Microsporidiosis is illness caused by recently discovered protozoan parasites called Microsporidia. The most common of the parasites is Enterocytozoon bieneusi, which infects the small intestine and has also been reported as a cause of sinusitis and, possibly, cholangitis (inflammation of the bile ducts in the liver). Other species of Microsporidia include Encephalitozoon hellem and cuniculi and Septata intestinalis.

As well as affecting the gut, these parasites can infect immune cells called macrophages and spread throughout the body, affecting the eyes, sinuses, kidney, liver, muscles, brain and several other tissues. Prior to the AIDS epidemic only eleven cases of microsporidiosis had ever been reported in the medical literature.

The mode of transmission of Microsporidia is unknown, though the oral-faecal route is suspected (Hutin 1998). Many people in Europe and North America with microsporidiosis had a history of extensive foreign travel or overseas residence. Transmission of Microsporidia has been linked to unprotected sexual activity, eating food contaminated with Microsporidia, and drinking or swimming in contaminated water. Symptoms do not always occur immediately after infection.

Symptoms and diagnosis

Microsporidiosis is associated with heavy watery diarrhoea and, because nutrients are not absorbed properly from the gut, weight loss. Other characteristics can include cramping stomach pains, nausea, wind and irregular bowel movements. These symptoms appear to be intermittent, and may have been coming and going for some months before the individual seeks medical advice. In some cases you may notice undigested food or tablets in the faeces.

In the past, diagnosis depended on detecting the parasites from a sample of tissue taken from the small bowel using an electron microscope.

Now, however, E. bieneusi infection can be easily diagnosed by examining a stool sample (faeces) using one of three staining techniques. When the organisms have spread to other parts of the body they can be detected by using the same tests on samples of urine or from water used to flush the sinuses. A newly developed PCR test may also be helpful, although an immunofluorescent-antibody test seems to be as sensitive and as specific as the PCR test (Alfa Cisse 2002).

Treatment

Since there are no proven specific treatments for microsporidiosis, starting or switching to a potent anti-HIV regimen appears to be the best available approach to treating the condition. Several observational studies have found that people with microsporidiosis have experienced dramatic improvement or resolution of symptoms after starting a highly active anti-HIV regimen (Goguel 1997; Carr 1998; Miao 2000; Maggi 2000).

The ability of other treatments to clear the parasite in the absence of immune recovery is less well established. No anti-parasitic drugs have been approved for the treatment of microsporidiosis but several have shown efficacy in clinical trials.

Albendazole is an effective treatment for some forms of microsporidiosis. It can improve symptoms and has proven efficacy in clearing S. intestinalis organisms, although it appears less effective against E. bieneusi (Zulu 2002; Mollina 1998; Dietrich 1994; Blanshard 1992). Albendazole is available in the UK on named-patient basis from IDIS and is known by the brand name Zentel.

The veterinary drug fumagillin is effective at eradicating E.bieneusi. A dosing study found that eight of eleven people who took 60mg daily for 14 days cleared E. bieneusi and remained free of microsporidiosis for over eleven months. Severe blood disorders such as thrombocytopenia, neutropenia and hyperlipasaemia have been linked to fumagillin; in this study, three of 29 people treated with fumagillin had to stop treatment due to side effects (Molina 1997; 2000).

Other treatments for microsporidiosis includine metronidazole, itraconazole, atovaquone, nitazanoxide and thalidomide. Metronidazole has shown some success in alleviating diarrhoea, but does not seem to eliminate the parasites themselves from the gut. In a number of individual cases itraconazole has been reported to be effective against microsporidiosis affecting the eye. One pilot study found that atovaquone reduced the number of stools per day and resulted in weight gain in eight treated men. Nitazanoxide, a drug which has proved successful in the treatment of cryptosporidiosis, has also proved effective in the treatment of microsporidiosis. Nitazonoxide is licensed for the treatment of anti-protozoal infections in much of Latin America. See Cryptosporidiosis in Symptoms and illnesses: A to Z of illnesses for further information.

