Isolated gastrointestinal histoplasmosis: case report and review of the literature.

Abstract: The usual manifestation of histoplasmosis is in the form of respiratory illness. We report the case of a 67-year-old man who presented with chronic diarrhea and did not respond to the conventional treatment, including that for Clostridium difficile. He was found to have isolated colonic histoplasmosis infection, which was treated with itraconazole. There was no evidence of any disseminated disease. His only immunocompromised state was end-stage renal disease, for which he was on chronic hemodialysis. Although it is well documented as a part of disseminated histoplasmosis, our extensive review of the literature did not reveal any reported case of isolated colonic histoplasmosis in a patient on hemodialysis.

Key Words: gastrointestinal, hemodialysis, histoplasmosis

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Histoplasmosis is a common endemic mycosis prevalent in the areas of the upper Mississippi and Ohio river valleys. (1) In a healthy host, histoplasmosis causes an acute pulmonary infection. However, it can also present as an opportunistic infection in patients with a structural defect in the lung, such as emphysema, where it manifests as chronic pulmonary histoplasmosis. In patients with immune deficiency states, such as acquired immunodeficiency syndrome, after chemotherapy, and so forth, it may present as progressive disseminated histoplasmosis. (2) We report an unusual case of a hemodialysis-dependent end-stage renal disease patient who presented with isolated gastrointestinal histoplasmosis. He had no history of human immunodeficiency virus (HIV) disease or being on immunosuppressive medications, and he had no evidence of disseminated histoplasmosis. Because renal failure is a common entity, this potential differential diagnostic consideration in patients in endemic areas presenting with diarrhea and constitutional symptoms warrants a note.

Discussion

Darling first described H. capsulatum as a cause of disease in humans in 1906. (3) He found this organism in histiocytes, and it was initially thought to be an encapsulated protozoan. It was later found that H. capsulatum is an unencapsulated dimorphic fungus that exists in nature in the mycelial phase and converts to yeast at body temperature.

Histoplasma usually causes a benign, self-limited respiratory disease, most commonly seen in endemic areas of the upper Mississippi and Ohio river valleys. (1) Other than residing in an endemic area, activities that lead to increased chances of histoplasmosis exposure are destroying chicken coops, cutting down trees known to be bird roosts, and spelunking in caves known to have large bat populations. (4)

In patients with cellular immune deficiency, histoplasmosis may present as a disseminated disease. (2), (5) The most common clinical setting for disseminated histoplasmosis is HIV infection, especially with CD4 counts less than 200/m[m.sup.3]. (6-8) Immune suppression secondary to drugs, malignancy, or corticosteroids is another common predisposing factor for disseminated histoplasmosis. (9-11)

Gastrointestinal (GI) tract involvement with histoplasmosis can also occur in patients with disseminated form of the disease. The lesions of GI tract histoplasmosis occur predominantly in the ileocecal region, presumably because of an abundance of lymphoid tissue. It most commonly presents as fever, diarrhea, abdominal pain, GI tract bleed, or hepatosplenomegaly. The upper GI tract can also be involved in the form of oropharyngeal ulceration, although perforation and obstruction have also been described.

[FIGURE 1 OMITTED]

Although a variety of clinical and pathologic features of GI tract histoplasmosis have been described in patients with predisposing factors, four pathologic patterns have been described: 1) no visible gross abnormalities but presence of infected macrophages in the lamina propria, 2) collection of infected macrophages presenting as pseudopolyps or plaques, 3) ulceration with tissue necrosis, and 4) localized inflammation leading to stricture formation. (12), (13)

Histoplasma colitis should be considered in residents of endemic areas presenting with unexplained diarrhea. Pathologic examination and fungal cultures of GI tract tissue specimens are sensitive methods for diagnosing GI tract histoplasmosis. Grocott-Gomori methenamine silver nitrate staining of the tissue specimen may be used to aid in diagnosis. (4) Although an invasive procedure is required to procure specimens, it provides a rapid and accurate diagnosis. (12) It is important to note that because colonization from Histoplasma does not occur, visualization of the responsible yeast in tissue specimens ensures the correct diagnosis. (4) Currently, treatment is recommended with amphotericin B for disseminated histoplasmosis without acquired immunodeficiency syndrome for unstable patients with severe disease. In stable patients such as the patient in our case, itraconazole treatment for 6 to 18 months may be the initial choice. (14)

