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Microsporidia (Microsporidiosis) Updated March, 2008
PARASITOLOGY Guided Medline Search Microsporidia are obligate intracellular spore-forming protists belonging to the phylum Microsporidia. More than 140 microsporidial genera and 1,200 species have been identified that are parasitic in every major animal group (68). To date, seven genera (Enterocytozoon, Encephalitozoon, Nosema, Pleistophora, Vittaforma, Trachipleistophora, and Brachiola) and unclassified Microsporidia, assigned to the collective group Microsporidium, have been implicated in human infections. Microsporidia are considered to be true eukaryotes because they have a membrane bound nucleus, an intracytoplasmic membrane system, and chromosome separation on mitotic spindles, but are unusual eukaryotes in that they have 70S ribosomes, no mitochondria, and have simple vesicular Golgi membranes. A unique life cycle involving a proliferative merogonic stage followed by a sporogonic stage results in distinct and environmentally resistant spores. Mature spores contain an exceptional tubular extrusion apparatus for injecting infective spore contents into the host cell (12). Berger S. Emergence of Infectious Diseases into the 21st Century, 2008. Baron EJ. Mold EPODEMIOLOGY Guided Medline Search Human microsporidiosis appears to occur most frequently in persons infected with HIV but it is emerging as an infection in other immunocompromised hosts as well as in otherwise healthy immunocompetent individuals. Human microsporidial infections have been documented globally. The sources of Microsporidia infecting humans and their modes of transmission are uncertain. Zoonotic transmission of microsporidial species has not been verified but appears likely because many Microsporidia species can infect both man and animals. Ingestion of the environmentally highly resistant spores is probably the normal mode of transmission. A possible transmission by the aerosol route has also been considered because Microsporidia have also been found in respiratory specimens. CLINICAL MANIFESTATIONSGuided Medline Search Human disease due to microsporidial infection appears to manifest primarily in immunocompromised persons (Table 1). The clinical manifestations of microsporidiosis are diverse and include intestinal, pulmonary, ocular, muscular, renal, cerebral, and disseminated infections affecting almost every organ system (68). The most frequent microsporidial infection is due to Enterocytozoon bieneusi causing chronic diarrhea among HIV-infected persons (71). Among immunocompetent persons, particularly among person who reside or have traveled in tropical countries, self-limited diarrhea due to Enterocytozoon bieneusi and Encephalitozoon sp. have been documented. Furthermore, case reports of deep stromal infections of the cornea due to different microsporidial species have been described (Table 1). LABORATORY DIAGNOSIS Guided Medline Search The most robust technique for diagnosis of microsporidiosis is light microscopical detection of the parasites' spores in tissue or body fluids. Spores of different microsporidial species are of different size, ranging from 1 to 4 µm. In stool specimens, spores can be visualized using a chromotrope (67) or a chemofluorescent stain (62); in urine using gram or chromotrope stain, and in tissue specimens using gram, chromotrope, giemsa or silver stains. Sufficient magnification, i.e. x630 or x1,000, is required for light microscopical detection of Microsporidia. The spores of Enterocytozoon bieneusi can be detected in stool specimens; spores of Encephalitozoon are excreted in stool, urine or respiratory secretions. Definitive species identification of Microsporidia is made by electron microscopy of tissue sections, or molecular or antigenic analyses of tissue or body fluids. PATHOGENESIS Guided Medline Search Microsporidiosis has been associated with abnormalities in structure and function of infected organs, but the mechanisms of pathogenicity are not understood. Patients with severe cellular immunodeficiency are at the highest risk for developing microsporidial disease.
SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo In vitro evaluation of antimicrosporidial drugs and treatment studies in humans and animals are limited. In vitro susceptibility testing is hampered because Microsporidia do not grow on axenic medium. Propagation of some pathogenic species (including Encephalitozoon spp., Vittaforma corneae, Trachipleistophora hominis, and Brachiola spp.) and drug susceptibility testing have been accomplished in cell culture using several different cell lines (55, 58). Despite many attempts to culture the most frequent species found in humans, Enterocytozoon bieneusi, only short-term propagation has been achieved (63). A major obstacle of treatment appears to be the thick wall of mature spores which resists penetration of drugs so that, even if the developing stages of Microsporidia are destroyed or sporogony is perturbed, the mature spores may lead to persistent infection (11, 14, 31). In Vitro Studies Albendazole as well as other benzimidazole derivatives have been found to cause growth deformities of Encephalitozoon spp. and to reduce or eradicate the parasites propagated in cell cultures (3, 31, 36, 55). Other in vitro studies, however, have indicated that albendazole does not destroy mature microsporidial spores such that these spores may lead to persistent infection (14, 31). The microtubule protein b-tubulin has been identified as the benzimidazole target in helminths and fungi. Correlations between benzimidazole activity and partial b-tubulin sequences of Encephalitozoon hellem and Encephalitozoon cuniculi were analyzed using molecular techniques; these analyses predicted that Encephalitozoon spp. would be benzimidazole susceptible (37, 43). In vitro studies indicated that host cells expressing a P-glycoprotein pump protect intracellular stages of Encephalitozoon from agents such as albendazole, probably by limiting the intracellular concentration of the drug (41). A P-glycoprotein pump was also demonstrated in developing stages of the parasite which may further contribute to protecting the parasite from albendazole. Chemosensitizing agents such as verapamil and cyclosporin inhibiting these pumps may therefore increase the efficacy of antiparasitic agents in these microsporidia (41). Fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus, has been shown to reduce Microsporidia (Nosema apis) in infected honey-bees (38) and to inhibit replication of Encephalitozoon cuniculi in infected cell cultures in vitro (3, 21, 31, 55), but lasting eradication of the parasites has not been achieved. The semisynthetic fumagillin analog TNP-470 appears to have similar in vitro activity against Encephalitozoon intestinalis and Vittaforma corneae (17, 21). Nikkomycin Z has been described to inhibit the replication of Encephalitozoon hellem (6). Different compounds including 5-fluorouracil, sparfloxacin (3), propamidine isethionate, thiabendazole and oxibendazole (31), sinefungin (11), the calcium-channel blocker nifedipine, two nitric oxide (NO) donors (S-nitroso-N-acetylpenicillamine and sodium nitroprusside (33)), and some polyamine analogues (16, 73), have been shown to inhibit replication or spore germination of Encephalitozoon spp. in vitro. Furthermore, chloroquine (3, 64), pefloxacin, azithromycin and rifabutin were partially effective, at high concentrations (3). Cytochalasin D, demecolcine, nifedipine and itraconazole were found to inhibit spontaneous and H2O2-stimulated polar filament extrusion (42). Most of these drugs, however, are either not licensed for human use or inactive in vivo. Compounds that were found to be inactive in vitro included pyrimethamine, piritrexim, sulfonamides, paromomycin, roxithromycin, atovaquone, flucytosine (3), itraconazole, toltrazuril, metronidazole, ronidazole, ganciclovir (31) as well as thalidomide (53) which was proposed to have some efficacy in preliminary clinical studies in HIV-infected patients suffering from microsporidiosis. In vitro evaluation of drugs to treat Enterocytozoon bieneusi has not been done. In Vivo Studies Enterocytozoon bieneusi has mainly been found in humans but also detected in healthy pigs and in Rhesus monkeys experimentally infected with simian immunodeficiency virus. Treatment trials, however, have not yet been conducted in these animals. Natural microsporidial infections due to another microsporidian of the family Enterocytozoonidae, Nucleospora (formerly Enterocytozoon salmonis), occurs in salmonid fish. Experimental N. salmonis infection in salmonid fish has successfully been treated with fumagillin as well as TNP-470, a semisynthetic analogue of fumagillin (17). Effects of benzimidazole derivatives (albendazole, mebendazole, fenbendazole) were investigated in fish naturally infected with Glugea anomala parasitizing connective tissue (54). All developmental stages of the Microsporidia were irreversibly damaged by either drug as documented by ultrastructural studies. Fenbendazole was found to be effective in preventing the establishment of experimental infection of Encephalitozoon cuniculi in rabbits, as well as for eliminating the parasite from the central nervous system of naturally infected rabbits (61). In the athymic nude mouse model of disseminated Encephalitozoon cuniculi infection, treatment studies with TNP-470 resulted in prolonged survival and the prevention of the development of ascites in infected animals (17). CD8 knockout mice infected with Encephalitozoon cuniculi showed improved survival when treated with alkylpolyamine analogues (73).
