Cytomegalovirus Colitis

Transcription

1 GASTROENTEROLOGY 1985;88:171-5 CASE REPORTS Cytomegalovirus Colitis Report of the Clinical, Endoscopic, and Pathologic Findings in Two Patients With the Acquired Immune Deficiency Syndrome MICK SCOTT MEISELMAN, JOHN P. CELLO, and WILLIAM MARGARETTEN Departments of Medicine and Pathology, San Francisco General Hospital and the University of California, San Francisco, California We report 2 homosexual patients with the acquired immune deficiency syndrome and histopathologic evidence for cytomegalovirus colitis. In each case, the initial endoscopic impression was Kaposi's sarcoma but the appropriate diagnosis was made by histologic demonstration of a cytomegalovirus vasculitis. Clinical manifestations may include diarrhea, abdominal pain, and hematochezia. Fulminant progression to gangrenous bowel was documented in 1 patient and was associated with histologic evidence of severe cytomegalovirus vasculitis. The pertinent clinical, endoscopic, and pathologic findings are reviewed. Histologic evidence of cytomegalovirus (CMV) has been documented in the intestinal tract of immunosuppressed patients. The immunosuppression may be either drug-induced or the consequence of an underlying disease process. Recently, histologic and culture evidence of CMV has been documented in patients with acquired immune deficiency syndrome (AIDS) (1-4). The clinical significance of CMV in gastrointestinal mucosal tissue, however, is controversial (5). Some authors feel that CMV merely superinfects devitalized tissue; others have suggested that CMV itself may be a direct pathogen (6-12). The first report of CMV vasculitis of the colon presenting with AIDS is described here in 2 homosexual male patients. The initial endoscopic impression in each case was Kaposi's sarcoma. The differential diagnosis was properly established by Received March 29, Accepted July 5,1984. Address requests for reprints to: John P. Cello, M.D., Chief, Gastroenterology, 3C-21, SFGHMC, 1001 Potrero Avenue, San Francisco, California by the American Gastroenterological Association /85/$3.30 histologic examination of endoscopic biopsy specimens. Clinical presentation as well as the endoscopic and pathologic findings are reviewed. Case Reports Case 1 A 32-yr-old white male homosexual was well until 4 mo before admission when he developed pneumocystis pneumonia, which was treated successfully with trimethoprim-sulfa. Three months before admission, a diagnosis of Kaposi's sarcoma of the skin was made, and the patient received local radiotherapy. He subsequently developed dysphagia, and endoscopic evaluation demonstrated Candida esophagitis. His dysphagia improved with ketoconazole therapy. Two months before admission, the patient developed diarrhea. Flexible fiberoptic sigmoidoscopy identified multiple submucosal erythematous lesions that were interpreted as Kaposi's sarcoma. Multiple endoscopic biopsy specimens revealed a nonspecific colitis with no evidence for Kaposi's sarcoma. Although viral cultures were positive for CMV, no viral inclusions were seen microscopically on multiple sections. Stool cultures were positive for Campylobacter, which was subsequently treated with two 10-day courses of erythromycin, resulting in diminution of the diarrhea. One month before admission, the diarrhea intensified with up to 20 liquid stools per day. As associated mucoid anal discharge and lower abdominal cramping pain were present. Stools tested for bacterial cultures, ova and parasites, Clostridium difficile toxin, and Coccidia species were negative. An empiric course of tetracycline resulted in no improvement. A significant weight loss was documented and the patient was admitted for further workup. The admitting physical examination was remarkable for Abbreviations used in this paper: AIDS, acquired immune deficiency syndrome; CMV, cytomegalovirus.

2 172 MEISELMAN ET AL. GASTROENTEROLOGY Vol. 88, No.1, Part 1 a palatal lesion consistent with Kaposi's sarcoma. The abdomen was benign. Stool output was recorded at 215 mil day, and repeated testing of stools for ova and parasites and for culture was negative. Flexible fiberoptic sigmoidoscopy revealed diffuse submucosal, violaceous hemorrhagic lesions from which biopsy specimens were obtained. In addition, multiple discrete ulcers, varying in size from 5 mm to 2 cm with an overlying exudate, were noted. The endoscopic impression was Kaposi's sarcoma, but pathologic examination demonstrated CMV-infected endothelial cells and neutrophilic infiltration of blood vessels (Figure 1). There was no evidence of Kaposi's sarcoma in the biopsy specimens. The patient was discharged without improvement and did not return for follow-up. Case 2 A 32-yr-old white male homosexual with a history of chronic herpes proctitis was well until 10 mo before admission, when he presented with fever and shortness of breath. A diagnosis of pneumocystis pneumonia was made. Treatment with trimethoprim-sulfa and pentamadine was instituted and the patient improved. He did well until 2 wk before admission, when anorexia, fever, weight loss, and watery diarrhea with up to 15 stools per day developed. On admission, exudates in the left fundus were noted. The abdomen was benign and the rectum was remarkable for excoriations and a small anal ulceration. Stools tested for bacterial cultures, ova and parasites, and Coccidia species were negative. Colonoscopy demonstrated submucosal, violaceous hemorrhagic lesions in the transverse and descending colon (Figure 2). The endoscopic impression was Kaposi's sarcoma, but histologic examination of the endoscopic biopsy specimens revealed numerous CMV inclusions in endothelial cells with associated inflammation and hemorrhage (Figure 3). There was no evidence of Kaposi's sarcoma. Viral cultures were positive for CMV and herpes simplex. Cytomegalovirus titers of immunoglobulin G (IgG) 1: 1028 and IgM 1: 8 were obtained. Shortness of breath developed and a transbronchial biopsy specimen demonstrated CMV inclusions. Transbronchial biopsy tissue and buffy coat of the blood and urine all cultured CMV. Hyperalimentation through a Hickman catheter was begun, but the patient's perirectal ulcerations worsened and an 8-day course of intravenous acyclovir was begun. The ulcerations disappeared and there was some improvement in the patient's overall condition, with a slight decrease in the patient's febrile episodes and stool frequency. The patient was discharged on a soft, solid diet as tolerated and parenteral nutrition, but returned 2 mo later with a 10-day history of worsening fevers and diarrhea. Figure 1. Mucosa of sigmoid colon. Note vasculitis with neutrophilic infiltration and enlarged cytomegalovirus-infected endothelial cells (arrow) (H & E, original magnification x400).

