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Cytomegalovirus colitis in patients with acquired immunodeficiency syndrome. Charisse V DeRodriguez MD Jack Fuhrer MD. Gerond Lake-Bakaar MD MRCP.
Journal of the Royal Society of Medicine Volume 87 April 1994

Cytomegalovirus colitis in patients with acquired immunodeficiency syndrome

Charisse V DeRodriguez MD Jack Fuhrer MD Gerond Lake-Bakaar MD MRCP Department of Medicine, SUNY Health Sciences Center at Stony Brook, Stony Brook, New York NY 11794, USA Keywords: cytomegalovirus; colitis; AIDS

Summary The spectrum of presentation of complications in patients with human immunodeficiency virus (HIV) disease is changing, in line with their improved survival. Infection ofthe colon with cytomegalovirus (CMV) is now more commonly encountered in clinical practice. We have reviewed the medical records of eleven patients with clinical and pathological evidence of CMV colitis. The clinical presentation, endoscopic and histological findings, and simultaneous infection of other organs with CMV are discussed. Diarrhoea in association with abdominal pain is the most frequent symptom complex in these patients and should raise the clinical index of suspicion for CMV colitis.

Introduction Early diagnosis and treatment with zidovudine, (AZT), has significantly improved the survival of patients infected with HIV1. This appears to have altered the spectrum of presentation of patients with HIV disease. Infection of the colon with cytomegalovirus CMV colitis is increasingly being recognized as a major complication of the acquired immunodeficiency syndrome2'3. This complication is potentially treatable with drug therapy4-6. Early clinical diagnosis may thus be important in patients with AIDS. Isolated case reports of CMV colitis in patients with acquired immunodeficiency syndrome, AIDS, have appeared sporadically in the literature7-"1. However, few large series have documented the pattern ofclinical presentation'2. We report our recent experience of CMV colitis in patients with H1V disease with specific reference to their clinical presentation, endoscopic findings and response to treatment. Materials and methods The medical records of all patients presenting to the Gastroenterology division at University Hospital Stony Brook between 1985-1991 with a putative diagnosis of CMV colitis were reviewed. Eleven patients were found in whom the diagnosis of CMV colitis had been established by endoscopy and by biopsies ofcolonic mucosa with characteristic histology showing CMV inclusion bodies, after exclusion of other known causes of diarrhoea. Fresh stool samples had also been examined in the routine laboratory for ova and parasites, specifically cryptosporidium, Correspondence to: G Lake-Bakaar MD, Division of Gastroenterology/Hepatology, State University of NewYork at Stony Brook, Health Sciences Center T17, 060, NY 11794, USA

and cultured for bacteria including mycobacterium avium intracellulare (MAD). The clinical presentation, endoscopic and histological findings, and infection of other organs with CMV were well documented.

Patients All 11 patients were men (age range 27 to 52 years). All were infected with HIV. None admitted to a history of intravenous drug abuse. Admitted risk factor was male homosexuality in the majority; one patient contracted HIV infection from a female prostitute. Endoscopy A flexible sigmoidoscopy was performed in seven and a full colonoscopy in four. Biopsies were placed immediately in formalin and processed through the routine histology laboratory. The finding of typical cytomegalovirus inclusions in both lamina propria and submucosa were considered diagnostic of CMV infection of the colon7"3"4. Treatment of cytomegalovirus infection Nine of the 11 patients received 9 (1,3-dihydroxy2-propoxymethyl guanine), Ganciclovir, at a dose of 5 mg/kg intravenously every 12 h for 14 days followed by maintenance therapy with 5 mg/kg daily. One patient diagnosed early in 1985 was treated with Acyclovir 300 mg three times a day. Two patients received phosphonoformate, Foscarnet 60 mg/kg q8h having failed treatment with Ganciclovir for CMV retinitis.

Results Clinical presentation The major presenting symptom was watery diarrhoea in nine of the 11 (82%) patients. The frequency of bowel movements varied from one to two watery stools a day, up to 10 to 15 bowel movements daily. Although this symptom was intermittent in some cases, in the majority it was continuous. Three patients also had bright red blood per rectum. Severe abdominal pain associated with nausea and or vomiting was a significant feature in five patients. The pain was frequently cramping in nature and localized to the left or right lower quadrant (four cases) or epigastrium (one case).

Endoscopic findings Four patients underwent colonoscopy with multiple biopsies. Macroscopic lesions were evident in the rectum, transverse colon, ascending colon and ileocaecal valve in two. In the other two, the rectum was spared and macroscopic lesions were present only at the ileo-caecal valve.

