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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children

Microsporidiosis

(Last updated:11/6/2013; last reviewed:11/6/2013)

Panel's Recommendations

Panel’s Recommendations

  • Avoiding untreated water sources, washing fresh fruit and vegetables, and washing the hands after possible exposure to an infected person or animal (AIII) are recommended. 
  • Effective combination antiretroviral therapy is the primary initial treatment for microsporidiosis in HIV-infected children (AII*). 
  • Supportive care with hydration, correction of electrolyte abnormalities, and nutritional supplementation should be provided (AIII). 
  • Albendazole is recommended for initial therapy of microsporidiosis caused by microsporidia other than Enterocytozoon bieneusi and Vittaforma corneae (AII*).
  • Topical therapy with fumagillin eye drops can be considered in HIV-infected children with keratoconjunctivitis caused by microsporidia (BII*). Oral albendazole is recommended in addition to topical therapy for keratoconjunctivitis (BIII).
  • Treatment for microsporidiosis should be continued until improvement in severe immunosuppression is sustained (more than 6 months at CDC immunologic category 1 or 2) and clinical signs and symptoms of infection are resolved (BIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion

Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents

Epidemiology

Microsporidia are obligate, intracellular, spore-forming organisms that primarily cause moderate to severe diarrhea in children. They are ubiquitous and infect most animal species. They are classified as fungi and defined by their unique single polar tube that coils around the interior of the spore.1 Many microsporidia were reported as pathogens in humans, but Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most common microsporidia that cause infection in HIV-infected patients. Other microsporidia, such as Encephalitozoon cuniculi, Encephalitozoon hellem, Trachipleistophora hominis, Trachipleistophora anthropophthera, Pleistophora spp., Pleistophora ronneeafiei, Vittaforma (Nosema) corneae, Mycobacterium africanum, Mycobacterium ceylonensis, Nosema ocularum, Anncaliia (syns Brachiola/Nosema) connori, Anncaliia (syn Brachiola) vesicularum, and Anncaliia (syns Brachiola/Nosema) algerae also have been implicated in human infections. The organisms develop in enterocytes, and are excreted in feces and transmitted by the fecal-oral route, including through ingestion of contaminated food or water, and possibly through contact with infected animals.2,3 Vertical transmission of infection from an infected mother to her child has not been demonstrated in humans but it does occur in animals.3 

Prior to the era of combination antiretroviral therapy (cART), prevalence rates for microsporidiosis were reported to be as high as 70% in HIV-infected adults with diarrhea.1,4-6 The role of microsporidiosis in chronic diarrhea was questioned early in the HIV epidemic but is now believed to be causal.7,8 The incidence of microsporidiosis has declined with the widespread use of effective cART, but it is still being detected in HIV-infected individuals who are not receiving effective cART.9 Among HIV-uninfected individuals, microsporidiosis is increasingly recognized in children, travelers, organ transplant recipients, contact lens wearers, and the elderly. 

Clinical Manifestations

The most common manifestation of microsporidiosis is gastrointestinal (GI) tract infection. Microsporidia-associated diarrhea is intermittent, copious, watery, and non-bloody. It may be accompanied by crampy abdominal pain; fever is uncommon. Chronic severe diarrhea can result in dehydration, malnutrition, and failure to thrive. Microsporidia species have been described as causing disease in multiple other organs besides the GI tract, as well as disseminated disease.4,10 Different infecting species may result in different clinical manifestations. E. bieneusi is associated with malabsorption, diarrhea, pulmonary disease, and cholangitis. E. cuniculi is associated with hepatitis, encephalitis, peritonitis, keratoconjunctivitis, sinusitis, osteomyelitis, pulmonary disease, and disseminated disease. Encephalitozoon (syn Septata) intestinalis is associated with diarrhea, cholangitis, dermatitis, disseminated infection, and superficial keratoconjunctivitis. E. hellem is associated with superficial keratoconjunctivitis, sinusitis, respiratory disease, prostatic abscesses, nephritis, urethritis, cystitis, and disseminated infection. Nosema, Vittaforma, and Microsporidium spp. are associated with stromal keratitis following trauma in immunocompetent hosts. Pleistophora, Anncaliia, and Trachipleistophora spp. are associated with myositis. Trachipleistophora spp. is associated with encephalitis, cardiac disease, and disseminated disease.

