Correspondence *Department of Surgery, University of Louisville, 550 S. Jackson Street, Louisville, KY 40292, USA

Email s0gala01@louisville.edu

The case

A 56-year-old female with a 30-year history of ileocolic Crohn's disease presented to a surgery clinic with a 1-month history of bloody diarrhea and decreased caliber of stools. She had previously undergone an ileocolic and sigmoid resection for an ileosigmoid fistula. The patient had been receiving antimetabolite therapy with 6-mercaptopurine (50 mg daily) and infliximab maintenance therapy (10 mg/kg every 8 weeks) for over a year. Physical examination of the perianal area of the patient revealed a broad indurated fissure with sharp borders to the left of the posterior midline. The fissure extended 1.5 cm beyond the anal verge and was tender to palpation. Examination also revealed a palpable inguinal lymph node, and, under general anesthesia, a fissure in ano to the left of the posterior midline (0.75 cm wide by 2 cm long; Figure 1). The left posterolateral quadrant of the anal canal was denuded of transitional epithelium and covered with granulation tissue. There was an additional anal fissure in the anterior midline (1 cm wide by 2 cm in length). Proctoscopy demonstrated nondistensibility of the rectum, with granulation tissue covering the lower 4 cm of the rectum. Deep serpiginous ulcers were present in the rectum proximal to the 4 cm area of distal rectum that was denuded of mucosa. Samples obtained by deep excisional biopsy of the perianal margin and anal canal portion of the fissure did not reveal carcinoma or dysplasia, only acute fibrotic inflammation with poorly formed granulomas and focal abscess formation.

Figure 1 Image of a fissure in ano suspicious for squamous cell carcinoma in a 56-year-old female patient with ileocolic Crohn's disease.

 

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Two months later, the patient presented to the clinic again with worsening perianal pain and incontinence. She was scheduled to undergo proctocolectomy and end ileostomy. The patient also had a nodular, tender lesion on the dorsum of her hand that had the clinical appearance of erythema nodosum. Before surgery, she was admitted to hospital with a fever of 101.6 °F and worsening anal pain. A CT scan of the patient's chest revealed innumerable predominantly subpleural nodules scattered throughout both her lungs that resembled infectious or inflammatory nodules, or granulomata that had not yet calcified. There was no evidence of thoracic adenopathy. The patient was questioned and revealed previous exposure to a histoplasmosis pandemic approximately 30 years earlier when she had lived in Indianapolis.¹ Serologic test results for antibodies directed against Histoplasma capsulatum were positive with a titer of 1:32 for both yeast and mycelial antigens. The patient's urinary histoplasmosis antigen level was 19 units (value for no detectable antigen is <2 units). The result of a whole-blood PCR assay for cytomegalus virus was negative, as was a stool analysis for the presence of ova and parasites. The patient underwent proctocolectomy and end ileostomy. Her anal wound was excised with 5 mm margins. At the time of surgery, the patient appeared to have a necrotizing perianal soft-tissue infection with destruction of large portions of the anal canal and exposure of the external anal sphincter laterally to the right and posteriorly (Figure 2). Gomori's methenamine silver (GMS) staining of the resected perianal tissue specimen revealed scattered fungal yeast forms that were compatible with H. capsulatum (Figure 3). The patient's pathology report cited transmural inflammation, ulceration, distortion of crypt architecture, caseating granulomas and benign lymph nodes with numerous foreign body cells and poorly formed granulomas (Figure 4). No acid-fast bacilli were identified. Fungal cultures were negative as were cultures for Cryptococcus.

Figure 2 Image of suspected necrotizing perianal infection in the case patient showing destruction of the posterior anal canal.

 

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Figure 3 A resected perianal tissue specimen from the case patient stained with Gomori's methenamine silver stain shows Histoplasma capsulatum yeast cells in the muscularis propria (magnification 1,000).

 

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Figure 4 Histologic image of a resected specimen from the anal canal of the case patient.

Shows severe chronic active inflammation and giant cell proliferation within the muscularis propria (stained with hematoxylin and eosin, magnification 400).

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The right-hand lesion was a deep palmar space abscess that was revealed to be a histoplasmosis abscess on the basis of GMS staining of resected tissue from the wound. This tissue, similar to the perianal tissue, showed necrotizing chronic inflammation positive for fungal organisms with a morphology compatible with histoplasmosis. Acid-fast bacilli stains and fungal culture were again negative.

Postoperatively, the patient was treated with liposomal amphotericin (5 mg/kg 3 days per week for 4.5 months). Her urinary histoplasmosis antigen levels were monitored every 2 weeks to determine therapeutic efficacy and relapse, and dropped to <2 units during amphotericin treatment. Liposomal amphotericin therapy was followed by 4.5 months of oral itraconazole therapy (200 mg twice daily) during which time the patient's urinary histoplasmosis antigen levels were monitored every 3 months. Since completion of oral itraconazole therapy, urinary histoplasmosis antigen levels have been monitored every 6 months and have remained undetectable. The patient's perianal wound healed as a result of liposomal amphotericin treatment. Her palmar space abscess also resolved, but multiple debridements and a muscle flap were required to treat the abscess and fill the soft-tissue defect, which did not fully heal until 6 months after proctocolectomy. The patient had no adverse reactions to liposomal amphotericin therapy other than a single episode of dyspnea with pulmonary edema that was treated with diuretics. At 18 months follow-up, she has no further signs of histoplasmosis and has recovered well. The patient continues to be followed up on a 6-monthly basis. The decision was made to avoid infliximab in the further treatment of her Crohn's disease because of concerns about reactivation of histoplasmosis. Infliximab was discontinued when the decision for surgery was made.

