Microsporidiosis

* Background.-Encephalitozoon (Septata) intestinalis is a common disseminating opportunistic intestinal microsporidian affecting patients with acquired immunodeficiency syndrome. This microsporidian does respond to albendazole therapy. A patient with acquired immunodeficiency syndrome and chronic diarrhea presented to George Washington University Hospital in January of 1996. Despite appropriate surgical specimens, no etiology had been found to explain his cholecystitis, cystitis, and enteritis 3 months previously at another hospital.

Design.-Tissue specimens were analyzed by light microscopy, using hematoxylin-eosin and the Armed Forces Institute of Pathology Brown-Brenn microsporidia stain, and by transmission electron microscopy. Urine and stool specimens were analyzed by modified chromotrope 2R trichrome and chitin fluorochrome stains and by transmission electron microscopy.

Results.-At George Washington University Hospital, disseminated E intestinalis was diagnosed from duodenal biopsy, urine, and stool specimens. On the 14th day of oral albendazole therapy, a partial small bowel resection was performed to correct a perforation (air under the diaphragm). There was no enterocyte microsporidian infection at that time, only spores undergoing macrophage digestion. Review of previous specimens showed severe E intestinalis cholecystitis, cystitis, and enteritis. Albendazole was restarted and, after 2 weeks, the patient had negative stool and urine specimens.

Conclusions.-Encephalitozoon intestinalis symptomatically targets many organs, including the urinary bladder. To our knowledge, this is the first tissue-documented case of cystitis. Left untreated with albendazole, small bowel infection can lead to perforation and peritonitis. (Arch Pathol Lab Med. 1997;121:880-887)

Encephalitozoon (Septata) intestinalis was the second diarrheagenic microsporidian described in human immunodeficiency virus (HIV)infected patients, after Enterocytozoon bieneusi. 1-3 Both species have been diagnosed worldwide, but to date, E intestinalis infection has been diagnosed less frequently as a cause of diarrhea than E bieneusi. 4-14 However, E intestinalis, unlike E bieneusi, can spread beyond the contiguous alimentary, biliary, and upper respiratory tracts and disseminate intravascularly.1, 2, 15-19 Encephalitozoon intestinalis has been identified in the portal vein and Kupffer cells of the liver, infecting renal epithelium, causing tubulointerstitial nephritis, 1, 2 and causing necrosis of the anterior pituitary (J.M.O., unpublished data, 1996). There is a complete clinical and parasitologic response of E intestinalis to albendazole, as opposed to only a minimal to moderate clinical, but absent parasitologic, response of E bieneusi.20-25 Encephalitozoon intestinalis is readily cultured from fluid and tissue specimens,26-28 whereas there has been only short-term culture of E bieneusi.29

The sentinel case of E intestinalis enteritis had small intestinal ulcers, something that has rarely been described subsequently.lz The actual ulcer depths have not been ascertained, since only endoscopic biopsy specimens have been available and perforations have not been diagnosed. Mucosal defects are not a feature of E bieneusi enteritis, which, at most, is associated with sloughing of distal villus enterocytes.b7

Herein we describe a patient with acquired immunodeficiency syndrome (AIDS) who presented with undiagnosed and untreated intestinal and disseminated E intestinalis microsporidiosis, which lead to small bowel perforations and peritonitis. The patient subsequently responded to albendazole therapy.

METHODS

Light Microscopy

Five-micrometer paraffin sections from biopsy and resection specimens were stained with hematoxylin-eosin, the Armed Forces Institute of Pathology's microsporidia modification of the Brown-Brenn Gram's stain,7 and Field modification of the Warthin-Starry stain."* Sections were viewed with routine transmitted light and polarizing lenses. Giemsa and Ziehl-Neelsen stains were also used.

Transmission Electron Microscopy

Tissue specimens were fixed in buffered 2.5% glutaraldehyde, postfixed in osmium tetroxide, dehydrated through graded ethanol and propylene oxide, and embedded in Spurr's epoxy.31 Semithin, 1-lim plastic sections were stained with the combined methylene blue, azure II, and basic fuchsin stain. Thin sections were prepared from selected blocks, stained with uranyl acetate and lead citrate, and viewed on a Zeiss EM10 electron microscope operating at 60 kV

Urine and Stool Specimens

Sediment from ultracentrifugation of urine specimens was mixed with warm fluid agar, which was then cooled to solid state cut into pieces, and processed for transmission electron microscopy (TEM). For light microscopy, stool and urine specimens were either air-dried on a slide or centrifuged onto a slide (Stat Spin) and stained with modified chromotrope 2R trichrome stain (urine and stool), fluorescent chitin stain (urine and stool), or standard cytology Papanicolaou stain (urine).32-35

REPORT OF A CASE

A 34-year-old man with AIDS presented to George Washington University Hospital on January 2, 1996, for nausea, vomiting, and diarrhea. He had a 6-year history of HIV infection and a recent CD4 lymphocyte count of 24/mmd.