Diagnosis

To diagnose microsporidia GI infection, thin smears of un-concentrated stool-formalin suspension or duodenal aspirates can be stained with modified trichrome stain. Chemofluorescence agents such as chromotrope 2R, calcofluor white (a fluorescent brightener), or Uvitex 2B are useful as selective stains for microsporidia in stool and other body fluids. Microsporidia spores are small (1–5 µm diameter), ovoid, stain pink to red with modified trichrome stain, and contain a distinctive equatorial belt-like stripe. They can also be visualized with hematoxylin-eosin, Giemsa, and acid-fast staining but are often overlooked because of their small size.

Urine sediment examination by light microscopy can be used to identify microsporidia spores causing disseminated disease (such as Encephalitozoonidae or Trachipleistophora). Transmission electron microscopy, staining with species-specific antibodies, or polymerase chain reaction (using specific primers) is needed for speciation.

Endoscopic biopsy should be considered for all patients with chronic diarrhea of longer than 2 months’ duration and negative stool examinations (CIII). Touch preparations are useful for rapid diagnosis (i.e., within 24 hours). The organisms can be visualized with Giemsa, tissue Gram stain, calcofluor white or Uvitex 2B, Warthin-Starry silver staining, or Chromotrope 2A.11 Sensitive assays using PCR amplification of DNA sequences extracted from stool or biopsy specimens have been developed for E. bieneusi12,13 but are research tools and not commercially available.

Prevention Recommendations

Preventing Exposure

Because microsporidia are most likely transferred from contaminated water, food, or contact with an infected individual or animal, direct contact should be avoided. Untreated water sources (drinking water that has not been chemically treated, filtered, or boiled to eliminate infectious agents) should also be avoided (AIII). Fresh fruit and vegetables should be thoroughly washed or peeled prior to eating. This recommendation is especially important for individuals with severe immunosuppression. Hand-washing after exposure to potentially contaminated material or contact with infected individuals or animals also is recommended (AIII). 

In a hospital, standard precautions (such as use of gloves and hand-washing after removal of gloves) should be sufficient to prevent transmission from an infected patient to a susceptible HIV-infected individual. However, contact precautions should be used in the case of a diapered or incontinent child.

Preventing Disease

No chemoprophylactic regimens are known to be effective in preventing microsporidiosis. Whether initiating cART will help prevent microsporidiosis is unknown.

Discontinuing Primary Prophylaxis

Not applicable.

Treatment Recommendations

Treating Disease

Immune reconstitution resulting from cART often results in clearance of microsporidia infections. Effective cART is the primary initial treatment for these infections in HIV-infected children and adults (AII*).14,15 Supportive care with hydration, correction of electrolyte abnormalities, and nutritional supplementation should be provided (AIII). Albendazole has activity against many species of microsporidia, but it is not effective against Enterocytozoon infections or V. corneae.16,17 This agent decreased diarrhea and sometimes eliminated the organism.17,18 Albendazole is recommended for initial therapy of microsporidiosis caused by microsporidia other than E. bieneusi and V. corneae (AII*). 

Although two drugs—fumagillin and nitazoxanide—have been studied in small numbers of patients for treatment of E. bieneusi infection, neither has definitive evidence for efficacy in adequate and controlled trials. Fumagillin (Sanofi-Synthelabo Laboratories, Gentilly, France) (a water-insoluble antibiotic made by Aspergillus fumigatus) and its synthetic analog, TNP-470,19 have both been used to treat microsporidiosis in animals and humans. In a placebo-controlled study of immunocompromised adults (10 of 12 of whom were HIV-infected adults) with E. bieneusi microsporidiosis, fumagillin (20 mg/dose orally 3 times daily for 2 weeks) was associated with decreased diarrhea and clearance of microsporidia spores, which was not observed in placebo patients.20 Placebo patients received fumagillin at the conclusion of the trial and all 6 demonstrated clearance of microsporidia. Thrombocytopenia occurred in 2 of the 6 patients randomized to receive fumagillin. No data are available on use of fumagillin or TNP-470 in HIV-infected children, and neither drug is available for systemic use in the United States. Data are insufficient to make recommendations on the use of these drugs in children (CIII). Consultation with an expert is recommended. One report indicated that treatment with nitazoxanide for 60 days might resolve chronic diarrhea caused by E. bieneusi in the absence of antiretroviral therapy,21 but this effect was minimal in patients with low CD4 T lymphocyte counts, and therefore, may be of limited utility (CIII).