[FIGURE 2 OMITTED]

After review of the literature, most of the cases of disseminated histoplasmosis described were in patients with HIV disease or known predisposing factors for cellular immune deficiency. Since 1975, there has been only one reported case of isolated perforated granulomatous colitis in which the associated medical conditions and the immune status of the patient were unclear. (15) In the hemodialysis population, we found a case report of a patient with disseminated histoplasmosis, (16) but no reports of isolated gastrointestinal histoplasmosis.

The diagnosis of gastrointestinal histoplasmosis in our patient was confirmed by the morphologic features on Grocott-Gomori methenamine silver nitrate staining of the tissue specimen from the descending colon. Our patient is unique because he did not have a history of HIV disease, malignancy, chemotherapy treatment, or use of immune suppressive drugs. His only risk factor for infection was that he had end-stage renal disease and was receiving chronic hemodialysis. Our patient was treated with itraconazole, and he responded adequately to the treatment.

Depression of cell-mediated immunity occurs in patients with chronic hemodialysis and has been attributed to shortened lymphocyte survival, lymphopenia, inhibition of lymphocyte transformation, and suppressor T-cell activity. (17) This cellular immune deficiency may have been the risk factor in our patient predisposing him to infection from H. capsulatum. (5), (9), (11)

To the best of our knowledge, this is the only patient with isolated GI tract histoplasmosis on hemodialysis in the absence of other cellular immune deficiency factors. Although rare, GI tract histoplasmosis should be in the differential diagnosis of patients from endemic areas on chronic hemodialysis who present with unexplained diarrhea and constitutional symptoms such as fever and weight loss.

Key Points

* The usual mode of presentation of histoplasmosis is respiratory illness.

* Isolated colonic histoplasmosis in hemodialysis patients in the absence of other immunocompromising states has not been reported.

* In patients in endemic areas with constitutional and gastrointestinal symptoms without any other obvious cause, histoplasmosis should be a part of the differential diagnosis.

Accepted May 16, 2003.

Copyright [c] 2004 by The Southern Medical Association 0038-4348/04/9702-0172

References

(1.) Medoff G, Kobayashi GS. Systemic fungal infections: An overview. Hosp Pract (Off Ed) 1991;26:41-52.

(2.) Goodwin RA Jr, Des Prez RM. State of the art: Histoplasmosis. Am Rev Respir Dis 1978;117:929-956.

(3.) Darling ST. A protozoan general infection producing pseudotubercles in the lungs and focal necroses in the liver, spleen and lymph nodes. JAMA 1906;46:1283-1285.

(4.) Bradsher RW. Histoplasmosis and blastomycosis. Clin Infect Dis 1996;22(Suppl 2):S102-S111.

(5.) Levitz SM. Overview of host defenses in fungal infections. Clin Infect Dis 1992;14(Suppl 1):S37-S42.

(6.) Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: Clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990;69:361-374.

(7.) Wheat LJ, Slama TG, Zeckel ML. Histoplasmosis in the acquired immune deficiency syndrome. Am J Med 1985;78:203-210.

(8.) Bonner JR, Alexander WJ, Dismukes WE, et al. Disseminated histoplasmosis in patients with the acquired immune deficiency syndrome. Arch Intern Med 1984;144:2178-2181.

(9.) Davies SF, Khan M, Sarosi GA. Disseminated histoplasmosis in immunologically suppressed patients: Occurrence in a nonendemic area. Am J Med 1978;64:94-100.

(10.) Kauffman CA, Israel KS, Smith JW, et al. Histoplasmosis in immunosuppressed patients. Am J Med 1978;64:923-932.

(11.) Wheat LJ, Slama TG, Norton JA, et al. Risk factors for disseminated or fatal histoplasmosis: Analysis of a large urban outbreak. Ann Intern Med 1982;96:159-163.

