Diverticular perforation with exclusive local invasion in cytomegalovirus infection during ganciclovir treatment: an autopsy case report

Abstract

Introduction and importance:

Cytomegalovirus (CMV) can cause severe colitis in immunocompromised patients. While its morphological manifestations vary, diverticular perforation is rare, with most lesions remaining intact. We report a rare case of CMV-related diverticular perforation in an elderly woman undergoing ganciclovir treatment. Despite intensive care, she died during hospitalization. Autopsy findings showed a congested small intestine without significant erosion or ulceration.

Clinical presentation:

An 83-year-old woman with prolonged methotrexate and steroid use for rheumatoid arthritis was referred to our hospital due to hypotension, hypoxemia, and altered mental status following bloody stools. Endoscopy revealed a rectal hemorrhage. After hemostasis, the patient developed septic shock and diarrhea, raising suspicion of CMV colitis, which was confirmed by CMV antigenemia. Despite treatment with ganciclovir, the patient developed a diverticular perforation. Histological examination of the surgical specimen revealed localized infiltration of CMV-infected cells in the granulation tissue at the perforation site, without other inflammatory changes. The patient died from liver failure on the 28th day of hospitalization.

Clinical discussion:

CMV colitis is reported in patients with autoimmune diseases and, in severe cases, can lead to gastrointestinal perforation. In this case, CMV infection caused diverticular perforation; however, autopsy revealed no significant inflammatory changes throughout the gastrointestinal tract. This suggests a highly localized CMV invasion, a rare clinical presentation.

Conclusion:

Ganciclovir failed to prevent focal bowel perforation, although it may have eradicated CMV within rectal ulcer lesions. Clinicians should be aware that CMV infection can present as diverticular perforation due to localized invasion, even during antiviral therapy.

Introduction

Infections are a major cause of life-threatening complications in immunocompromised patients. Cytomegalovirus (CMV) infection is common in the general population, with a reported prevalence ranging from 40 to 100%. While typically benign in immunocompetent individuals^[1], CMV, like other herpesviruses, establishes lifelong latency in hematopoietic progenitor cells following acute infection. In immunocompromised individuals, CMV reactivation can lead to severe complications, including organ dysfunction and death, with significantly poorer outcomes^[2].

CMV colitis is frequently reported in patients with autoimmune diseases, as their treatment often involves immunosuppressive drugs that increase susceptibility to infection^[1]. The endoscopic features of CMV colitis vary widely; however, perforation confined to isolated diverticula is rare. We report a case of CMV-related diverticular perforation diagnosed via computed tomography, which revealed free air in the abdomen, and confirmed through exploratory surgery in an elderly woman receiving ganciclovir treatment for CMV infection.

Case report

An 83-year-old woman with rheumatoid arthritis and recent pulmonary embolism was referred to our hospital with hypotension, hypoxemia, and altered mental status following bloody stools. The patient had been admitted to another hospital for rehabilitation during the convalescent phase after pulmonary embolism treatment. Her medical history included 13 years of methotrexate (MTX) and tacrolimus therapy, which were discontinued 4 months prior due to acute liver injury caused by hepatitis B virus reactivation. Since then, she had been receiving 30 mg of methylprednisolone and tenofovir daily. Additionally, she had been on edoxaban for a pulmonary embolism diagnosed 3 months before referral. On arrival, her vital signs were: temperature 36.6°C, heart rate 91 beats per min, blood pressure 71/43 mmHg (on vasopressor support), respiratory rate 17/min, and SpO₂ 95% on a 10 L/min reservoir mask. Her Glasgow Coma Scale (GCS) score was 9 (E3V2M4). Physical examination revealed no abdominal pain or tenderness, but bloody stools were confirmed. Laboratory findings showed anemia (Hb 9.0 g/dL), coagulopathy (activated partial thromboplastin time 42.9 s, prothrombin time-international normalized ratio 1.29), and elevated inflammatory markers (white blood cell count 12,280/µL, C-reactive protein 2.98 mg/dL). Abdominal ultrasound showed no inferior vena cava collapse. Computed tomography (CT) revealed no contrast extravasation in the gastrointestinal tract or free air. The tentative diagnosis was shock due to gastrointestinal hemorrhage and/or infection of unknown etiology. Treatment with hydrocortisone, blood transfusion (4 units of packed red blood cells), and intravenous antibiotics (ceftazidime and vancomycin) was initiated for hypovolemic and septic shock. Although initial treatment temporarily stabilized her condition, ongoing massive bloody stools led to severe anemia. On hospitalization day 2, colonoscopy identified two oozing rectal ulcers, and hemostasis was successfully achieved. Only the rectum was evaluated due to clinical instability, and we could not completely rule out proximal perforation. Blood cultures taken at admission were positive for Enterobacter cloacae, prompting a switch to meropenem monotherapy on hospitalization day 4. Vasopressor support was discontinued, and the patient’s mental status improved (GCS 13, E3V4M6).