Keratoconjunctivitis caused by microsporidia in HIV-infected adults responds to topical therapy with investigational fumagillin eye drops prepared from Fumidil-B® (fumagillin bicyclohexylammonium, a commercial product used to control a microsporidia disease of honeybees) in saline (to achieve a concentration of 70 µg/mL of fumagillin).22 Topical therapy with investigational fumagillin eye drops can be considered for HIV-infected children with keratoconjunctivitis caused by microsporidia (BII*). The addition of oral albendazole to topical fumagillin is recommended for keratoconjunctivitis because microsporidia may remain systemically despite clearance from the eye with topical therapy alone (BIII).23 Children with suspected keratoconjunctivitis that is non-responsive to antibacterial or antiviral therapy should be referred to a pediatric ophthalmologist for evaluation for possible microsporidiosis. 

Other agents including nitazoxanide, atovaquone, metronidazole, and fluoroquinolones have been reported to reduce diarrhea associated with microsporidia infection. However, metronidazole and atovaquone are not active in vitro or in animal models and should not be used to treat microsporidiosis (AII*). The role of alternative agents or the use of combination regimens for initial therapy is unknown and albendazole remains the preferred therapy for GI tract and disseminated infection caused by microsporidia other than E. bieneusi and V. corneae (AII*).17,18

Monitoring and Adverse Events (Including IRIS)

Patients with diarrhea should be closely monitored for signs and symptoms of volume depletion, electrolyte and weight loss, and malnutrition. In severely ill patients, total parenteral nutrition may be indicated (AIII).

Albendazole side effects are rare, but hypersensitivity (e.g., rash, pruritus, fever), neutropenia (reversible), central nervous system effects (e.g., dizziness, headache), GI disturbances (e.g., abdominal pain, diarrhea, nausea, vomiting), hair loss (reversible), and elevated hepatic enzymes (reversible) have been reported. Dose-related bone marrow toxicity is the principal adverse effect of systemic fumagillin, with reversible thrombocytopenia and neutropenia being the most frequent adverse events; topical fumagillin has not been associated with substantial side effects.

There has been one report of immune reconstitution inflammatory syndrome (IRIS) following initiation of cART in a patient with E. bieneusi infection24 but IRIS has not been described in association with treatment for non-E. bieneusi microsporidiosis. Concern for IRIS should not delay institution of cART in the presence of microsporidia infection (AIII).

Managing Treatment Failure

The only feasible approaches to managing treatment failure are supportive treatment and optimization of cART to achieve full virologic suppression (AIII). The role of alternative and combination therapy is unknown.

Preventing Recurrence

No pharmacologic interventions are known to be effective in preventing recurrence of microsporidiosis. However, the use of cART alone in patients with microsporidiosis has resulted in clearance of infection and symptoms15 suggesting that improvements in the immune system after successful cART are critical to recovery. Continued albendazole therapy after treatment for an acute episode of GI or disseminated infection caused by microsporidia other than E. bieneusi and V. corneae should be considered in those with severe immunosuppression (Centers for Disease Control and Prevention [CDC] immunologic category 3) until immune recovery is observed (longer than 6 months at CDC immunologic category 1 or 2) (BIII).

For keratoconjunctivitis, albendazole treatment can be discontinued after resolution of infection in patients without severe immunosuppression (CDC immunologic category 3) but should be continued indefinitely if severe immunosuppression persists because recurrence or relapse may follow treatment discontinuation (BIII). 

Discontinuing Secondary Prophylaxis

See above.