ANTIPARASITIC THERAPY Guided Medline Search Smart search Little information on clinical experience in the therapy of human microsporidiosis is available, and, with two exceptions, blinded, placebo-controlled comparative treatment trials are lacking. Virtually all published studies to date have involved severely immunocompromised, HIV-infected patients. Case reports of patients infected with different Encephalitozoon species as well as one controlled trial of eight HIV-infected patients with E. intestinalis associated diarrhea (47, 49) have suggested that treatment of Encephalitozoon infections with albendazole may be curative. In contrast, experience in treating intestinal Enterocytozoon bieneusi infection has met with only limited success, and only a few prospective, open label studies and one small randomized controlled trial have been reported. Drug of Choice Immunocompetent Persons Only single case observations of immunocompetent patients with microsporidial infection have been reported (9, 65, 66). In these patients, microsporidiosis presented as a self-limiting disease without any sequelae. Thus, treatment of microsporidiosis in otherwise healthy persons appears not to be indicated. Immunocompromised Patients
Encephalitozoon spp. Infection:
Case reports have indicated that a 2- to 4-week course of oral albendazole, 400 mg twice daily, led to clinical improvement in HIV-infected patients with Encephalitozoon intestinalis, E. hellem or E. cuniculi infection (49, 50a, 72); paralleling the clinical improvement was the disappearance of spores from stool, urine, respiratory specimens or conjunctival scrapings. A response to albendazole was found in patients with clinical and radiographic improvement of Encephalitozoon-associated chronic sinusitis or lower respiratory tract infections (20, 40, 62, 69); urethritis (15); reversible renal failure in a patient with serum urea and creatinine peaks of 37.6 mm/L and 487 μmol/L, respectively (1); intermittent clinical and radiologic improvement of cerebral encephalitozoonosis in one patient (69); and clinical and parasitologic improvement of patients with disseminated infection (19, 22, 27). Further studies are needed to determine whether maintenance therapy will be necessary and what dose regimen would be appropriate. Long-term follow-up observations and autopsy studies in some of these patients indicated that Encephalitozoon infections indeed were cured after albendazole treatment (20, 35, 60). In other patients, however, cessation of therapy resulted in clinical relapse that required reinstitution of therapy (27, 49, 62, 72). Complete treatment failures were rare but at least one fatal treatment failure in a patient with cerebral Encephalitozoon cuniculi infection has been reported (69). A double-blind placebo-controlled trial including eight patients with AIDS and diarrhea due to Encephalitozoon intestinalis infection has confirmed that treatment with albendazole, 400 mg twice daily for 3 weeks, results in clinical improvement as well as clearance of microsporidia from the intestine in all patients (46). Enterocytozoon Bieneusi Infection: No recommendations regarding a specific antiparasitic treatment of HIV-associated Enterocytozoon bieneusi infection can be made at this time, although clinical studies with oral fumagillin in patients with HIV infection were promising (47, 48). However, the drug had substantial adverse effects and is not approved for clinical use. No therapy has been unquestionably proven effective for Enterocytozoon bieneusi infection. Preliminary reports of a clinical response among patients treated with metronidazole (28), azithromycin (34), atovaquone (2), albendazole, and various other antibiotics or antiprotozoal drugs could not be substantiated (47). Preliminary results indicated at least partial efficacy of fumagillin (48,50). Some reports have suggested that treatment with albendazole may lead to clinical improvement in some patients, although parasites were still present in intestinal biopsy specimens, and microsporidial spores were still detected in stool specimens obtained after treatment (8). In an open-label prospective trial of HIV-infected patients, conducted before potent antiretroviral therapy was available, 400 mg albendazole (twice daily for 4 weeks or longer) was used. In 13 out of 26 patients, there was a greater than 50% reduction in bowel movements, and in nine there was a partial response. Small-bowel biopsy revealed persistent microsporidial infection in all patients, irrespective of their clinical response to albendazole (24). Thalidomide, an anti-Tumor Necrosis Factor-a agent, was studied in 18 severely immunodeficient HIV-infected patients with chronic diarrhea due to Enterocytozoon bieneusi that had not responded to albendazole (57). After a one-month course of 100 mg thalidomide, complete clinical response was observed in seven, and partial clinical response in 3 patients, but parasite load as determined in biopsy specimens did not decrease in any patient. There was a significant decrease in stool frequency from 5.3 to 3.1 per day, and body weight increased by 1.2 kg. The investigators speculated that thalidomide may have been effective via an anti-HIV or anticytokine effect, an antagonist of hormonal and chemical mediators of diarrhea, a direct antimicrobial effect on the Microsporidia, or as a nonspecific side effect of the drug. In vitro thalidomide was found to lack antimicrosporidial activity (53). Preliminary results of a double blind placebo controlled trial in a small number of HIV-infected patients with chronic diarrhea suggested that thalidomide can effectively