In a mini review published in Frontiers in Cellular and Infection Microbiology, researchers Mohammed Adnan Khan, Rima Taifour, and Samer Al-Dury evaluate the diagnostic dilemmas surrounding cytomegalovirus detection in adults hospitalized with severe colitis. The authors propose a pragmatic, unvalidated clinical testing framework designed to assist clinicians in navigating diagnostic pitfalls and distinguishing clinically significant tissue-invasive cytomegalovirus disease from incidental, low-level viral reactivation. Cytomegalovirus represents a recognized complication of severe colitis, appearing most prominently among individuals with ulcerative colitis, corticosteroid-refractory inflammation, or intensive therapeutic immunosuppression. However, the authors note that clinically meaningful viral involvement also arises in patients who lack conventional immunosuppressive risk factors. Because macroscopic endoscopic appearances and clinical symptoms in cytomegalovirus colitis heavily overlap with severe idiopathic ulcerative colitis, standard bedside assessment cannot reliably determine viral causation. Consequently, the review examines the specific roles, technical capabilities, and diagnostic limitations of hematoxylin and eosin histology, tissue immunohistochemistry, quantitative tissue polymerase chain reaction, and peripheral blood molecular assays during acute patient presentations.

Following primary human infection, cytomegalovirus establishes lifelong mucosal latency that is typically constrained by host cell-mediated immune responses. In the setting of severe colitis, the biological relationship between active mucosal inflammation and viral reactivation is recognized as fundamentally bidirectional. Severe colonic inflammation creates a microenvironment that facilitates local viral reactivation, while active tissue-invasive cytomegalovirus can perpetuate mucosal damage, drive relentless tissue inflammation, and induce resistance to standard immunosuppressive treatments. Beyond recognized pharmacological risk factors such as corticosteroid exposure and biologic or immunosuppressive therapy, older age and significant medical comorbidities are documented features in clinical cohorts presenting with cytomegalovirus colitis. Nevertheless, the authors emphasize that simple viral deoxyribonucleic acid detection within inflamed tissue does not automatically prove tissue-invasive disease. Latent virus frequently reactivates at low levels in severely inflamed bowel tissue without causing true cytomegalovirus-mediated organ damage or cellular infection. Establishing a definitive diagnosis of cytomegalovirus colitis requires demonstrable tissue and clinical evidence rather than uncritical reliance on viral presence alone.

Although documented in adults without recognized immunosuppression, the broader population prevalence of tissue-invasive cytomegalovirus colitis remains completely unknown. The review examines retrospective data, including an observational case-control investigation by Ko and colleagues that identified fifty-one non-immunosuppressed patients with cytomegalovirus colitis. In that specific cohort, recent corticosteroid therapy and red blood cell transfusion emerged as independent risk factors, with the cohort experiencing a thirty-day mortality rate of 7.8 percent. Another retrospective study evaluated fifty-six immunocompetent patients diagnosed with gastrointestinal cytomegalovirus disease, finding that these patients were significantly older and more frequently critically ill than immunocompromised individuals, resulting in a six-month mortality rate of 39 percent. The review highlights that this elevated mortality was probable reflection of underlying medical comorbidity and acute illness severity rather than isolated viral infection. Because published evidence stems from highly selected, hospital-based inpatient populations, the authors argue that these observational data cannot justify universal screening or routine cytomegalovirus testing for all immunocompetent patients admitted with acute colitis flares.

To clarify diagnostic accuracy, the review synthesizes findings from a 2026 systematic review and meta-analysis of twenty-three studies encompassing patients with inflammatory bowel disease hospitalized with acute colitis. According to these meta-analytic estimates, quantitative tissue polymerase chain reaction achieved a pooled sensitivity of 95 percent but a limited pooled specificity of only 66 percent. Peripheral blood polymerase chain reaction exhibited a substantially lower sensitivity of 61 percent, accompanied by a higher specificity of 91 percent. Routine hematoxylin and eosin histology demonstrated high specificity at 99 percent through visible viral inclusions, but its clinical utility was constrained by a low pooled sensitivity of 44 percent. While immunohistochemistry allows direct identification of infected mucosal cells without a pooled meta-analytic estimate, its diagnostic yield depends directly on biopsy sampling adequacy and tissue cell burden. Given that blood testing frequently yields negative results in localized colonic infection and tissue molecular assays risk detecting clinically incidental viral material, diagnostic testing requires nuanced multimodal interpretation.

Current professional clinical guidelines diverge regarding the exact thresholds and timing for initiating cytomegalovirus diagnostic investigations in severe colitis. The 2025 British Society of Gastroenterology guidelines recommend sending colonic tissue biopsies for cytomegalovirus immunohistochemistry or polymerase chain reaction in all patients hospitalized with an inflammatory bowel disease flare, as well as selected refractory outpatients, irrespective of ongoing immunosuppressive therapy. Conversely, the 2026 European Crohn’s and Colitis Organisation infection guidelines focus recommendations primarily on immunosuppressed patients experiencing acute severe ulcerative colitis or refractory disease, citing the strongest supportive evidence among patients failing three to five days of intravenous corticosteroids. Neither professional guideline establishes a validated tissue viral-load threshold for initiating antiviral therapy, nor do they define standardized protocols for evaluating severe de novo colitis presenting in previously healthy individuals. Furthermore, general population cytomegalovirus seroprevalence alone does not constitute an appropriate or established indication for performing invasive colonic tissue testing during acute colitis flare assessments.