References

  1. Mathis A. Microsporidia: emerging advances in understanding the basic biology of these unique organisms. Int J Parasitol. Jun 2000;30(7):795-804. Available at http://www.ncbi.nlm.nih.gov/pubmed/10899524.
  2. Hutin YJ, Sombardier MN, Liguory O, et al. Risk factors for intestinal microsporidiosis in patients with human immunodeficiency virus infection: a case-control study. J Infect Dis. Sep 1998;178(3):904-907. Available at http://www.ncbi.nlm.nih.gov/pubmed/9728570.
  3. Didier ES, Stovall ME, Green LC, Brindley PJ, Sestak K, Didier PJ. Epidemiology of microsporidiosis: sources and modes of transmission. Vet Parasitol. Dec 9 2004;126(1-2):145-166. Available at http://www.ncbi.nlm.nih.gov/pubmed/15567583.
  4. Kotler DP, Orenstein JM. Clinical syndromes associated with microsporidiosis. Advances in parasitology. 1998;40:321-349. Available at http://www.ncbi.nlm.nih.gov/pubmed/9554078.
  5. Wittner M, Weiss L. The Microsporidia and Microsporidiosis. Washington, DC: ASM Press; 1999.
  6. Deplazes P, Mathis A, Weber R. Epidemiology and zoonotic aspects of microsporidia of mammals and birds. Contributions to microbiology. 2000;6:236-260. Available at http://www.ncbi.nlm.nih.gov/pubmed/10943515.
  7. Eeftinck Schattenkerk JK, van Gool T, van Ketel RJ, et al. Clinical significance of small-intestinal microsporidiosis in HIV-1-infected individuals. Lancet. Apr 13 1991;337(8746):895-898. Available at http://www.ncbi.nlm.nih.gov/pubmed/1672978.
  8. Molina JM, Sarfati C, Beauvais B, et al. Intestinal microsporidiosis in human immunodeficiency virus-infected patients with chronic unexplained diarrhea: prevalence and clinical and biologic features. J Infect Dis. Jan 1993;167(1):217-221. Available at http://www.ncbi.nlm.nih.gov/pubmed/8418171.
  9. Stark D, Barratt JL, van Hal S, Marriott D, Harkness J, Ellis JT. Clinical significance of enteric protozoa in the immunosuppressed human population. Clin Microbiol Rev. Oct 2009;22(4):634-650. Available at http://www.ncbi.nlm.nih.gov/pubmed/19822892.
  10. Didier ES, Weiss LM. Microsporidiosis: current status. Curr Opin Infect Dis. Oct 2006;19(5):485-492. Available at http://www.ncbi.nlm.nih.gov/pubmed/16940873.
  11. Weiss LM, Vossbrinck CR. Microsporidiosis: molecular and diagnostic aspects. Advances in parasitology. 1998;40:351-395. Available at http://www.ncbi.nlm.nih.gov/pubmed/9554079.
  12. McLauchlin J, Amar CF, Pedraza-Diaz S, Mieli-Vergani G, Hadzic N, Davies EG. Polymerase chain reaction-based diagnosis of infection with Cryptosporidium in children with primary immunodeficiencies. Pediatr Infect Dis J. Apr 2003;22(4):329-335. Available at http://www.ncbi.nlm.nih.gov/pubmed/12690272.
  13. Menotti J, Cassinat B, Porcher R, Sarfati C, Derouin F, Molina JM. Development of a real-time polymerase-chain-reaction assay for quantitative detection of Enterocytozoon bieneusi DNA in stool specimens from immunocompromised patients with intestinal microsporidiosis. J Infect Dis. May 1 2003;187(9):1469-1474. Available at http://www.ncbi.nlm.nih.gov/pubmed/12717629.
  14. Chen XM, Keithly JS, Paya CV, LaRusso NF. Cryptosporidiosis. N Engl J Med. May 30 2002;346(22):1723-1731. Available at http://www.ncbi.nlm.nih.gov/pubmed/12037153.
  15. Miao YM, Awad-El-Kariem FM, Franzen C, et al. Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy. J Acquir Immune Defic Syndr. Oct 1 2000;25(2):124-129. Available at http://www.ncbi.nlm.nih.gov/pubmed/11103042.
  16. Weber R, Sauer B, Luthy R, Nadal D. Intestinal coinfection with Enterocytozoon bieneusi and Cryptosporidium in a human immunodeficiency virus-infected child with chronic diarrhea. Clin Infect Dis. Sep 1993;17(3):480-483. Available at http://www.ncbi.nlm.nih.gov/pubmed/8218693.
  17. 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. May 1998;177(5):1373-1377. Available at http://www.ncbi.nlm.nih.gov/pubmed/9593027.
  18. Hicks P, Zwiener RJ, Squires J, Savell V. Azithromycin therapy for Cryptosporidium parvum infection in four children infected with human immunodeficiency virus. J Pediatr. Aug 1996;129(2):297-300. Available at http://www.ncbi.nlm.nih.gov/pubmed/8765631.
  19. 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. Jun 2006;50(6):2146-2155. Available at http://www.ncbi.nlm.nih.gov/pubmed/16723577.
  20. Molina JM, Tourneur M, Sarfati C, et al. Fumagillin treatment of intestinal microsporidiosis. N Engl J Med. Jun 20 2002;346(25):1963-1969. Available at http://www.ncbi.nlm.nih.gov/pubmed/12075057.
  21. 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. Jan 2000;44(1):167-168. Available at http://www.ncbi.nlm.nih.gov/pubmed/10602740.
  22. Diesenhouse MC, Wilson LA, Corrent GF, Visvesvara GS, Grossniklaus HE, Bryan RT. Treatment of microsporidial keratoconjunctivitis with topical fumagillin. Am J Ophthalmol. Mar 15 1993;115(3):293-298. Available at http://www.ncbi.nlm.nih.gov/pubmed/8117342.
  23. Didier ES. Effects of albendazole, fumagillin, and TNP-470 on microsporidial replication in vitro. Antimicrob Agents Chemother. Jul 1997;41(7):1541-1546. Available at http://www.ncbi.nlm.nih.gov/pubmed/9210681.
  24. Sriaroon C, Mayer CA, Chen L, Accurso C, Greene JN, Vincent AL. Diffuse intra-abdominal granulomatous seeding as a manifestation of immune reconstitution inflammatory syndrome associated with microsporidiosis in a patient with HIV. AIDS Patient Care STDS. Aug 2008;22(8):611-612. Available at http://www.ncbi.nlm.nih.gov/pubmed/18627278.