Very promising early results have been reported using thalidomide as a treatment for microsporidiosis. However, a placebo-controlled trial of thalidomide for people with microsporidiosis or cryptosporidiosis in London was halted due to poor recruitment.

Some success in relieving the symptoms has been reported using standard anti-diarrhoea medicines such as loperamide or lomotil. Cutting down the amount of fat in the diet and increasing simple carbohydrates may also help. Low-fat nutritional products may help in meeting nutritional needs and relieving some symptoms. Grinding up tablets or capsules may help if these are passing through the system undigested.

While anti-diarrhoeal agents may be able to relieve symptoms, it should be remembered that they do not tackle the parasite. This means that as soon as the drug is stopped, the diarrhoea will return.

Research

Kotler (1994) studied 250 HIV-infected patients sent for gastrointestinal assessment. 194 had diarrhoea. Gut pathogens (infectious agents) were found in 85% of 141 of people with AIDS and diarrhoea, 2% of 53 of people with AIDS without diarrhoea, and 3% of 56 non-AIDS patients. Microsporidia was the most common pathogen, found in 39% of AIDS patients.

Hutin (1998) conducted a prospective, unmatched case-control study of 30 people with microsporidiosis and 56 controls, all with CD4 counts below 200. Multivariate analysis found the following factors associated with microsporidiosis: CD4 count below 100; male homosexual activity and swimming in a pool in the previous 12 months. This led the authors to propose that Microsporidia are transmitted by oral-faecal transmission during sexual activity and swimming.

Rabeneck (1993) reported that E.bieneusi was isolated from the f棥s of 18 out of 55 (33%) HIV-infected men with diarrhoea and 13 of 51 (25%) men without diarrhoea. Among people with chronic diarrhoea, no difference was observed in the intensity of infection between cases and controls. The researchers suggest that any association between microsporidiosis and diarrhoea may not be as strong as is currently believed.

Benhamou (1997) reported the clearance of Cryptosporidium and Microsporidium parasites in stool of 85% of participants following improvements in immune function during anti-HIV therapy including a protease inhibitor in a pilot study.

Carr (1998) reported resolution of diarrhoea among nine patients with cryptosporidiosis or microsporidiosis treated with combination antiretroviral therapy including at least one protease inhibitor. One person relapsed. During treatment parasites were no longer detectable in stool of 8/9.

Goguel (1997) reported that microsporidiosis symptoms resolved and E.bieneusi could no longer be isolated in the stool of 15 individuals with microsporidiosis within a median of 3.5 months after they started combination antiretroviral therapy that included a protease inhibitor.

Maggi (2000) reported that 50 people with microsporidiosis or cryptosporidiosis had an excellent response to combination antiretroviral therapy. Resolution of diarrhoea was related to CD4 increase.

Gajdatsy (2001) reported a man who developed microsporidiosis within 2 weeks of commencing combination antiretroviral therapy. Treatment with albendazole led to resolution of ocular symptoms. The case is thought to be an instance of immune restoration disease.

Miao (2000) prospectively studied 6 people with HIV-related diarrhoea associated with microsporidiosis or cryptosporidiosis. After one month of highly active antiretroviral therapy (HAART), symptoms had improved. Full clearance of parasites occurred within 6 months of starting HAART.

Sharpstone (1995) treated 12 HIV-positive men with microsporidiosis and chronic diarrhoea of 12 months duration with thalidomide (100mg nightly for 3 weeks). All recipients improved, often within three days. Bowel frequency fell from a mean of six per day to 2.8 per day. Mean anti-diarrhoeal use dropped from six tablets per day to 2.8. In all cases stools, which had previously been liquid, became semi-solid. One recipient developed a generalised rash requiring cessation. Three complained of drowsiness and two reduced dose to 50 mg nightly without recurrence of diarrhoea. One recipient had a total relapse of diarrhoea after 1 week on treatment. No peripheral neuropathy was reported.

