What causes pseudomembranous colitis other than Clostridioides (C.) difficile?

Causes of Pseudomembranous Colitis Other Than C. difficile

While Clostridioides difficile is the predominant cause of pseudomembranous colitis, several other etiologies can produce similar pseudomembranous changes in the colon, including ischemia, cytomegalovirus infection, and other infectious agents. 1, 2, 3

Non-C. difficile Causes of Pseudomembranous Colitis

Infectious Causes

• Cytomegalovirus (CMV): Particularly in immunocompromised patients 1
• Other bacterial pathogens: Various bacterial infections can mimic pseudomembranous colitis 4
• Parasitic infections: Can cause similar inflammatory patterns 4
• Viral infections: Beyond CMV, other viruses may cause pseudomembrane formation 4

Non-Infectious Causes

• Ischemic colitis: A significant cause that is often overlooked 2
• Inflammatory bowel disease: Can present with pseudomembranous changes 3
• Behçet's disease: May produce pseudomembranes 3
• Collagenous colitis: Can mimic pseudomembranous appearance 3
• Medications and toxins: Various drugs beyond antibiotics can cause pseudomembranous changes 3, 4
• Chemical injury: Direct toxicity to colonic mucosa 2, 3

Diagnostic Approach for Non-C. difficile Pseudomembranous Colitis

When C. difficile tests are negative but pseudomembranes are present, consider:

1. Endoscopic evaluation: Essential for visualizing pseudomembranes and obtaining biopsies 1
2. Histopathology: Critical for differentiating between causes 3
3. Imaging: CT findings may include colonic wall thickening, dilation, pericolonic stranding, and "accordion sign" 5
4. Vascular assessment: For patients with risk factors for ischemia 2
5. Viral studies: PCR or immunohistochemistry for CMV in immunocompromised patients 1

Clinical Pearls

• Pseudomembranous colitis in neutropenic patients may not show typical pseudomembranes despite active infection due to lack of neutrophils needed for membrane formation 1
• Persistent symptoms despite negative C. difficile testing and appropriate empiric treatment should prompt investigation for alternative etiologies 3
• Ischemic colitis can be easily misdiagnosed as C. difficile infection when pseudomembranes are present 2
• Early gastroenterology consultation and lower endoscopy with biopsies are recommended when standard C. difficile treatment fails 3

Common Pitfalls

• Assuming all pseudomembranous colitis is caused by C. difficile
• Failing to consider vascular disease in patients with risk factors
• Not obtaining biopsies during endoscopy when pseudomembranes are visualized
• Missing CMV infection in immunocompromised patients
• Continuing ineffective antimicrobial therapy without investigating alternative diagnoses

Remember that while C. difficile remains the most common cause of pseudomembranous colitis, maintaining a broad differential diagnosis is essential when patients fail to respond to standard therapy or have negative C. difficile testing.