Digestive Diseases and Sciences, Vol. 36, No. 1 (January 1991), pp. 108-111

CASE REPORT

Primary Cytomegalovirus Infection and Gastric Ulcers in Normal Host

D A V I D O. A R N A R , MD, G U N N A R G U D M U N D S S O N , MD, A S G E I R T H E O D O R S , MD, G U N N A R V A L T Y S S O N , MD, A S B J O R N S I G F U S S O N , MD, and J O N G. J O N A S S O N , MD

KEY WORDS: gastric ulcers; cytomegalovirus; primary infection; normal host.

Cytomegalovi rus (CMV) infection is c o m m o n and has been associated with a spec t rum of clinical manifestat ions. In a normal host the infection is usually a symptomat i c but can cause a mononucle - osis-like syndrome, occasional ly with involvement of m a n y organs (1). About 50% of the adult popu- lation has antibodies against C M V (2).

In immunoco m prom i s ed individuals it can cause severe infections, as can be seen in AIDS pat ients and allograft recipients. These infections c o m m o n l y affect the lungs, liver, and central nervous sy s t em and can cause ulcerat ions anywhere in the gastro- intestinal tract, but mos t commonly in the s tomach and colon (2-5).

Only a few cases of CMV inclusions in ulcers of the gastrointestinal t ract in normal hosts have been repor ted (6-16). We repor t a case where CMV inclusions were found in biopsies f rom gastr ic ul- cers in a patient wi th no detectable immunological abnormali t ies .

CASE REPORT

A 42-year-old white female was admitted on New Year's Eve 1988. She had a six-day history of epigastric pain radiating to the back and progressive vomiting. She denied hematemesis or coffee-ground-like vomit, and there had been no melena or hematochezia. She had been afebrile and did not have a sore throat and had not noticed any lymphadenopathy. Her previous medical history was negative, especially no prior history of gastrointestinal

Manuscript received April 10, 1990; revised manuscript re- ceived August 30, 1990; accepted August 30, 1990.

From the Department of Medicine, St. Josephs Hospital, Hafnarfjordur, Iceland; Department of Immunology, National University Hospital, Reykjavik, Iceland; Department of Pathol- ogy, University of Iceland, Reykjavik, Iceland; and Department of Pathology, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts.

Address for reprint requests: Dr. Asgeir Theodors, Depart- ment of Medicine, St. Josephs Hospital, Sudurgata 41, 220 Hafnarfjordur, Iceland.

disease. She had given birth to a healthy child 10 months earlier. She had never received a blood transfusion. She was a cigarette smoker. There was no history of recent alcohol ingestion or intake of medications that could contribute to upper gastrointestinal tract symptoms.

On admission she was afebrile. There was no lymphad- enopathy or skin rash. Ophthalmoscopy was normal. There was direct tenderness in the epigastrium on palpa- tion but no hepatomegaly or splenomegaly. Rectal exam- ination was normal.

Laboratory data revealed hemoglobin 155 g/liter (nor- mal 117-155 g/liter) and hematocrit 0.470. The white cell count was slightly elevated 7.5 • 109 (normal 3.5-7.4 x 109) and the differential showed 66% lymphocytes (nor- mal 20-45%), some of them atypical. Electrolytes, creat- inine, amylase, alkaline phosphatase, and total bilirubin were normal, but alanine aminotransferase (ALAT), 40 IU/liter (normal less than 31), was slightly elevated. Gastrin also was elevated, 231 pg/ml (normal 0-80 pg/ml). Protein electrophoresis, an electrocardiogram, and a chest x-ray were normal.

Upper gastrointestinal endoscopy revealed three ulcers in the stomach, two on the angulus in the posterior part of the stomach and one in the prepyloric area. Multiple endoscopic biopsies were obtained from the margins of the ulcers. Histologic examination (hematoxylin and eo- sin stain) confirmed ulcerations with marked acute and chronic inflammation. Numerous glandular epithelial cells in the gastric mucosa and occasional cells in the lamina propria, apparently capillary endothelial cells, revealed characteristic CMV intranuclear inclusions (Fig- ure 1).

Immunological evaluations revealed serum IgM of 1.2 g/liter, IgG 9.94 g/liter, and IgA 3.25 g/liter. Lymphocyte count was 5.4 x 109/liter (normal 1.5-3.5 x 109) of which 68% were CD3 positive (normal 60-85%), 27% CD4 positive (normal 35-55%) and 39% CD8 positive (normal 20-35%). The CD4/CD8 ratio was 0.7 (normal >1). Serum complement C3 and C4 were normal, as was hemolytic complement activity (CH50). Skin test for delayed hyper- sensitivity with five antigens was positive for Proteus, Candida, and streptokinase, but negative for tuberculin and mumps. Peripheral blood lymphocyte ability to re- spond to phytohemagglutinin (PHA) and pokeweek mito-

108 Digestive Diseases and Sciences, VoL 36, No. 1 (January 1991) 0163-2116/91/0100-0108506.50/0 �9 1991 Plenum Publishing Corporation

CMV INFECTION AND ULCERS

Fig 1. Two cytomegalic cells are evident within gastric glands, containing characteristic CMV intranuclear inclusions. Hema- toxylin and eosin (x 1000).

gen (PWM) with proliferation was somewhat low but present.

No antibodies to the human immunodeficiency virus (HIV) were detected by ELISA (Wellcome) or Western blot. Both IgG and IgM antibodies to CMV were de- tected, indicating a recent primary infection. This was confirmed by the absence of CMV antibodies in stored serum from her last pregnancy 17 months earlier. CMV culture from urine was negative.