decrease the number of bowel movements in patients without an identified intestinal pathogen or with a pathogen that is non-responsive to specific treatment (52). Furazolidone, a synthetic nitrofuran with antiprotozoal activity against trichomonas, giardia, and entamoeba, was studied in six patients with AIDS and Enterocytozoon bieneusi infection (26). Transient clinical remission was reported in most patients, and ultrastructural changes of all stages of E. bieneusi were described in four patients who underwent endoscopic evaluation after treatment (25). Others did not find any clinical efficacy of furazolidone in patients with E. bieneusi infection (47). Oral purified fumagillin was recently used in a pilot study to treat 9 HIV-infected patients with E. bieneusi-associated chronic diarrhea (47). The investigators reported a rapid and lasting eradication of the parasite. The drug, however, induced severe but rapidly reversible thrombocytopenia in all patients. A further open-label study confirmed that fumagillin may eradicate the parasites transiently in many patients but serious adverse events and parasitic relapse were frequently observed (48). Twenty-one out of 29 patients transiently cleared Microsporidia from their stools. By week 6, however, all patients in groups treated with doses below 60 mg/day had parasitic relapse. Of note, eight out of 11 patients treated with 60 mg/day cleared Microsporidia from their gastrointestinal tract and gained weight. No parasitic relapse were reported in these eight patients during a mean follow-up of 11.5 months (48). Parasitologic clearance and clinical efficacy of oral fumagillin (20 mg three times daily on an empty stomach) was finally proven in a randomized, double-blind placebo-controlled trial including 10 patients with AIDS and two patients who had received organ transplants. Serious adverse events (neutropenia and thrombocytopenia) occured in three patients. During a follow-up of 10 months, two out of 12 patients had a relapse of microsporidiosis indicating that the parasites were not completely eradicated (50). Finally, one case report suggests potential clinical efficacy of nitazoxanide for the treatment of an HIV-infected patient with Enterocytozoon infection (5). Other Microsporidia: An HIV-infected patient with myositis due to a newly described microsporidian, Trachipleistophora hominis, was successfully treated with a combination of albendazole (400 mg twice daily), sulfadiazine (1 g four times daily), pyrimethamine (50 mg daily), and folinic acid (7.5 mg daily) (29). Two immunocompetent patients with corneal ulcers due to Vittaforma corneae (formerly Nosema corneum) and Nosema ocularum, respectively, underwent successful keratoplasty after topical therapy and antimicrobial agents proved to be of no benefit (10, 18). In vitro cultivation of Vittaforma corneae has been achieved; albendazole had in vitro activity against this microsporidian (59). Special Situations Cerebral Microsporidiosis: Two cases of presumably immunocompromised (but HIV-seronegative) children with seizure disorders attributed to Encephalitozoon infection have been described (4, 44). One child was treated with penicillin and sulfisoxazole and seemed to improve but the role of chemotherapy remained unclear. Unfortunately, no follow-up data on these children have been published. An HIV-infected patient with cerebral Encephalitozoon cuniculi infection was treated with albendazole (70) based upon the clinical observation of successful use of albendazole in cerebral cysticercosis which suggested that the drug may diffuse across the blood-brain barrier; however, no data on cerebrospinal fluid drug levels are available. During the first 4 to 8 weeks, albendazole therapy appeared to be successful as indicated by a decrease of the brain lesions on MRI scan and a substantial reduction of spore shedding in the urine. Persistent parasite excretion in urine, however, was documented, and the patient eventually died, probably due to cerebral Encephalitozoon infection. The small number of spores that continued to be excreted appeared morphologically intact but were not viable because spores could not be propagated in cell cultures. Nevertheless, persistence of viable parasites despite albendazole was assumed because of continued shedding of spores during the three-month treatment period (70). Keratoconjunctival Microsporidiosis: Topical application of fumagillin in some HIV-infected patients with keratoconjunctivitis due to Encephalitozoon hellem was associated with clinical improvement (23). Topical treatment, however, appears rarely indicated because keratoconjunctival encephalitozoonosis is almost always a manifestation of disseminated infection and the parasites are rarely, if ever, limited to superficial ocular structures (68). Consequently, detection of Microsporidia in keratoconjunctival tissue of HIV-infected patients should prompt a thorough search of other sites and bodily fluids, and systemic treatment with albendazole is usually indicated in these immunodeficient patients. Alternative Therapy In vitro studies have indicated that ten other benzimidazole derivatives including mebendazole and fenbendazole can inhibit growth of Encephalitozoon spp. in cell culture systems (36). Nevertheless, there are no clinical data available on possible alternative options for antimicrobial treatment of patients infected with Encephalitozoon spp. who cannot tolerate albendazole. There are no data on the use of fenbendazole in humans, and mebendazole is poorly absorbed. Therefore, it is unclear whether either would provide an appropriate alternative to albendazole.