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symptoms recurred within 2 months in one of the responders. One of the four Ganciclovir responders developed reactivation of his CMV retinitis whilst on maintenance treatment. Although the dose was doubled, there was no change in the diarrhoeal symptoms. Later, with the appearance of a new CMV lesion in the left eye, he was started on Foscarnet with resolution of his diarrhoea after three days of treatment. A second non-responder had a total of four endoscopies performed with biopsies, all of which repeatedly showed CMV inclusions. Foscarnet was started because of reactivation of CMV retinitis. His diarrhoea resolved on this treatment. Concomitant CMV infection Figure 1. Endoscopic appearance of the sigmoid mucosa in a patient with cytomegalovirus colitis showing oedema and multiple areas of punctate erythema

Seven ofthe 11 patients had concomitant CMV retinitis and one also had documented CMV duodenitis.

Seven patients underwent flexible sigmoidoscopy only. Multiple biopsies were obtained. The rectum was macroscopically normal in two, although biopsies of rectal mucosa were positive in one. The mucosal lesions described were shallow ulcers or erosions, scattered areas of erythema, oedema and friability (Figure 1). Enlarged cells with characteristic CMV inclusions were found on histology (Figure 2). One patient had raised purple erythematous lesions which were diagnosed macroscopically as Kaposi's sarcoma but showed characteristic inclusion bodies on histology.

Discussion The number of patients with AIDS presenting with symptoms referable to the gastrointestinal tract continues to increase. Recognition of specific clinical patterns of presentation in patients with this syndrome, particularly with regard to infections which are amenable to therapy is therefore of increasing importance. Although sporadic reports of CMV colitis in AIDS have appeared frequently in the literature, they have tended to comprise isolated case reports7-". Few large series have been reported2"2. The present study focuses only on patients with an unequivocal diagnosis of CMV colitis based on accepted histological findings. It makes no attempt for example to define a true incidence of the disease. It highlights those clinical findings which appear to be characteristic of the condition and which might be of importance in making an early diagnosis. Although approximately 40% of patients with HIV disease attending our institution admitted to intravenous drug abuse, none of the 11 with CMV colitis were IVDA. The majority were male homosexuals, suggesting that this group might be at particular risk. The most common symptom present in our patients was diarrhoea which was the presenting symptom in nine of 11 (82%). It was continuous in all but two patients in whom the diarrhoea was intermittent. One of the two also had urgency and incontinence. The diarrhoea was frequently watery. It contained blood and mucus in only two. In a large series of 44 patients reported recently'2, all had diarrhoea which was intermittent in 13 (30%). Similar results have been reported previously in seven patients with CMV colitis2. In both series, as with ours, bleeding was

Response to treatment The patient treated with Acyclovir showed no response in the frequency of his diarrhoea and he died 2 months later. At autopsy, extensive shallow irregularly shaped ulcerations were found throughout the large bowel. Nine patients were treated with Ganciclovir. In eight, the specific indication for treatment was CMV retinitis; one patient was treated specifically for CMV colitis. Of seven with diarrhoea, three improved and four showed no change. Three patients with abdominal pain received Ganciclovir. The pain resolved after induction treatment in two; the other continued to complain of mild abdominal pain. Abdominal

uncommon212. The next most common symptom which was elicited in five of 11 (46%) patients was abdominal pain. This was often severe and associated with nausea and vomiting. This symptom has been described in up to 64% of patients'2. Cytomegalovirus colitis was the commonest cause of diarrhoea associated with diffuse abdominal pain in a recently reported series15. The association of diarrhoea and abdominal pain should therefore raise the index suspicion for CMV colitis in a patient with AIDS. The mucosal lesions were as others have described and varied from a normal appearing mucosa to oedema, friability and ulceration2'32. Violaceous mucosal lesions reminiscent of Kaposi's sarcoma, but

Figure 2. Light microscopy of rectal mucosal biopsy (haematoxylin and eosin) showing enlarged cells with characteristic cytomegalovirus inclusions