(12.) Suh KN, Anekthananon T, Mariuz PR. Gastrointestinal histoplasmosis in patients with AIDS: Case report and review. Clin Infect Dis 2001;32:483-491.

(13.) Heneghan SJ, Li J, Petrossian E, et al. Intestinal perforation from gastrointestinal histoplasmosis in acquired immunodeficiency syndrome: Case report and review of the literature. Arch Surg 1993;128:464-466.

(14.) Wheat J, Sarosi G, McKinsey D, et al. Practice guidelines for the management of patients with histoplasmosis: Infectious Diseases Society of America. Clin Infect Dis 2000;30:688-695.

(15.) Lee SH, Barnes WG, Hodges GR, et al. Perforated granulomatous colitis caused by Histoplasma capsulatum. Dis Colon Rectum 1985;28:171-176.

(16.) Ma KW. Disseminated histoplasmosis in dialysis patients. Clin Nephrol 1985;24:155-157.

(17.) Goldblum SE, Reed WP. Host defenses and immunologic alterations associated with chronic hemodialysis. Ann Intern Med 1980;93:597-613.

RELATED ARTICLE: Case Report

A 67-year-old white man who was a resident of central Illinois was admitted to the hospital in August 2001 with a history of ongoing diarrhea of 6 months' duration. He was having six to eight bowel movements per day, 50% of which were semiformed and 50% of which were watery. He also complained of intermittent crampy abdominal pain, nausea, and vomiting. He had a 40-lb weight loss associated with decrease in appetite. He denied any fever. There was no history of any recent travel outside central Illinois.

His medical history was significant for ischemic cardiomyopathy and end-stage renal disease secondary to hypertension and diabetes for which he was on chronic hemodialysis. He had a history of antibiotic use 6 weeks previously for bronchitis, which led to worsening of his diarrhea. At that time, his stools were found to be positive for Clostridium difficile toxin, and he was treated initially with metronidazole and then with vancomycin but without any improvement.

On physical examination, he was alert and oriented, with no acute distress. The only positive finding on examination was vague abdominal tenderness, without any peritoneal signs. Laboratory data revealed a white blood cell count of 11,800/m[m.sup.3], with a neutrophil count of 10,010/m[m.sup.3] and a lymphocyte count of 650/m[m.sup.3]. The stool tests repeated during this admission were negative for C. difficile toxin, ova, and parasites. The stool cultures were positive for yeast and negative for Escherichia coli, Shigella, Salmonella, Yersinia, and Campylobacter. Computed tomographic scan of the abdomen was unremarkable. Colonoscopy showed a bluish-red raised area in the descending colon at 50 cm, from which biopsy specimens were taken (Fig. 1). A few areas of nonspecific erythema scattered throughout the colon were seen. There were no pseudomembranous lesions.

Random biopsy specimens taken from the right and left sides of the colon were unremarkable. The descending colon biopsy specimen from the ulcer demonstrated diffuse collections of large histiocytes associated with a mixed inflammatory infiltrate in the lamina propria. Many of the histiocytes contained rounded intracytoplasmic structures morphologically consistent with Histoplasma capsulatum. The fungal structures measured 2 to 4 [micro]m in diameter and occasionally showed budding forms. Histochemical staining with Gomori methenamine silver stain highlighted numerous organisms within the histiocytes (Fig. 2).

He was found to be negative for HIV, serum cryptococcal antigen, and urine Histoplasma antigen. Fungal serologies were also negative. Blood cultures were negative. Chest radiography did not show any evidence of histoplasmosis. The patient was subsequently treated with itraconazole 200 mg administered once daily for 6 months. On subsequent follow-up visits, the patient had almost complete resolution of his diarrhea.

Shaily Jain, MD, Janak Koirala, MD, and Fernando Castro-Pavia, MD

From the Division of Gastroenterology, Southern Illinois University School of Medicine, Springfield, IL.

Reprint requests to Shaily Jain, MD, Division of Digestive Diseases, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216. Email: [e-mail]