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

Cytomegalovirus (CMV) is an important complication of severe colitis, particularly in patients with ulcerative colitis (UC), corticosteroid-refractory disease, and significant immunosuppression. However, clinically relevant CMV involvement may also occur in patients without conventional immunosuppressive risk factors, whilst CMV may be detected as secondary or low-level reactivation in severely inflamed mucosa. Distinguishing clinically significant CMV-associated disease from incidental viral detection remains a diagnostic challenge. Clinical and endoscopic features are insufficiently specific, and interpretation is complicated by differences in the sensitivity, specificity, and clinical meaning of diagnostic tests. This Mini Review examines the roles and limitations of histology, immunohistochemistry (IHC), tissue polymerase chain reaction (PCR), and blood CMV PCR in adults presenting with severe colitis. Attention is given to mucosal sampling, the patchy distribution of CMV, the limited sensitivity of blood-based testing for isolated colonic disease, and the uncertain significance of low-level tissue CMV DNA detected by highly sensitive molecular techniques. We propose a pragmatic testing framework in which immune status informs, but does not alone determine, the threshold for CMV investigation. Disease severity, clinical trajectory, response to initial therapy, and compatible endoscopic features should guide the decision to obtain tissue-based testing. IHC remains central to identifying infected mucosal cells, whilst tissue PCR should be interpreted alongside histopathology, viral burden, and clinical context rather than used alone to establish disease. A severity- and trajectory-guided approach may improve recognition of clinically significant CMV involvement whilst reducing both inappropriate escalation of immunosuppression in unrecognised CMV disease and unnecessary antiviral treatment of low-level viral reactivation.