Therapy was started with the H,-receptor antagonist ranitidine and parenteral fluids. Her symptoms ceased after the therapy was initiated, and she was discharged in a markedly improved condition on the seventh day of her hospital course.

A control endoscopy of the upper gastrointestinal tract four weeks after discharge showed that the ulcers had healed but random biopsies from the gastric mucosa showed CMV intranuclear inclusions in only a single glandular epithelial cell of the gastric mucosa. Therapy with ranitidine then was discontinued. Six months later another endoscopy was performed, which showed gastric erosions in the antrum but no ulcers and no CMV inclusions were found in random biopsies. The patient had been asymptomatic since discharge from the hospital seven months earlier. Immunological evaluation was re- peated at this point, revealing a normal lymphocyte number (1,8 x 109) with 70% CD3 positive cells and a CD4/CD8 ratio of 1.4. Proliferative response to PHA and PWM then was normal and HIV ELISA was negative. A repeated serum gastrin measurement was normal (74 pg/ml).

DISCUSSION

Although CMV infections in the gastrointestinal tract of immunocompromised individuals have been reported with increasing f requency in recent years (4, 5, 17-19), there have been only a few reports of CMV infections in the gastrointestinal tract of nor- mal hosts (6-16).

In these reports CMV inclusions have been found almost anywhere in the gastrointestinal tract. They most often occur in association with mucosal le- sions but can occur in normal mucosa also (9).

Many of these reports did not include a thorough immunological evaluation of the patients reported. In the reports published prior to the recognition of HIV infection, it is possible that some of these patients may have been infected by the human immunodeficiency virus. CMV can be transmitted with blood transfusions (1). Some of the patients in these reports had received blood transfusions prior to the diagnosis of CMV infection. Our patient had been previously healthy, never received a blood transfusion, and had not been taking steroids or immunosuppressive drugs. She was not in an AIDS risk group, and testing for HIV antibodies was negative. Immunological evaluation confirmed a normal immune system. On admission the CD4/ CD8 ratio was decreased, but this is seen frequently during active CMV infection (20). Seven months later the CD4/CD8 ratio had returned to normal, so the decreased ratio observed during her illness was thought to be due to active virus infection.

The patient had a recent primary CMV infection as indicated by IgM antibodies to CMV and atypical lymphocytes in a peripheral blood smear. It was possible to obtain stored serum from her last preg- nancy 17 months prior to her illness, and no CMV antibodies were present.

CMV infections in immunocompromised patients can be very difficult to treat (2). The fact that the ulcers and the CMV inclusions resolved without specific antiviral t reatment gives further support to our belief that the immune system in our patient is normal.

We are aware of only two cases of documented seroconversion in patients with CMV infections of the gastrointestinal tract. One of these cases was a trauma victim who developed acute erosive esoph- agitis with CMV inclusions after multiple blood transfusions and a splenectomy (15). The other case was a heterosexual man with proctitis (14). He had been receiving a steroid-containing rectal foam for a few weeks preceding the CMV infection. Since local steroids can be absorbed from inflamed and ulcerated mucosa (21), it is possible that this steroid treatment could have caused some degree of immu- nosuppression.

The relationship of symptomatic ulcer disease to the finding of CMV inclusions in mucosal biopsies of ulcers is not clear. It is unknown whether CMV

Digestive Diseases and Sciences, VoL 36, No. 1 (January 1991) 109

ARNAR ET AL

is a primary cause of gastrointestinal lesions or whether CMV colonizes preexisting lesions. Vogel (22) inoculated mice with CMV and found that the virus produced intranuclear inclusions in areas of proliferating endothelial cells but was absent in nonproliferating endothelium. Goodman et al (17) reviewed 13 cases of colonic perforation associated with CMV in immunocompromised patients. Their conclusion was that it was likely that mucosal injury due to another cause may be followed by CMV infection of the granulation tissue, which then may lead to further injury and perforation. Villar et al (15) suggested that CMV, although uncommon, plays an important role in the pathogenesis of localized gastrointestinal disease. It is our belief that CMV may have a role in the pathogenesis of acute gastrointestinal ulcers.

We emphasize the usefulness of endoscopic biop- sies in detecting CMV inclusions in the gastrointes- tinal mucosa (23). Biopsies showed typical CMV inclusion bodies, seen on standard examination with hematoxylin and eosin staining. The demon- stration of CMV in biopsies with modern immunos- taining, in situ hybridization, and polymerase chain reaction techniques could increase the finding of CMV in biopsies (24-26). This could help to define the role of CMV in gastrointestinal disease.

In summary it seems that CMV infection is un- common in the gastrointestinal tract of the normal host. If CMV inclusions are seen in endoscopic biopsies, they should raise suspicion that the pa- tient is immunocompromised. However, as this case indicates, CMV inclusions can be found in acute ulcers of the gastrointestinal mucosa in a normal host and possibly have a role in the patho- genesis of these tilcers.

SUMMARY

A 42-year-old woman presented with epigastric pain and vomiting. Upper gastrointestinal endos- copy revealed three gastric ulcers. Histologic exam- ination of biopsies from the ulcers showed cytome- galovirus inclusion bodies. The appearance of IgM antibodies to cytomegalovirus indicated a recent and primary infection. Stored serum from her last pregnancy 17 months previously contained no cy- tomegalovirus antibodies. A thorough evaluation of her immune system revealed no abnormality. We are aware of only two other cases where serocon- version was documented in normal hosts. Cytome- galovirus infections in the gastrointestinal tract of

normal hosts are very unusual but a common cause of morbidity in immunocompromised hosts. We believe that cytomegalovirus may have a role in the pathogenesis of gastrointestinal lesions in nonim- munocompromised patients.

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