Discussion of diagnosis

H. capsulatum is a dimorphic fungus that grows as a mold at temperatures <35 °C, or as a yeast in tissues at temperatures >35 °C.² Endemic areas of the US include the Ohio and Mississippi River valleys. Mold sporulation is accelerated by bird and bat feces.³ Immune-competent patients manifest H. capsulatum infection with a flu-like pulmonary illness and arthralgias. The usual route of infection is inhalation with hematogenous dissemination to other tissues during the first 2 weeks of infection.⁴ Dissemination can be acute following pulmonary infection or can occur years after the initial exposure. The case patient had lived in an area where several histoplasmosis pandemics had occurred during the 1970s and early 1980s.¹ Invasive disseminated disease occurs because of a breakdown in the cell-mediated immune response of immunocompromised individuals.⁵ The case patient was immunocompromised because of her Crohn's disease as well as the immunosuppressive treatment she had received.

Patients with disseminated histoplasmosis can present with symptoms including fever (91%), cough (65%), hepatosplenomegaly or lymphadenopathy (52%), weight loss (48%) and anemia (39%).⁶ Disseminated histoplasmosis can affect lymphoid tissue from the mouth to the anus and most commonly involves the terminal ileum.⁷ The most common presentation of gastrointestinal histoplasmosis is weight loss with bloody diarrhea (30–50%).⁸ The case patient had bloody diarrhea, an increase in the frequency of her bowel movements and worsening continence, but no weight loss.

Lesions caused by histoplasmosis and seen at endoscopy range from patchy or continuous superficial mucosal ulcerations to deep ulcers with or without frank perforation.⁹ Histoplasmosis can also present as a large inflammatory mass mimicking cancer as seen in the case patient who presented with a large fissure. Annular constricting lesions or polypoid masses can occur from the cecum to the rectum and can cause stricture formation leading to obstruction.¹⁰

Although tuberculin testing is routine in patients requiring anti-tumor necrosis factor (anti-TNF) therapy before therapy is initiated, testing for the presence of serum antibodies or urinary histoplasmosis antigen levels is not routine. A history of prior histoplasmosis infection or exposure to infection should be obtained, and serum and urinary histoplasmosis antigen titers determined if necessary in patients requiring anti-TNF therapy, particularly in endemic areas.

Fungal culture is the gold standard method for diagnosing histoplasmosis infection and was, therefore, performed for the case patient; however, H. capsulatum is a slow-growing fungus that takes up to 6 weeks to isolate and can give negative culture results even in patients with active infection, as occurred in this case. GMS stain is used to visualize the fungal organism in tissue sections.¹¹ Resected specimens from the case patient were, therefore, examined with GMS stain while the results of the fungal culture were awaited.

Differential diagnosis

The differential diagnosis of disseminated histoplasmosis with involvement of the anus should include causes of anal lesions and infections.

Treatment and management

Histoplasmosis is a common infection in endemic regions of North America.¹ Immunosuppressive conditions such as AIDS are a risk factor for the development of disseminated histoplasmosis. The treatment of Crohn's disease involves immunosuppression, which can increase a patient's risk of reactivating previous histoplasmosis or mycobacterial infections or of developing disseminated disease. The case patient's prior exposure to an area of a histoplasmosis pandemic might have been much more significant than the norm; however, the 30-year delay between that exposure and this reactivation of infection is impressive. A full diagnostic work up including determination of urinary antigen levels and serum antibody titers should be performed in patients with suspected histoplasmosis. GMS staining of the resected tissue (both intestinal and hand) allowed the true extent of the infection to be appreciated in the case patient. The Infectious Disease Society of America recommends treating disseminated histoplasmosis with liposomal amphotericin (3 mg/kg daily) for 1–2 weeks, followed by oral itraconazole (200 mg three times daily for 3 days and then 200 mg twice daily for a total of at least 12 months).¹⁴ Treatment failure is indicated by failure of histoplasmosis antigen levels to fall, and relapse is indicated by a rise in antigen level.

Conclusions

There are several case reports of gastrointestinal and anal histoplasmosis in patients with HIV, and several reports of reactivation of tuberculosis and histoplasmosis in patients receiving anti-TNF therapy. This report highlights a case of disseminated histoplasmosis with anal ulceration (mimicking squamous cell carcinoma) and a necrotizing perianal soft-tissue infection following infliximab maintenance therapy in a patient with Crohn's disease. Histoplasmosis is uncommon in immunosuppressed patients, even in endemic areas. Screening for histoplasmosis with serology or skin testing does not predict which patients will experience reactivation of disease. There is no accepted indication for screening a patient for histoplasmosis exposure before starting immunosuppressive therapy;¹⁵ therefore, the possibility of disseminated histoplasmosis must be considered in patients receiving such therapy who develop atypical symptoms.

Acknowledgments

Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Infection | Large intestine