Three months previously, he had been hospitalized elsewhere for chronic diarrhea, dehydration, and malabsorption. He underwent laparoscopic cholecystectomy for acute cholecystitis and cystoscopy, with biopsy, for persistent suprapubic pain (Table). One month later, he underwent upper gastrointestinal endoscopy with distal duodenal and jejunal biopsies for evaluation of diarrhea. All three specimens were diagnosed as showing severe nonspecific inflammation. His symptoms were only somewhat ameliorated by the cholecystectomy.

On admission to George Washington University Hospital, the patient was febrile to 38.6oC and had a leukocyte count of 2.3 x 103/mm3 with 16% neutrophils and 34% bands. Abdominal computed tomographic scan showed small bowel dilation, consistent with obstruction, and mesenteric lymphadenopathy. An upper gastrointestinal series disclosed diffuse jejunal dilation, thickened mucosal folds, and multiple ulcerations. Stool smears stained with modified trichrome 2R stain were positive for microsporidia. Upper endoscopy on hospital day (HD) 3 revealed ulcerative duodenitis. Light microscopy and TEM of the duodenal biopsy specimen disclosed ulcerating E (Septata) intestinalis enteritis (Figs 1 and 2). Urine sediment (HD 11) contained intracellular and free E intestinalis organisms (Figs 2, D and 3). Treatment with albendazole (400 mg twice daily), an oral drug, was initiated as soon as it was available (HD 13).

The patient had upper gastrointestinal bleeding (HD 23 through 26) requiring nine units of packed erythrocytes. Upper endoscopy failed to reveal the source of the bleeding, but arteriogram showed extravasation of contrast into the distal jejunum. As he was considered a poor surgical candidate, treatment was repeat transfusions.

After 14 days of albendazole therapy, the bleeding resolved and the patient's diarrhea decreased, but on HD 27, routine chest roentgenography revealed free abdominal air and an emergent exploratory laparotomy was performed. The small bowel was necrotic from the ligament of Treitz through the mid-ileum (Fig 4). The large intestine, from the hepatic flexure to the sigmoid colon, was firmly adherent to the diseased small bowel. Segmental small bowel resection and subtotal colectomy were performed without immediate reanastomosis.

Postoperatively, the patient returned to the intensive care unit for fluid resuscitation and correction of anemia and coagulopathy. The patient's no-oral-intake status precluded albendazole therapy. On postoperative day 2, the planned reanastomosis was completed with duodenojejunostomy, colostomy, and gastric tube placement. An additional 12 cm of necrotic jejunum was removed. On HD 38, postoperative day 10, enteral nutrition and albendazole treatment were resumed. Over the next 2 weeks, the stool cleared of microsporidia, and only rare spore remnants were found in urine. The patient was transferred to a chronic care facility on HD 67.

HISTOPATHOLOGY

Duodenal Biopsy

Light microscopy of the duodenal biopsy specimen taken at our institution showed E intestinalis organisms in villus enterocytes and adjacent lamina propria macrophages. Organisms were also present free and within macrophages in the necroinflammatory debris and granulation tissue of an ulcer. The Brown-Brenn Gram's and Warthin-Starry stains enhanced the visualization of the organisms, especially using polarized light microscopy (Fig 1). Transmission electron microscopy also demonstrated organisms developing within enterocytes (Fig 2), myofibroblasts, and macrophages, as well as spores undergoing lysosomal digestion within macrophages and neutrophils. No other pathogens were identified.

Urine and Stool Specimens

A urine specimen taken before albendazole administration (HD 11) was rich in infected tubular and transitional epithelial cells and macrophages, and free spores (Figs 2, D and 3). The next available urine specimen, received 3 days after restarting albendazole, showed few organisms, and urine specimens 5 and 10 days later showed only rare empty spores.

The first two stool specimens (HD 2 and HD 22) had moderate numbers of spores. Fewer spores were found 10 days after stopping albendazole therapy, and no spores were detected 6 and 13 days after restarting albendazole.

Resection Specimen

The first resection specimen consisted of 106 cm of adherent loops of dilated small bowel (6 to 12 cm in diameter) and 16 cm of firmly attached colon, showing a mixture of acute and chronic peritonitis. The proximal mucosa was flattened and had a brown-black melanotic coating. The mid-portion of the specimen was strictured and had numerous irregular hemorrhagic erosions and ulcerations measuring up to several centimeters in greatest surface dimension (Fig 4, A). These ulcerations often encompassed perforations measuring up to 2 cm in diameter (Fig 4, B).

While some perforations ended at the serosa of adherent bowel loop, others communicated freely with the peritoneal cavity. The serosa, especially adjacent to perforations, was coated with dense fibrinopurulent exudate. The mucosa of the colon was intact.

Light microscopy revealed severe enteritis with ulcers and perforations of varying sizes and vintages (Fig 5, A and B). Defects ranged from fissurelike to flasklike in shape and often had regenerating epithelium. Polypoid formations of mucosa and granulation tissue were common. A large portion of the serosal surface was coated with a fibrinous exudate containing foreign material and bacteria. The serosa was variably thickened by granulation tissue and collagen and contained thrombosed and recanalized vessels.

