution occurs and enables the patient's own defenses to eradicate microsporidia (245Miao YM, Awad-El-Kariem FM, Franzen C, et al. Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy. J Acquir Immune Defic Syndr 2000;25:124-9., 264Goguel J, Katlama C, Sarfati C,et al. Remission of AIDS-associated intestinal microsporidiosis with highly active antiretroviral therapy. AIDS 1997;11:1658-9.).

No specific therapeutic agent is available for E. bieneusi infection. A controlled clinical trial suggested that E. bieneusi might respond to oral fumagillin (60 mg/day), a water-insoluble antibiotic made by Aspergillus fumigatus (BII) (266Molina JM, Goguel J, Sarfati C, et al. Trial of oral fumagillin for the treatment of intestinal microsporidiosis in patients with HIV infection. AIDS 2000;14:1341-48., 267Molina JM, Tourneur M, Sarfati C, et al. Fumagillin treatment of intestinal microsporidiosis. N Engl J Med 2002;346:1963-9.), or to its synthetic analog TNP-470 (BIII) (268Didier PJ, Phillips JN, Kuebler DJ, et al. Antimicrosporidial activities of fumagillin, TNP-470, ovalicin, and ovalicin derivatives in vitro and in vivo. Antimicrob Agents Chemother 2006;50:2146-55.). However, fumagillin and TNP-470 are not available for systemic use in the United States. One report indicated that treatment with nitazoxanide for 60 days might resolve chronic diarrhea caused by E. bieneusi in the absence of ART (269Bicart-See A, Massip P, Linas MD, Datry A. Successful treatment with nitazoxanide of Enterocytozoon bieneusi microsporidiosis in a patient with AIDS. Antimicrob Agents Chemother 2000;44:167-8.); however, the effect appeared to be minimal among patients with low CD4+ counts. Therefore, this drug cannot be recommended with confidence (CIII).

Albendazole, a benzimidazole that binds to ß-tubulin, has activity against many species of microsporidia, but it is not effective against Enterocytozoon infections or V. corneae. The tubulin genes of both E. bieneusi (270Akiyoshi DE, Weiss LM, Feng X, et al. Analysis of the beta-tubulin genes from Enterocytozoon bieneusi isolates from a human and rhesus macaque. J Eukaryot Microbiol 2007;54:38-41.) and V. corneae (271Franzen C, Salzberger B. Analysis of the beta-tubulin gene from Vittaforma corneae suggests benzimidazole resistance. Antimicrob Agents Chemother 2007;52:790-3.) have amino acid residues associated with albendazole resistance. Therefore, albendazole is recommended for initial therapy of intestinal and disseminated microsporidiosis caused by microsporidia other than E. bieneusi and V. corneae (AII) (272Molina JM, Chastang C, Goguel J, et al. Albendazole for treatment and prophylaxis of microsporidiosis due to Encephalitozoon intestinalis in patients with AIDS: a randomized double-blind controlled trial. J Infect Dis 1998;177:1373-7., 273Diesenhouse MC, Wilson LA, Corrent GF, et al. Treatment of microsporidial keratoconjunctivitis with topical fumagillin. Am J Ophthalmol 1993;115:293-8., 274Dieterich DT, Lew EA, Kotler DP, Poles MA, Orenstein JM. Treatment with albendazole for intestinal disease due to Enterocytozoon bieneusi in patients with AIDS. J Infect Dis 1994;169:178-83.).

Itraconazole might be useful in disseminated disease when combined with albendazole, especially in infections caused by Trachipleistophora or Anncaliia (CIII).

Ocular infections caused by microsporidia should be treated with topical Fumidil B (fumagillin bicylohexylammonium) in saline (to achieve a concentration of 70 µg/mL of fumagillin) (BII) (273Diesenhouse MC, Wilson LA, Corrent GF, et al. Treatment of microsporidial keratoconjunctivitis with topical fumagillin. Am J Ophthalmol 1993;115:293-8.). Topical fumagillin is the only formulation available for treatment in the United States and is investigational. Although clearance of microsporidia from the eye can be demonstrated, the organism often is still present systemically and can be detected in urine or in nasal smears. Therefore, the use of albendazole as a companion systemic agent to fumagillin is recommended in ocular infections (BIII).