Journal of the Royal Society of Medicine Volume 87 April 1994

with typical histological features of CMV colitis, have been noted infrequently2'7 and was present in one of our patients. The distribution of the lesions at endoscopy were of interest. The rectum appeared macroscopically normal in four of the 11 (28%), although CMV inclusions were found on mucosal biopsy tissue in one. These findings are consistent with those of Dieterich and Rahminl2 who suggested that flexible sigmoidoscopy would miss 39% of the diagnosis in CMV colitis. However, they contrast with an earlier study which detected rectosigmoid involvement in all of seven patients2. As in previously reported studies2'12, cells infected with CMV in endoscopically intact areas of mucosa were demonstrated. This suggests that in patients undergoing colonoscopic evaluation for suspected CMV colitis, multiple biopsies should be taken throughout the colon, even from areas which might appear normal. The response to treatment with Ganciclovir was unimpressive. Only three of seven (23%) reported significant improvement in diarrhoeal symptoms and two of three noted improvement in abdominal pain. This contrasts sharply with previously reported studies. In the largest series reported to date, significant improvement was noted in 23 of 31 (74%) patients with CMV colitis4. Unlike this study, ours was uncontrolled and would have failed to detect small changes in stool frequency not noted by the patient. Efficacy of Ganciclovir has also been noted in small uncontrolled series4'5. The clinical response to Foscarnet also appeared favourable. Symptoms resolved in two patients who had failed treatment with Ganciclovir. However, these results should be interpreted with caution since our study was uncontrolled and heavily reliant on

subjective impressions. CMV colitis in patient's with AIDS is frequently associated with non-bloody diarrhoea and abdominal pain. In patients undergoing colonoscopic evaluation for its diagnosis, multiple biopsies of typical lesions and also of apparently normal mucosa should be performed. Symptoms may be relieved by treatment with Ganciclovir. Foscarnet may be effective in patients who fail to respond to Ganciclovir.

Acknowledgments: We acknowledge the help of several members of the Department of Medicine who assisted in the care of these patients. We are especially grateful to the staff in the Divisions of Gastroenterology/Hepatology and Infectious Diseases.

References 1 Moore RD, Hidalgo J, Sugland BW, Chaisson RE. Zidovudine and the natural history of the acquired immunodeficiency syndrome. N Engl J Med 1991; 324:1412-16 2 Rene E, Marche C, Chevalier T, Rouzioux C, Regnier B, Saimct AG, et aL Cytomegalovirus colitis in patients with acquired immunodeficiency syndrome. DigDis Sci 1988;33: 741-50 3 Jacobson MA, Mills J. Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS). Clinical findings, diagnosis and treatment. Ann Intern Med 1988;108:585-94 4 Chachoua A, Dieterich D, Krasinski K, et aL 941,3dihydroxy-2-propoxymethyl)guanine (Ganciclovir) in the treatment of cytomegalovirus gastrointestinal disease with the acquired immunodeficiency syndrome. Ann Intern Med 1987;107:133-7 5 Collaborative DHPG Treatment Study Group. Treatment of serious cytomegalovirus infections with 9-(1,3-dihydroxy-2-propoxymethyl)guanine in patients with AIDS and other immunodeficiencies. NEngl JMed 1986;314:801-5 6 Laskin OL, Stahl-Bayliss CM, Kalman CM, Rosecan LR. Use of Ganciclovir to treat serious cytomegalovirus infections in patients with AIDS. J Infect Dis 1987;155:323-7 7 Meiselman MS, Cello JP. Cytomegalovirus colitis. Report of the clinical, endoscopic, and pathological findings in two patients with the acquired immune deficiency syndrome. Gastroenterology 1985;88:171-5 8 Lepinski SM, Hamilton JW. Isolated cytomegalovirus ileitis detected by colonoscopy. Gastroenterology 1990; 98:1704-6 9 Guttman D, Raymond A, Gelb A, Ehya H, Mather U, Mildvan D, et aL Virus-associated colitis in homosexual men: Two case reports. Am JGastroenterol 1983;78:167-9 10 Orloff JJ, Saito R, Lasky S, Dave H. Toxic megacolon in cytomegalovirus colitis. Am J Gastroenterol 1989; 84:794-7 11 O'Donnell JJ, Jacobson MA, Mills J. Development of cytomegalovirus (CMV) retinitis in a patient with AIDS during ganciclovir therapy for CMV colitis. N Engl J Med 1987;316:1607-8 12 Dieterich DT, Rahmin M. Cytomegalovirus colitis in AIDS: Presentation in 44 patients and a review of the literature. J Acquir Immune Defic Syndr 1991; 4(suppl 1):S29-S35 13 Foucar E, Mukai K, Foucar K, Sutherland DE, Van Buren CT. Colonic ulceration in lethal cytomegalovirus infection. Am J Clin Pathol 1981;76:788-801 14 Henson D. Cytomegalovirus inclusion bodies in the gastrointestinal tract. Arch Pathol 1972;93:477-82 15 Thuluvath PJ, Connolly GM, Forbes A, Gazzard BG. Abdominal pain in HIV infection. Q J Med 1991; 78:275-85

(Accepted 27 July 1993)

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