ADJUNCTIVE THERAPY Guided Medline Search Antimotility drugs including loperamide, diphenoxylate, tincture of opium, and octreotide have been useful as palliative treatment in HIV-infected patients with severe, refractory Enterocytozoon bieneusi associated diarrhea. Also, nutritional therapy that emphasizes diets with low fat and simple carbohydrates may be beneficial (39). Keratoplasty has successfully been performed in otherwise healthy immunocompetent persons with corneal ulcers due to localized microsporidial infection (without systemic dissemination).
ENDPOINTS FOR MONITORING THERAPY Guided Medline Search Cessation of microsporidial spore excretion and clearing of the parasites from tissue has been well documented in HIV-infected patients with microsporidiosis who responded to chemotherapy. Such a response to treatment can be monitored by light microscopical examination of bodily fluids, i.e. stool specimens to follow patients with Enterocytozoon bieneusi or Encephalitozoon intestinalis infection (72), or urine sediments to follow patients with Encephalitozoon cuniculi and Encephalitozoon hellem infection (70). An intermittent decrease in parasite load as concluded from examination of a limited number of biopsy specimens or from semiquantitative assessment of microsporidial spores in stool samples should be interpreted with caution because of a focal distribution of infected enterocytes, and a wide day-to-day variation in spore-shedding in untreated patients (62).
VACCINES Guided Medline Search Vaccines to prevent microsporidial infections are not available.
PREVENTION OR INFECTION CONTROL MEASURES Guided Medline Search Smart search Antiparasitic Agent Prophylaxis Primary chemoprophylaxis to prevent Enterocytozoon bieneusi infection among patients at risk, i.e. severely immunodeficient patients, is not possible because there is no effective drug available. Primary prevention of encephalitozoonosis using albendazole seems not to be indicated because this microsporidial infection is rare even among HIV-infected or immunodeficient persons. As long as HIV infected patients, who were treated for clinically manifest Encephalitozoon spp. infection, remain severely immunodeficient (i.e. have CD4 lymphocyte counts below 0.1 x 109/L), secondary prophylaxis using antiparasitic maintenance therapy appears to be indicated. Albendazole was shown to significantly delay the occurrence of relapse in patients with AIDS and E. intestinalis infection who were prospectively followed in a controlled trial (46).
COMMENTS AND CONTROVERSIES Improvement of the Immune Function and Parasite Clearance Enterocytozoon bieneusi-associated diarrhea as well as systemic infection due to Encephalitozoon spp. are mainly observed in severely immunodeficient patients with CD4 lymphocyte counts below 0.05 to 0.1 x 109/L. Therefore, it was hypothesized that HIV-infected patients with low CD4 lymphocyte counts and microsporidiosis could benefit from the new highly active antiretroviral treatment (including potent proteinase inhibitors). Clinical observational studies indeed have suggested that an improvement of immune functions can result in complete clinical response and normalization of intestinal architecture which parallels the clearance of intestinal opportunistic parasites including Enterocytozoon bieneusi (13, 30, 32, 45). However, recurrent diarrhea and parasitological relapse was observed in HIV-infected patients with failure of antiretroviral therapy associated with declining blood CD4 lymphocyte counts (13). Also, these observations indicated that intestinal parasites can probably not be eradicated in immunodeficient patients with only transient improvement of host immune function. Are Microsporidia Pathogenic? Some investigators have questioned the association between Enterocytozoon bieneusi infection and diarrhea because a case control study comparing intestinal biopsies of 55 HIV-infected patients with chronic diarrhea and 51 HIV-infected patients without diarrhea found no significant difference in the occurrence of microsporidiosis in the two patient groups (51). Most clinical and epidemiological studies, however, have indicated that E. bieneusi is consistently associated with intestinal and/or biliary illness (68). Chemotherapy-induced Ultrastructural Changes of Microsporidia Although intermittent symptomatic relief, a decrease in the intestinal parasite load, and ultrastructural changes in different developmental stages of Enterocytozoon bieneusi following treatment with albendazole, furazolidone and thalidomide have been described (7, 26), eradication of the parasite and long-lasting clinically relevant improvement have never been documented. Also, ultrastructural changes of Enterocytozoon bieneusi following albendazole treatment were not substantiated by other investigators (24).
Table 1. Microsporidial species pathogenic in humans, clinical manifestations and treatment. [Download PDF]
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