However, persistent watery diarrhea developed on hospitalization day 5. Clostridium difficile infection was deemed unlikely given the absence of toxins and antigens. A blood test for CMV antigenemia (C7-HRP) on day 5 detected four positive cells per 45,600. Ganciclovir (100 mg daily) was initiated on day 8 and continued until the patient’s death on day 28, for a total of 21 days. Subsequently, the patient developed a high fever (38.3 °C) and hyperbilirubinemia. Abdominal CT revealed bilateral pleural effusion and ascites without a clear inflammatory focus. On day 10, she experienced abdominal pain with distention. A repeat abdominal CT showed free air in the abdominal cavity, leading to a diagnosis of gastrointestinal perforation (Fig. 1). Emergency surgery revealed a solitary 5 mm defect in the rectosigmoid colon with massive contaminated ascites (Fig. 2a and b). A large-volume peritoneal lavage and end colostomy were performed. Macroscopically, the surgical specimen had a small depressed lesion but no other significant abnormalities (Fig. 3). Microscopic examination showed a diverticulum extending into the subserosa with focal perforation (Fig. 4a). Some cells in the granulation tissue contained nuclear inclusion bodies (Fig. 4b). Immunohistochemical staining confirmed the localized presence of CMV at the perforation site (Fig. 4c). Based on intraoperative and pathological findings, the patient was diagnosed with diverticulitis with perforation, likely due to CMV infection. Despite temporary improvement, her liver function deteriorated, and she succumbed on day 28.

HIGHLIGHTS

• CMV infection caused diverticular perforation despite ganciclovir treatment.

• Perforation occurred with minimal inflammation elsewhere in the gastrointestinal tract.

• CMV colitis can manifest as localized perforation, not just widespread mucosal damage.

• Endoscopy may not always predict CMV-related bowel perforation risk.

• Close monitoring is crucial for CMV patients on antiviral therapy to detect complications.

Figure 1.

Abdominal CT findings on hospital day 10. Axial CT image showing free air in the abdominal cavity (arrow) and massive ascites, consistent with gastrointestinal perforation.

Figure 2.

Intraoperative findings. (a) A solitary 5 mm defect in the rectosigmoid (RS) colon, marked with pyoctanin. (b) Massive contaminated ascites.

Figure 3.

Macroscopic findings of the surgical specimen. The arrow indicated a small depressed lesion, likely a diverticulum.

Figure 4.

Histological findings of the surgical specimen. (a) Hematoxylin and eosin staining of the surgical specimen revealed a diverticulum extending into the subserosa, with focal perforation. (b) Cytomegalovirus (CMV) inclusion (indicated by arrow) was identified within the granulation tissue. (c) Immunohistochemical staining for CMV antigen (arrows indicated CMV positive cells)

An autopsy revealed no significant abnormalities, including in the gastrointestinal tract. Two scarring lesions in the rectum exhibited focal inflammatory cell infiltration, but no evidence of CMV infection was found (Fig. 5a, b). CMV-infected cells were also absent in other organs, including the central nervous system, lungs, and liver.

Figure 5.

Autopsy analysis of the colorectal region. (a) Macroscopic findings: Two scarred lesions are highlighted by red circles. (b) Focal infiltrates of inflammatory cells were observed at the scarring site, and no cytomegalovirus-positive cells were detected. The observed tissue laceration was an artifact.

Discussion

In this case, focal CMV infection led to diverticular perforation despite ganciclovir treatment in an immunocompromised patient. Autopsy findings showed an intact gastrointestinal tract without significant inflammatory changes. While gastrointestinal imaging and colonoscopy are useful for assessing mucosal lesions, not all patients with CMV colitis-related perforation can undergo endoscopic evaluation. Additionally, assessing small intestine involvement remains particularly challenging. The autopsy further confirmed the absence of additional perforation sites throughout the gastrointestinal tract.