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Dosing Recommendations for Preventing and Treating Microsporidiosis
Preventative Regimen 
Indication First Choice Alternative Comments/Special Issues
Primary Prophylaxis
N/A
N/A
Not recommended
Secondary Prophylaxis
Disseminated, Non-Ocular Infection or GI Infection Caused by Microsporidia Other Than E. Bieneusi or V. Corneae:
  • Albendazole 7.5 mg/kg body weight (maximum 400 mg/dose) by mouth twice daily 

Ocular Infection:
  • Topical fumagillin bicyclohexylammonium (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 United States) plus albendazole 7.5 mg/kg body weight (maximum 400 mg/dose) by mouth twice daily for management of systemic infection 
N/A
Criteria For Discontinuing Secondary Prophylaxis
  • Continue until sustained immune reconstitution (more than 6 months at CDC immunologic category 1 or 2), or 
  • After initiation of cART and resolution of signs and symptoms 
Treatment Effective cART Therapy
  • Immune reconstitution may lead to microbiologic and clinical response 

For Disseminated (Not Ocular) and Intestinal Infection Attributed to Microsporidia Other Than E. bieneusi or V. corneae:
  • Albendazole 7.5 mg/kg body weight (maximum 400 mg/dose) by mouth twice daily 

Treatment Duration: 

  • Continue until sustained immune reconstitution (longer than 6 months at CDC immunologic category 1 or 2) after initiation of cART and resolution of signs and symptoms 

For E. bieneusi or V. corneae infections:
  • Fumagillin adult dose 20 mg by mouth 3 times daily, or
  • TNP-470 (a synthetic analogue of fumagillin) recommended for treatment of infections due to E. bieneusi in HIV-infected adults

For Ocular Infection:
  • Topical fumagillin bicyclohexylammonium (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 United States) plus albendazole 7.5 mg/kg body weight (maximum 400 mg/dose) by mouth twice daily for management of systemic infection 

Treatment Duration: 

  • Continue until sustained immune reconstitution (longer than 6 months at CDC immunologic category 1 or 2) after initiation of cART and resolution of signs and symptoms. 
N/A
  • Supportive care: Hydration, correct electrolyte abnormalities, nutritional support 
  • Fumagillin for systemic use is unavailable in the United States and data on dosing in children are unavailable. Consultation with an expert is recommended.
 
Key to Acronyms: cART = combination antiretroviral therapy; CDC = Centers for Disease Control and Prevention; GI = gastrointestinal; QID = four times a day