Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Microsporidiosis Epidemiology Microsporidia organisms 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 . They are ubiquitous organisms and are likely zoonotic and/or waterborne in origin . The microsporidia reported as pathogens in humans include Encephalitozoon cuniculi, Encephalitozoon hellem, Encephalitozoon (Septata) intestinalis, Enterocytozoon bieneusi, Trachipleistophora hominis, Trachipleistophora anthropopthera, Pleistophora species, P. ronneeafyi, Vittaforma (Nosema) corneae, Microsporidium sp., Nosema ocularum, Brachiola (Nosema) connori, Brachiola vesiculatum, and Brachiola (Nosema) algerae In the pre-ART era, reported prevalence rates of microsporidiosis varied between 2% and 70% among HIV-1--infected patients with diarrhea, depending on the diagnostic techniques employed and the patient population described . The incidence of microsporidiosis has declined dramatically with the widespread use of effective ART. In the immunosuppressed host, microsporidiosis is most commonly observed when the CD4+ T lymphocyte count is <100 cells/µL Clinical Manifestations The most common manifestation of microsporidiosis is gastrointestinal tract infection with diarrhea; however, encephalitis, ocular infection, sinusitis, myositis, and disseminated infection are also described . Clinical syndromes might vary by infecting species. Enterocytozoon bieneusi is associated with malabsorption, diarrhea, and cholangitis. Encephalitozoon cuniculi is associated with hepatitis, encephalitis, and disseminated disease. Encephalitozoon (Septata) intestinalis is associated with diarrhea, disseminated infection, and superficial keratoconjuctivitis. Encephalitozoon 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, Brachiola, and Trachipleistophora are associated with myositis. Trachipleistophora is associated with encephalitis and disseminated disease. Diagnosis Although microsporidia belonging to the genera Encephalitozoon, Brachiola (B. algerae), Vittaforma (V. corneae), 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 (fluorescent brightener), and Uvitex 2B (fluorescent brightener) are useful as selective stains for microsporidia in stool and other body fluids . In biopsy specimens, microsporidia can be visualized with Giemsa, Brown-Hopps Gram stain, acid-fast staining, Warthin-Starry silver staining, hematoxylin and eosin, or Chromotrope 2A . 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 encephalitozoonidae or Trachipleistophora, examination of urine often 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 or by PCR using species or genus specific primers  Treatment Recommendations ART with immune restoration (an increase of CD4+ T lymphocyte count to >100 cells/µL) is associated with resolution of symptoms of enteric microsporidiosis, including that caused by E. bieneusi. All patients should be offered ART as part of the initial management of their infection (AII). Nevertheless, data indicate that microsporidia are suppressed but not eliminated . No specific therapeutic agent is active against E. bieneusi infection. A controlled clinical trial suggests that E. bieneusi might respond to oral fumagillin (60 mg/day), a water insoluble antibiotic made by Aspergillus fumigatus (BII). However, fumagillin is not available for systemic use in the United States One report indicates that 60 days of nitazoxanide might resolve chronic diarrhea caused by E. bieneusi in the absence of ART. However, the effect might be minimal among patients with low CD4+ T cell counts. Nitazoxanide is approved for use among children and is expected to be approved by the FDA for use among adults. Albendazole and fumagillin have demonstrated consistent activity against other microsporidia in vitro and in vivo . Albendazole, a benzimidazole that binds to b-tubulin, has activity against many species of microsporidia, but it is not effective for Enterocytozoon infections, although fumagillin has activity in vitro and in vivo. Albendazole is recommended for initial therapy of intestinal and disseminated (not ocular) microsporidiosis caused by microsporidia other than E. bieneusi  (AII). Itraconazole also might be useful in disseminated disease when combined with albendazole especially in infections caused by Trachipleistophora or Brachiola (CIII). Ocular infections caused by microsporidia should be treated with topical Fumidil B (fumagillin bicylohexylammonium) in saline (to achieve a concentration of 70 mg/mL of fumagillin)  (BII). 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 the urine or in nasal smears. In such cases, the use of albendazole as a companion systemic agent is recommended (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). Malnutrition and wasting should be treated with nutritional supplementation (AIII). Monitoring and Adverse Events 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 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. 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 (CIII). Prevention of Recurrence Treatment for ocular microsporidiosis should be continued indefinitely because recurrence or relapse might follow treatment discontinuation (BIII). Whether treatment can be safely discontinued after immune restoration with ART is unknown, although it is reasonable, on the basis of the experience with discontinuation of secondary prophylaxis (chronic maintenance therapy) for other opportunistic infections during advanced HIV-1 disease, to discontinue chronic maintenance therapy if patients remain asymptomatic with regard to signs and symptoms of microsporidiosis and have a sustained (e.g. >6 months) increase in their CD4+ T lymphocyte counts to levels >200 cells/µL after ART (CIII). Special Considerations During Pregnancy Among animals (i.e., rats and rabbits), albendazole is embryotoxic and teratogenic at dosages of 30 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 might be considered when therapy with this agent is appropriate (CIII).