What is the diagnostic approach for Cytomegalovirus (CMV) colitis?

How to Diagnose CMV Colitis

Diagnose CMV colitis using colonoscopy with multiple biopsies analyzed by immunohistochemistry (IHC), which is the gold standard with 78-93% sensitivity, supplemented by tissue PCR when IHC is negative but clinical suspicion remains high. 1

When to Suspect CMV Colitis

High-Risk Clinical Scenarios

• Steroid-refractory inflammatory bowel disease (IBD), particularly ulcerative colitis with acute severe flares (OR: 4.24 for CMV disease) 1
• Patients on multiple immunosuppressants: azathioprine/methotrexate (OR: 1.95), anti-TNF therapy (OR: 11.13), or combination therapy 1
• HIV-infected patients with CD4+ counts <100 cells/µL presenting with diarrhea 1
• Solid organ or hematopoietic stem cell transplant recipients on immunosuppression 2
• Age >30 years in IBD patients with active disease 1

Key Clinical Features

• Diarrhea (often bloody), abdominal pain, fever, and weight loss in immunocompromised hosts 2
• Note: Classical CMV viremia symptoms (pharyngitis, lymphadenopathy, splenomegaly) are typically absent in CMV colitis 2

Diagnostic Testing Algorithm

Step 1: Endoscopic Evaluation with Tissue Sampling

Perform colonoscopy with extensive biopsy sampling as the cornerstone of diagnosis 1:

• Biopsy location matters: Target ulcer bases and edges where CMV-positive cells are most concentrated 1
• Minimum biopsy numbers:
  • Ulcerative colitis: at least 11 biopsies (primarily left colon) 1
  • Crohn's disease: at least 16 biopsies (include right colon) 1
• Endoscopic findings: Large, shallow, well-defined "punched-out" ulcerations (present in up to 80% of cases) 1, 2

Step 2: Tissue-Based Testing (Gold Standard)

Immunohistochemistry (IHC) is the primary diagnostic test 1:

• Sensitivity: 78-93%, Specificity: 98.7% 1
• Detects CMV-specific antigens in tissue
• Critical limitation: Standard H&E staining alone has only 12.5% sensitivity and misses most cases 1

Tissue PCR (tPCR) as adjunct 1:

• Use when IHC is negative but clinical suspicion remains high
• Suggested cutoff: >250 viral copies/mg tissue 1
• Important caveat: Positive tPCR without histological inflammation has unclear clinical significance and may not require treatment 1

Step 3: Blood-Based Testing (Supportive, Not Diagnostic)

Blood PCR or pp65 antigenemia have limited utility 1:

• Blood PCR sensitivity: only 60% (specificity: 100%) 1
• pp65 antigenemia sensitivity: only 39.7% (specificity: 90.7%) 1
• Suggested serum PCR cutoff: >250 copies/mL 1
• Use blood tests to support tissue diagnosis, not as standalone diagnostic tools 1

Step 4: Tests to Avoid

Do NOT rely on 1, 2:

• CMV serology (IgG/IgM): No diagnostic value, as 70% of adults are CMV-seropositive 2
• Viral culture alone: Insufficient without histopathologic changes, as viremic patients may have positive cultures without disease 1
• Negative IgG: Only useful to exclude CMV as the cause 1

Diagnostic Interpretation Framework

Definitive CMV Colitis (Requires Treatment)

• Mucosal ulcerations on endoscopy PLUS 1
• Characteristic intranuclear and intracytoplasmic "owl's eye" inclusions on histology OR 1
• Positive IHC showing CMV-infected cells 1

CMV Reactivation Without Disease (Usually No Treatment)

• Positive tissue PCR alone without histological inflammation 1
• Positive blood PCR without tissue confirmation 1
• These patients often do not benefit from antivirals 3

Special Populations

IBD Patients with Acute Severe Colitis

• Screen all patients with steroid-refractory acute severe UC for CMV 1
• CMV colitis increases colectomy risk and mortality in this population 1
• Consider rapid steroid tapering if CMV confirmed 1

HIV-Infected Patients

• Diagnosis requires compatible clinical syndrome plus CMV in tissue 1
• Periventricular enhancement on CT/MRI suggests CMV encephalitis, not colitis 1

Common Diagnostic Pitfalls

• Relying on H&E staining alone: Misses 87.5% of cases compared to IHC 1
• Treating positive PCR without histological disease: May lead to unnecessary antiviral therapy 1, 3
• Using blood tests as primary diagnostic tool: Sensitivity too low (39-60%) to rule out disease 1
• Inadequate biopsy sampling: Taking too few biopsies or from wrong locations reduces diagnostic yield 1
• Delaying diagnosis in critically ill patients: High mortality risk necessitates rapid endoscopic evaluation when feasible 4

Emerging Diagnostic Tools

Stool CMV PCR shows promise as a screening tool 5:

• Negative predictive value: 94.3% (can help exclude CMV disease) 5
• Positive predictive value: only 44.4% (requires tissue confirmation) 5
• Not yet standard of care but may reduce need for invasive testing in the future 4, 5