3 January 1985 CYTOMEGALOVIRUS COLITIS IN AIDS PATIENTS 173 Figure 2. Endoscopic photograph of a typical hemorrhagic lesion present in the descending colon. He was readmitted and on the following day developed diffuse abdominal pain and hematochezia. Sigmoidoscopic examination disclosed a necrotic distal colon covered with a black eschar. Rectal bleeding continued and proctocolectomy was performed. Pathologic examination evinced a necrotizing CMV colitis with hemorrhagic necrosis of the sigmoid colon and rectum. Cytomegalovirus inclusions were present in swollen endothelial cells with concomitant luminal compromise. Intraluminal fibrin thrombi were noted in some vessels, whereas other vessels displayed a prominent polymorphonucleocyte infiltrate with panmural necrosis. No Kaposi's lesions were identified. The postoperative course was complicated by respiratory failure, disseminated intravascular coagulation, and encephalopathy. The patient succumbed on the 21st postoperative day. Autopsy examination disclosed pneumonitis with CMV inclusions and CMV vasculitis involving the skin, pons, and cerebral cortex. Discussion Cytomegalovirus-infected cells have been demonstrated throughout the gastrointestinal tract. Although viral inclusions may exist in apparently normal tissue, there are cases associated with idiopathic steatorrhea, afferent loop syndrome, mucosal ulceration, and inflammatory bowel disease (6-9). Several studies have viewed CMV as a secondary pathogen of an underlying, chronic pathology. Goodman et al. (10) reviewed 7 cases of CMV inclusions in the colon. In each case, the inclusions were identified in granulation tissue of either ulcers or perforation, and in no case were inclusions seen in intact endothelial cells. These findings were interpreted as being consistent with a "superinfection" of damaged colonic tissue, and subsequent exacerbation of the underlying disease process. Moreover, Cooper et al. (11) evaluated colonic resection specimens in 46 patients with idiopathic ulcerative colitis. Cytomegalovirus inclusions were found in specimens from 6 patients, 5 of whom had developed toxic megacolon. In contrast, toxic megacolon was a feature of only 2 of 40 patients in whom CMV inclusions were not identified. They concluded that CMV superinfection may deleteriously alter the course of idiopathic ulcerative colitis. In contrast to the conclusions reached from these studies, Foucar et al. (12) implicated CMV as a primary pathogen. Six renal transplant patients with severe CMV infection who developed colonic ulcerations and lower gastrointestinal bleeding were described. Cells infected with CMV were found in both areas of ulceration and in intact mucosa. In each case, histologic

4 174 MEISELMAN ET AL. GASTROENTEROLOGY Vol. 88, No. 1, Part 1 Figure 3. Mucosa of sigmoid colon. Note numerous cytomegalovirus-infected cells with a single large intranuclear inclusion (arrows) and multiple small cytoplasmic inclusions. Endothelial and stromal cytomegalovirus-infected cells are present. The background contains numerous mononuclear inflammatory cells and extravasated erythrocytes. (H & E, original magnification x460). evidence of CMV vasculitis was identified as being integrally involved in the pathogenesis of mucosal damage. Recently, cases of colitis with associated CMV inclusions have been identified in homosexual males with AIDS. Knapp et al. (3) described 1 patient with a diffuse gastroenterocolitis attributed to CMV. Colonoscopic examination demonstrated mucosal erythema in a patchy distribution. Although endoscopic biopsy specimens revealed CMV inclusions, ShigeIla was cultured from the stool and the patient responded promptly to treatment with ampicillin and prednisone. Thus, the precise role of CMV in the pathogenesis of the colitis was uncertain. Gertler et al. (4) reported another AIDS patient who presented with watery diarrhea and fever. Flexible sigmoidoscopy revealed yellow plaques suggestive of pseudomembranous colitis, but cultures for pathogens including Clostridium difficile were negative as was C. difficile toxin. Although endoscopic biopsy specimens demonstrated only acute and chronic inflammation, postmortem examination docuii\ented colonic ulcerations with CMV inclusions. In addition, CMV was cultured from postmortem colon specimens. Although CMV was implicated as the responsible colonic pathogen, conclusive evidence was not presented and superinfection of damaged colonic tissue remains a possibility. The clinical and pathologic findings presented in this paper firmly establish CMV as an enteric pathogen in patients with AIDS. In 1 patient, endoscopic and culture evidence of CMV infection preceded the development of mucosal ulcerations and pathologic findings of a colonic CMV vasculitis. In the other patient, the initial endoscopy documented colonic lesions that were associated with the histologic demonstration of CMV-infected endothelial cells. Within a 4-mo period, disseminated CMV infection and progression to gangrenous bowel occurred. Histologic evaluation of a colonic resection specimen revealed severe CMV vasculitis. In addition, CMV vasculitis involving the skin and brain was demonstrated on postmortem examination. This unique documentation of a commensurate progression in the clinical and pathologic findings of CMV colitis makes the concept of superinfection