Metronidazole and atovaquone are not active in vitro or in animal models and should not be used to treat microsporidiosis (DII). Fluid support should be offered if diarrhea has resulted in dehydration (AIII). Patients with malnutrition and wasting should be treated with nutritional supplementation (AIII). Antimotility agents can be used if required for diarrhea control (BIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Albendazole side effects are rare but hypersensitivity (rash, pruritis, fever), neutropenia (reversible), CNS effects (dizziness, headache), gastrointestinal disturbances (abdominal pain, diarrhea, nausea, vomiting), hair loss (reversible), and elevated hepatic enzymes (reversible) have been reported. Albendazole is not known to be carcinogenic or mutagenic. Topical fumagillin has not been associated with substantial side effects. Oral fumagillin has been associated with thrombocytopenia, which is reversible on stopping the drug.

An IRIS has not been described in association with treatment for E. bieneusi or non-E. bieneusi microsporidiosis.

Management of Treatment Failure

Supportive treatment and optimizing ART to attempt to achieve full virologic suppression are the only feasible approaches to the management of treatment failure (AIII).

Preventing Recurrence

Treatment for ocular microsporidiosis should be continued indefinitely because recurrence or relapse might follow discontinuation of treatment (BIII). Whether treatment of other manifestations can be safely discontinued after immune restoration with ART is unknown; however, such a practice is reasonable, based on experience with discontinuation of secondary prophylaxis (chronic maintenance therapy) for other OIs present during advanced HIV disease. Therefore, certain specialists recommend discontinuing chronic maintenance therapy if patients no longer have signs and symptoms of microsporidiosis and have a sustained (e.g., >6 months) increase in their CD4+ counts to levels >200 cells/µL after ART (BIII) (245Miao YM, Awad-El-Kariem FM, Franzen C, et al. Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy. J Acquir Immune Defic Syndr 2000;25:124-9.).

Special Considerations During Pregnancy

The primary approach to treatment of microsporidiosis in pregnancy should be initiation of ART to restore immune function. Among animals (i.e., rats and rabbits), albendazole is embryotoxic and teratogenic at dosages of 20 mg/kg body weight. Therefore, albendazole is not recommended for use among pregnant women (DIII). However, well-controlled studies in human pregnancy have not been performed. Systemic fumagillin has been associated with increased resorption and growth retardation in rats. No data on use in human pregnancy are available. However, because of the antiangiogenic effect of fumagillin, this drug should not be used among pregnant women (EIII). Topical fumagillin has not been associated with embryotoxic or teratogenic effects among pregnant women and may be considered when therapy with this agent is appropriate (CIII).

Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Microsporidiosis
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Excerpted from Table 2
Initiate or optimize ART; immune restoration to CD4+ count >100 cells/µL is associated with resolution of symptoms of enteric microsporidiosis (AII)

Severe dehydration, malnutrition, and wasting should be managed by fluid support and nutritional supplement (AIII)

Antimotility agents can be used for diarrhea control if required (BIII)

Preferred therapy for gastrointestinal infections caused by Enterocytozoon bienuesiAlternative therapy for gastrointestinal infections caused by E. bienuesi
transparent gifgrey bulletFumagillin 20 mg PO tid (not available in U.S.) (BII)
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transparent gifgrey bulletTNP-470 (a synthetic analog of fumagillin) might also be effective (not available in U.S.) (BIII)
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transparent gifgrey bulletNitazoxanide 1,000 mg bid with food for 60 days -- effects might be minimal for patients with low CD4+ count (CIII)
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Preferred therapy for disseminated (not ocular) and intestinal infection attributed to microsporidia other than E. bienuesi and Vittaforma corneaeAlternative therapy for disseminated disease
transparent gifgrey bulletAlbendazole 400 mg PO bid (AII), continue until CD4+ count >200 cells/µL for >6 months after initiation of ART (BIII)
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transparent gifgrey bulletItraconazole 400 mg PO daily plus albendazole 400 mg PO bid for disseminated disease attributed to Trachipleistophora or Anncaliia (CIII)
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For ocular infection
transparent gifgrey bulletTopical fumagillin bicylohexylammonium (Fumidil B) 3 mg/mL in saline (fumagillin 70 µg/mL) eye drops - 2 drops every 2 hours for 4 days, then 2 drops qid (investigational use only in U.S.) (BII) plus albendazole 400 mg PO bid for management of systemic infection (BIII)
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transparent gifgrey bulletTreatment should be continued indefinitely to prevent recurrence or relapse (BIII)
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References