Substantial clinical variation persists because published studies employ heterogeneous methodologies, differing biopsy protocols, varied assay platforms, and inconsistent operational definitions of clinically significant infection. Existing literature contains divergent viral-load thresholds that correlate with distinct clinical endpoints rather than validated treatment responses. For instance, research by Roblin and colleagues observed that tissue viral loads exceeding 250 copies per milligram of tissue predicted resistance to successive ulcerative colitis therapies. Conversely, work by Jain and colleagues identified a much higher threshold of 2,000 copies per milligram of tissue as predictive of intravenous steroid failure and short-term colectomy. In another study, Yamakawa and colleagues used a threshold of 1,300 copies per microgram of extracted deoxyribonucleic acid to forecast antigenemia rather than therapeutic antiviral efficacy. Because assay platforms, tissue cellularity, and extraction protocols vary, these units cannot be mathematically converted between laboratories, leaving tissue viral loads incapable of independently selecting which patients will benefit from antiviral administration.

To resolve these diagnostic challenges, the authors outline an unvalidated, five-step testing framework tailored for adults hospitalized with severe colitis meeting established Truelove and Witts criteria or exhibiting equivalent systemic toxicity. The proposed framework encompasses patients presenting with de novo severe colitis as well as individuals with established ulcerative colitis experiencing severe acute flares, while excluding mild outpatient flares and isolated proctitis. Step 1 mandates comprehensive baseline blood investigations, stool microbiological testing to exclude enteric pathogens such as Clostridioides difficile, and early flexible sigmoidoscopy. Because cytomegalovirus exhibits a patchy mucosal distribution, multiple mucosal biopsies should be targeted specifically at ulcer bases and margins when safely accessible. The authors cite retrospective data indicating that eleven biopsies provided an estimated 80 percent probability of detecting at least one positive sample in ulcerative colitis, while noting this remains a study-specific yield estimate rather than a mandatory requirement for every clinical procedure.

Step 2 implements guideline-supported tissue testing, prioritizing routine histology and immunohistochemistry alongside quantitative tissue polymerase chain reaction as an adjunct, with blood testing reserved for severe systemic toxicity. Step 3 introduces individualized clinical considerations for testing patients outside standard guideline indications, particularly de novo severe colitis without known immunosuppression. Suspicion should increase when patients exhibit deep or extensive ulcerations, marked hypoalbuminemia, an unusually deteriorating trajectory despite initial care, or severe colitis persisting after successful treatment for an enteric infection such as Clostridioides difficile. Step 4 governs clinical management and therapeutic decision-making based on integrated pathology. When histology or immunohistochemistry confirms cytomegalovirus-infected cells, clinicians should consider renal-adjusted intravenous ganciclovir with eventual oral valganciclovir step-down. Observational data indicate that cases with five or more histological inclusions demonstrate greater therapeutic benefit from antivirals, whereas isolated polymerase chain reaction positivity without infected cells may reflect low-level reactivation where continued inflammatory bowel disease therapy and observation remain reasonable.

The authors illustrate the clinical application of their framework through four hypothetical composite vignettes rather than individual case histories. Scenario A addresses de novo severe colitis presenting with deep ulceration without immunosuppression, highlighting that atypical severity justifies mucosal biopsy evaluation. Scenario B depicts severe ulcerative colitis persisting after treated enteric infection, emphasizing that absent immunosuppression does not preclude clinically important viral disease. Scenario C illustrates steroid-refractory colitis during early biologic induction, where cytomegalovirus must be investigated as a driver of therapeutic failure. Scenario D highlights severe endoscopic ulceration mimicking viral colitis but demonstrating entirely negative histology and immunohistochemistry, confirming that endoscopy cannot confirm viral causation and that guideline-based ulcerative colitis therapy should proceed. For patients whose illness remains refractory or atypical despite negative initial tests, Step 5 outlines systematic re-evaluation. Clinicians should reconsider alternative etiologies, including intestinal ischemia, drug-induced mucosal injury, or secondary enteric infections, while considering repeat endoscopy with targeted biopsies if suspicion for patchy cytomegalovirus remains high.

In their concluding synthesis, the authors acknowledge that their proposed testing framework remains entirely unvalidated in prospective clinical trials. Current medical literature is severely constrained by small patient cohorts, retrospective study designs, variable endoscopic biopsy protocols, platform-dependent molecular quantification units, and contradictory definitions of active cytomegalovirus disease. The authors emphasize that finding cytomegalovirus deoxyribonucleic acid in inflamed mucosa does not establish causality or justify uncritical antiviral prescription, particularly when immunohistochemistry fails to detect infected cells. Conversely, delaying appropriate investigation in severely ill patients can lead to inappropriate escalation of immunosuppressive medications in the presence of unrecognized, tissue-invasive viral infection. Future prospective studies are urgently needed to determine whether integrating tissue histopathology, immunohistochemistry, quantitative viral burden, and clinical trajectory improves patient outcomes while curtailing unnecessary antiviral exposure. Until prospective validation establishes standardized, cross-laboratory molecular thresholds, clinical management of cytomegalovirus in severe colitis must continue to balance disease severity, therapeutic response, and rigorous mucosal histopathology.

Subject of Research: Diagnostic evaluation of cytomegalovirus involvement in adult severe colitis

Article Title: Cytomegalovirus in severe colitis: diagnostic pitfalls and a pragmatic testing framework

Article References: Khan, M. A., Taifour, R., & Al-Dury, S. (2026). Cytomegalovirus in severe colitis: diagnostic pitfalls and a pragmatic testing framework. Frontiers in Cellular and Infection Microbiology, 16, Article 1813808. https://doi.org/10.3389/fcimb.2026.1813808

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1813808

Keywords: Cytomegalovirus, Severe colitis, Ulcerative colitis, Immunohistochemistry, Tissue PCR, Diagnostic accuracy, Gastrointestinal infection, Inflammatory bowel disease, severe, colitis, diagnostic, pitfalls