5 January 1985 CYTOMEGALOVIRUS COLITIS IN AIDS PATIENTS 175 untenable. The pathogenic potential of CMV was further confirmed by the evaluation of the histologic findings. The dominant finding in each case was CMV inclusions in endothelial cells, which progressed to a CMV vasculitis. In our cases, as well as those of Foucar (12), vasculitis was noted only in vessels directly infected with CMV. The affected vessels were most often capillaries that were situated in both the mucosa and submucosa. Enlarged CMVinfected cells, platelet thrombosis (presumably induced by damaged endothelium), and frank CMV vasculitis with neutrophilic infiltration were observed with coexistent vessel occlusion. The predictable consequences included necrosis and hemorrhage. The latter was well correlated with the hemorrhagic lesions noted on endoscopy. The endoscopic appearance in both patients was diffuse violaceous submucosal hemorrhagic lesions. The striking similarity of these lesions to Kaposi's sarcoma led to an initial erroneous endoscopic impression of Kaposi's sarcoma in each case. The absence of a positive biopsy specimen does not, of course, definitively rule out the presence of Kaposi's sarcoma, as endoscopic biopsy specimens may be positive in only one-third of colonic Kaposi's sarcoma (13). However, the possibility that these submucosal hemorrhagic lesions were actually Kaposi's sarcoma was made extremely unlikely by the histopathologic findings in each case and the absence of Kaposi's sarcoma on the resected colonic specimen in case 2. Additional endoscopic findings included erythema, friability, and, in case 1, numerous wellcircumscribed ulcers with an overlying exudate. The ulcers varied in size from 5 mm to 2 em and their appearance strongly resembled that of ordinary peptic ulcers. The differential diagnosis remains difficult and is based upon histology. Enhanced clinical awareness of the entity of CMV colitis in patients with AIDS may allow a more accurate diagnosis. References 1. st. Onge G, Bezahler GH. Giant esophageal ulcer associated with cytomegalovirus. Gastroenterology 1982;83: Guttman 0, Raymond A, Gelb A, et al. Virus-associated colitis in homosexual men: two case reports. Am J Gastroenterol 1983;78: Knapp AB, Horst DA, Eliopoulos G, et al. Widespread cytomegalovirus gastroenterocolitis in a patient with the acquired immunodeficiency syndrome. Gastroenterology 1983;85: Gertler SL, Pressman J, Price P, Brozinsky S, Miyai K. Gastrointestinal cytomegalovirus infection in a homosexual man with severe acquired immunodeficiency. Gastroenterology 1983;85: Gottlieb MS, Groopman JE, Weinstein WM, Fahey JL, Detels R. The acquired immunodeficiency syndrome. Ann Intern Med 1983;99: Levine RS, Warner NE. Johnson CF. Cytomegalic inclusion disease in the gastrointestinal tract of adults. Ann Surg 1964;159: Campbell DA, Piercy JR, Shnitka TK, Goldsand G, Devine RD, Weinstein WM. Cytomegalovirus-associated gastric ulcer. Gastroenterology 1977;72: Tamura H. Acute ulcerative colitis associated with cytomegalic inclusion virus. Arch PathoI1973;96: Henson D. Cytomegalovirus inclusion bodies in the gastrointestinal tract. Arch Pathol 1972;93: Goodman ZD, Boitnott JK, Yardley JM. Perforation of the colon associated with cytomegalovirus infection. Dig Dis Sci 1979;24: Cooper HS. Raffensperger EC, Jonas 1. Cytomegalovirus inclusions in patients with ulcerative colitis and toxic dilation requiring colonic resection. Gastroenterology 1977;72: Foucar E, Mukai K, Foucar K, Sutherland DE, Van Buren CT. Colonic ulceration in lethal cytomegalovirus infection. Am J Clin Pathol 1981;76: Friedman S, Wright T, Altman D. Kaposi's sarcoma and the gastrointestinal tract. The San Francisco experience (abstr). Gastroenterology 1983;84:1160.