245. Miao YM, Awad-El-Kariem FM, Franzen C, et al. Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy. J Acquir Immune Defic Syndr 2000;25:124-9.
255. Wittner M, Weiss L. The microsporidia and microsporidiosis. Washington DC: ASM Press, 1999.
256. Mathis A. Microsporidia: emerging advances in understanding the basic biology of these unique organisms. Int J Parasitol 2000;30:795-804.
257. Deplazes P, Mathis A, Weber R. Epidemiology and zoonotic aspects of microsporidia of mammals and birds. Contrib Microbiol 2000:6:236-60.
258. Didier ES, Weiss LM. Microsporidiosis: current status. Curr Opin Infect Dis 2006;19:485-92.
259. Kotler DP, Orenstein JM. Clinical syndromes associated with microsporidiosis. Adv Parasitol 1998:40:321-49.
260. Weber R, Bryan RT, Owen RL, et al. Improved light-microscopical detection of microsporidia spores in stool and duodenal aspirates. N Engl J Med 1992;326:161-6.
261. Beauvais B, Sarfati C, Molina JM, et al. Comparative evaluation of five diagnostic methods for demonstrating microsporidia in stool and intestinal biopsy specimens. Ann Trop Med Parasitol 1993;87:99-102.
262. Weiss LM, Vossbrinck CR. Microsporidiosis: molecular and diagnostic aspects. Adv Parasitol 1998:40:351-95.
263. Maggi P, Larocca AM, Quarto M, et al. Effect of antiretroviral therapy on cryptosporidiosis and microsporidiosis in patients infected with human immunodeficiency virus type 1. Eur J Clin Microbiol Infect Dis 2000;19:213-7.
264. Goguel J, Katlama C, Sarfati C,et al. Remission of AIDS-associated intestinal microsporidiosis with highly active antiretroviral therapy. AIDS 1997;11:1658-9.
265. Conteas CN, Berlin OG, Speck CE, et al. Modification of the clinical course of intestinal microsporidiosis in acquired immunodeficiency syndrome patients by immune status and anti-human immunodeficiency virus therapy. Am J Trop Med Hyg 1998;58:555-8.
266. Molina JM, Goguel J, Sarfati C, et al. Trial of oral fumagillin for the treatment of intestinal microsporidiosis in patients with HIV infection. AIDS 2000;14:1341-48.
267. Molina JM, Tourneur M, Sarfati C, et al. Fumagillin treatment of intestinal microsporidiosis. N Engl J Med 2002;346:1963-9.
268. Didier PJ, Phillips JN, Kuebler DJ, et al. Antimicrosporidial activities of fumagillin, TNP-470, ovalicin, and ovalicin derivatives in vitro and in vivo. Antimicrob Agents Chemother 2006;50:2146-55.
269. Bicart-See A, Massip P, Linas MD, Datry A. Successful treatment with nitazoxanide of Enterocytozoon bieneusi microsporidiosis in a patient with AIDS. Antimicrob Agents Chemother 2000;44:167-8.
270. Akiyoshi DE, Weiss LM, Feng X, et al. Analysis of the beta-tubulin genes from Enterocytozoon bieneusi isolates from a human and rhesus macaque. J Eukaryot Microbiol 2007;54:38-41.
271. Franzen C, Salzberger B. Analysis of the beta-tubulin gene from Vittaforma corneae suggests benzimidazole resistance. Antimicrob Agents Chemother 2007;52:790-3.
272. Molina JM, Chastang C, Goguel J, et al. Albendazole for treatment and prophylaxis of microsporidiosis due to Encephalitozoon intestinalis in patients with AIDS: a randomized double-blind controlled trial. J Infect Dis 1998;177:1373-7.
273. Diesenhouse MC, Wilson LA, Corrent GF, et al. Treatment of microsporidial keratoconjunctivitis with topical fumagillin. Am J Ophthalmol 1993;115:293-8.
274. Dieterich DT, Lew EA, Kotler DP, Poles MA, Orenstein JM. Treatment with albendazole for intestinal disease due to Enterocytozoon bieneusi in patients with AIDS. J Infect Dis 1994;169:178-83.
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