Sharpstone (1997) treated 18 people with chronic diarrhoea caused by E.bieneusi that had not responded to albendazole, and one untreated person with E.intestinalis, with thalidomide (100mg/day at night for one month). Seven people with E.bieneusi experienced complete responses, and three partial responses. Stool frequency decreased significantly from 5.3 to 3.1 per day, and weight increases significantly by 1.2kg. There was apparent disruption of E.bieneusi at all stages of its life cycle.

Eeftinck Schattenkerk (1991) treated 19 patients with Microsporidium-associated diarrhoea with metronidazole (Flagyl) 500 mg three times a day, by mouth. Diarrhoea improved in 10 and resolved completely in five. 12/15 responders relapsed within 4 weeks of stopping drug. The effect of metronidazole was symptomatic only; duodenal biopsies showed Microsporidia regardless of response to treatment.

Blanshard (1991), however, reported that treatment with metronidazole (800mg three times daily for three days or 400mg four times daily for seven days) had no effect on stool volume or frequency among four people with microsporidiosis.

Blanshard (1992) treated six AIDS patients with intestinal microsporidiosis with albendazole 400mg twice a day for 4 to 6 weeks. All patients improved clinically (reduced daily stool frequency). Four patients who relapsed at 19-31 days after the cessation of treatment responded to a second course of albendazole. Degenerative changes occurred in the parasites after treatment, which had not been seen either in pre-treatment biopsies or, in four patients, following therapy with other drugs.

Dieterich (1994) treated 29 people with AIDS, chronic diarrhoea, and confirmed E. bieneusi infection with albendazole (400mg twice daily). 26 patients were evaluable (three patients who died in the first month were excluded from analysis). After 28 days of treatment, the mean daily number of bowel movements decreased from 7.0 to 3.8 stools/day and the mean weight of the group increased 0.56kg. E. bieneusi was not cleared from the patients' follow-up small-bowel biopsies. No significant side effects were observed.

Molina (1998) randomized eight people with microsporidiosis to receive either albendazole (400mg twice daily) or placebo for three weeks. At three weeks, all the treated patients but none of the placebo recipients had cleared E.intestinalis. Placebo recipients were switched to albendazole, and all experienced complete clearance. In a randomized maintenance phase, three out of five people receiving no maintenance therapy suffered relapses, compared to none of the three receiving albendazole (400mg twice daily).

Zulu (2002) treated 153 people with HIV-related diarrhoea with albendazole (800mg twice daily for 3 weeks). 87 had parasitic infections including 23 with microsporidiosis. At 6 weeks,

34/87 (39%) had a complete clinical response and 21% had a partial clinical response.

Anwar-Bruni (1996) treated 8 men with microsporidiosis with atovaquone (750mg three times daily). At initiation of therapy, mean number of stools/day was 10, with liquid consistency. All participants experienced clinical improvement, with the mean beginning after 13 days. Mean weight gain was 3kg, and the stools decreased to 2 per day. Stool examinations showed persistent but reduced numbers of organisms.

Molina (1997) reported that among 60 patients with microsporidiosis due to E.bieneusi treated for three weeks with agents including atovaquone, doxycycline plus nifuroxazide, itraconazole, paromomycin, sparfloxacin, sulphadiazine plus pyrimethamine, chloroquine, flubendazole, albendazole plus metronidazole, and fumagillin, only fumagillin was found to induce rapid and lasting eradication of the organisms from stools and intestinal biopsies. The four participants who received fumagillin remained free of E.bieneusi after a mean follow-up of 10 months. However, fumagillin caused severe but reversible thrombocytopenia in all recipients.

Molina (2000) conducted a dosing study of fumagillin in 29 HIV-infected with microsporidiosis caused by E.bieneusi. Doses ranged from 10mg/day to 60mg/day, administered over 14 days. 21/29 people had transient clearance of the parasite but all patients who received the 3 low doses relapsed with 6 weeks. 8/11 people on the 60mg/day dose had sustained parasitic clearance and no relapse after 11.5 months of follow-up.

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