Vesiculated ("foamy") Gaucher-like macrophages bordered defects and were scattered throughout the lamina propria and bowel wall, even reaching the peritoneal surface (Fig 5, C). Foamy macrophages were also seen in the walls of vessels and in lumina of veins. Very few Gram'sor Warthin-Starry-staining or polarizing spores were present within the foamy macrophages, and none were found within enterocytes. Identical macrophages were also detected in draining mesenteric lymph nodes. The adherent edematous segment of colon lacked any sign of microsporidiosis.

The second jejunal resection was similar to the first resection specimen but lacked perforations. Transmission electron microscopy of the resection specimen revealed spores in various stages of lysosomal digestion within macrophages (Fig 2, E). Parasites were not detected in enterocytes by light microscopy or TEM. Neither light microscopy nor TEM revealed any other pathogen (eg, cytomegalovirus, amebae, and toxoplasma).

RETROSPECTIVE EXAMINATION OF BIOPSY SPECIMENS

Distal Duodenal and jejunal Biopsies

The histopathology of the original biopsies was similar to that of the duodenal biopsy specimen obtained at George Washington University Hospital. Encephalitozoon intestinalis infected enterocytes and lamina propria macrophages, and shedding epithelium, erosions, and ulcerations were present.

Urinary Bladder Biopsy

Biopsy of the urinary bladder showed ulcerative cystitis with microsporidia infecting remaining transitional epithelial cells and distributed free and within macrophages throughout the bladder wall (Fig 6).

Gallbladder

Severe necrotizing E intestinalis cholecystitis was evident in the gallbladder The epithelium was rich in developing organisms, whereas the lamina propria contained abundant free parasites and infected macrophages.

COMMENT

Encephalitozoon (Septata) intestinalis should now be considered a potential cause of acute abdomen and small bowel perforation in patients with AIDS and chronic diarrhea. Assuredly, it is a much less frequent cause of perforation than cytomegalovirus. However, it is also true that a microsporidial etiology has rarely if ever been entertained, yet unexplained perforations, especially of the distal ileum, are not uncommon in AIDS.3S38

This patient had diarrhea for over 3 months, and necrotizing intestinal microsporidiosis (retrospectively documented) for at least 2 months before E intestinalis was diagnosed by stool and biopsy studies. The resection specimen showed chronic peritonitis and transmural free and intramacrophage spores, especially near perforations and deep ulcers, evidence that some perforations had been present for months. Perforations may have been walled off from the peritoneal cavity by adherent loops of bowel. The event leading to the communication and pneumoperitoneum could have been a new transmural defect or dissociation of adherent loops, possibly as a consequence of the albendazole therapy.

Albendazole has been shown to eradicate E intestinalis from mucosa, stool, and urine, and to cure patients of diarrhea.-22 It seems reasonable to conclude that this patient's perforations could have been prevented with albendazole therapy had the diagnosis of E intestinalis microsporidiosis been made on any of the three previous tissue specimens. There are now multiple histochemical stains that greatly facilitate the diagnosis of microsporidiosis, for example, the Armed Forces Institute of Pathology's modification of the Brown-Brenn Gram's stain, Field modification of Warthin-Starry stain, several chitin fluorochrome stains, and even a well-performed Giemsa stain.ll,30,32,39-3 This patient's microsporidiosis could also have been diagnosed on stool, small bowel luminal aspirate, or urine specimens using, for example, modified trichrome chromotrope 2R, chitin fluorescence, Giemsa, Papanicolaou, and routine Gram's stains.32-35,40,44

As evidenced by the positive urinary bladder biopsy specimen, this patient had intravascularly disseminated E intestinalis microsporidiosis for at least 2 months prior to the definitive diagnosis.45 While only the symptomatic cystitis was documented, there was probably also a renal infection, something that appears to be typical of Encephalitozoon species.7-9 Despite many diagnoses of E intestinalis infection of the urinary tract, to our knowledge this is the first tissue-documented case of E intestinalis cystitis. This finding is not unexpected, since Encephalitozoon hellem, a close taxonomic relative of E intestinalis, has been documented to cause cystitis, urethritis, and prostatitis.3 Encephalitozoon hellem, E cuniculi, and E intestinalis all disseminate to involve the urinary tract, and all respond to albendazole therapy.444-52 Thus, even if the exact species is unknown, finding microsporidia spores in urine should prompt immediate albendazole treatment.

Microsporidia-infected enterocytes were absent from the resection specimens removed 2 weeks after the patient started albendazole therapy. Few, if any, organisms still present in this specimen were likely to be still viable, since they were undergoing lysosomal digestion within macrophages.220 The birefringence of the spores was lost as the chitin was digested. Epithelial regeneration and healing of ulcers had begun to occur during the 2 weeks of therapy; however, the extent of the bowel disease was apparently so great that perforation occurred before the inflammatory process abated to allow for sufficient healing. Thus, E intestinalis is an aggressive microsporidian in patients with AIDS that, if left unattended, can lead to serious consequences, including small bowel perforation and peritonitis.

Partial support for this study was provided by grant NIH NIDR DE-12585 from the National Institutes of Health, Bethesda, MD. We acknowledge the expert technical assistance of Faridah Dahlan and An Nguyen.

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