CMV gastrointestinal infections can cause perforations in immunocompromised patients^[3,4], with human immunodeficiency virus being the most common comorbidity^[5]. CMV colitis also occurs in patients with organ transplants, inflammatory bowel diseases (IBD), acquired immune deficiency syndrome, or autoimmune diseases, possibly due to immunosuppressive therapy.^[5-8] Immunocompromised patients with CMV infection often receive corticosteroids or immunosuppressants like cyclophosphamide, cyclosporine, MTX, and/or azathioprine^[9]. This patient’s long-term MTX and tacrolimus use for rheumatoid arthritis likely predisposed her to CMV colitis. While CMV infections are common in rheumatic diseases, they are rare in rheumatoid arthritis^[9].

Morphologically, CMV infection presents endoscopically as wide mucosal defects, punched-out ulcers, longitudinal or irregular ulcers, and a cobblestone-like appearance^[10]. CMV primarily infects the gastrointestinal interstitial space, causing vasculitis and constrictive ulcers^[11,12]. In patients with IBD, CMV-infected cells may appear in multiple ulcers but do not always cause significant pathology^[13,14]. In the present case, CMV likely induced inflammation, leading to diverticular perforation. Fisher et al^[5] reported that colorectum was involved in 58% of perforated CMV enterocolitis cases, though CMV’s mucosal localization was often unknown, except at the perforation site. Perforated CMV colitis without an apparent local cause is exceedingly rare^[15]. We hypothesized that CMV caused the rectal ulcer bleeding; however, no evidence of CMV invasion was found at autopsy, suggesting transient infection or clearance by ganciclovir. Earlier endoscopy might not have detected severe CMV enteritis or predicted diverticular perforation. In our case, at the time of colonoscopy, the patient did not report any abdominal pain, and the initial abdominal CT scan showed no evidence of free air. In retrospect, we speculate that the perforation site, identified in the rectosigmoid colon, had already been visualized during the initial colonoscopy. At that time, there were no endoscopic signs of perforation, and the mucosa appeared intact. Therefore, it is reasonable to assume that gastrointestinal perforation had not yet occurred during this early phase. The autopsy confirmed an intact gastrointestinal tract with no inflammatory changes. While some reports link CMV infection to colorectal perforation^[16,17], no autopsy cases have demonstrated exclusive localized CMV invasion causing diverticular perforation.

Ganciclovir, a viral DNA polymerase inhibitor and guanine analog, is more effective than acyclovir against CMV and herpes simplex virus. It has shown remission rates of 67–100% in CMV colitis associated with IBD^[18,19]. Fisher et al^[5] reported that anti-CMV therapy improved survival in perforated CMV enterocolitis. However, in our case, ganciclovir did not prevent focal bowel perforation despite clearing CMV from rectal ulcers. This underscores the need for further studies on risk factors for enterocolonic perforation in CMV-infected patients and the role of endoscopy in predicting such complications.

This autopsy report demonstrates that CMV infection can induce diverticular perforation despite ganciclovir treatment, even when other gastrointestinal regions show minimal inflammation. These findings underscore the need for close monitoring of patients receiving antiviral therapy, as gastrointestinal perforation may still occur.

The work has been reported in line with the Revised SCARE 2025 criteria^[20].

Conclusion

We presented a rare case of diverticular perforation due to localized CMV invasion during ganciclovir therapy. While ganciclovir likely eliminated CMV from rectal ulcers, it did not prevent focal bowel perforation. Unlike typical CMV enterocolitis, which involves widespread mucosal damage, this case exhibited a distinct localized presentation. Clinicians should remain vigilant for the potential of CMV-induced diverticular perforation, even during antiviral treatment.

Ethical approval

Ethics approval or consent to participate was not applicable.

Consent

Verbal and written consent for publication was obtained from patient’s next of kin.

Source of funding

None.

Author contributions

Y.I. and A.K. took care of the patient, wrote the draft, and critically revised the manuscript. S.I. advised on pathological consideration and critically revised the manuscript. All authors read and approved the final manuscript.

Conflicts of interest disclosure

None.

Guarantor

The guarantor is Yoshitaka Ishiguro.

Research registration unique identifying number (UIN)

This case report is not applicable for registration.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.