Pseudomembranous colitis: Not always Clostridium difficile

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Colon ischemia usually affects elderly or debilitated patients who have multiple comorbidities. Known risk factors include aortoiliac surgery, cardiovascular disease, diabetes mellitus, hemodialysis, and pulmonary disease. The ischemia can be related to an occlusive arterial or venous thromboembolism, but hypoperfusion without occlusion of the mesenteric or internal iliac arteries is the primary mechanism. Low blood flow states such as atherosclerosis and septic shock can affect the watershed areas, typically the splenic flexure and rectosigmoid junction.

We reported a case of a patient with vascular disease who was incorrectly diagnosed and treated as having refractory C difficile infection when pseudomembranes were seen on flexible sigmoidoscopy. Further investigation revealed ischemic colitis secondary to a high-grade inferior mesenteric artery stenosis as the true cause.29

Microvascular thrombosis is the likely mechanism in a number of non-C difficile causes of pseudomembranous colitis. For example, in most patients with enterohemorrhagic E coli O157:H7 infection, histologic review of colonic mucosal biopsies has revealed fibrin and platelet thrombi in the capillaries, suggesting microvascular thrombosis.15,30

Cocaine has been associated with pseudomembranes in the setting of ischemia in the cecum and ascending colon. Cocaine can cause vasoconstriction after stimulation of alpha-adrenergic receptors and hence intestinal ischemia, thrombosis of vessels in the large and small intestines, and direct toxic effects.31

Inflammatory conditions

Collagenous colitis is an inflammatory disease that often affects middle-aged women and presents with copious watery diarrhea. It is a type of microscopic colitis—the endoscopic appearance is often normal, while the histologic appearance is abnormal and characterized by collagen deposition in the lamina propria. Medications that have been implicated in microscopic colitis include acid-suppressive agents (eg, histamine receptor antagonists, proton pump inhibitors) and nonsteroidal anti-inflammatory drugs.

An increasing number of cases of pseudomembranous changes are being reported in patients diagnosed with collagenous colitis.32–36 Although the pathophysiologic mechanism is unknown, some authors have suggested that pseudomembrane formation is actually part of the presenting spectrum of collagenous colitis.36

Inflammatory bowel disease. Crohn disease and ulcerative colitis have been associated with pseudomembranous colitis. Pseudomembranes can be found on endoscopy in patients with inflammatory bowel disease during a disease exacerbation with or without C difficile.37,38 In patients with inflammatory bowel disease and C difficile infection, pseudomembranes can be found endoscopically in up to 13% of cases.39 Pseudomembranous colitis has been reported in a patient with ulcerative colitis exacerbation in association with cytomegalovirus colitis.40

Behçet disease is a rare, immune-mediated small-vessel systemic vasculitis. It usually presents with mucous membrane ulcerations and ocular disease but can affect any organ.41 Pseudomembranous colitis can occur in Behçet disease in the absence of C difficile infection or any infectious colitis. Treatment includes corticosteroids and immunosuppressants such as azathioprine and anti-tumor necrosis factor agents.41


The initial evaluation of a patient with suspected or confirmed pseudomembranous colitis should include a comprehensive medical history with information on recent hospitalizations or procedures, antibiotic use, infections, exposure to sick contacts, recent travel, and medications taken.

Testing for C difficile

As most patients with pseudomembranous colitis have C difficile infection, it should be excluded first. Empiric anti-C difficile treatment is recommended in seriously ill-appearing patients, ideally starting after a stool sample is obtained.

Diagnosis of C difficile infection requires laboratory demonstration of the toxin or detection of toxigenic organisms. The gold standard test is the cell culture cytotoxicity assay, but it is labor- and time-intensive.42 More widely available tests are polymerase chain reaction for the toxin gene or genes, enzyme immunoassay, and stool evaluation for glutamate dehydrogenase, which can yield results readily within hours.

Polymerase chain reaction has a sensitivity of 97% and a specificity of 93%. Results can be falsely positive if empiric treatment is started before specimen collection, in which case C difficile DNA may still be present and detectable, but not the organism itself.43

Enzyme immunoassay for toxins A and B carries a sensitivity of 75% and a specificity of 99%, but 100 to 1,000 pg of toxin must be present for a positive result.44,45

If the initial enzyme immunoassay or polymerase chain reaction result is negative, current guidelines do not recommend repeat testing, which has limited value.44,46 Repeat testing after a negative result is positive in less than 5% of samples and greatly increases the chances of false-positive results.44,46 Nevertheless, if a laboratory’s enzyme immunoassay test has a low sensitivity, repeating negative tests may improve its sensitivity.

Glutamate dehydrogenase is an enzyme produced by both toxigenic and nontoxigenic strains of C difficile. As a result, stool testing for glutamate dehydrogenase is sensitive but not specific for C difficile infection, although multistep testing sequences (glutamate dehydrogenase followed by polymerase chain reaction) have proven to be useful screening tools.44

Treatment for C difficile infection

If testing for C difficile is positive, treatment is generally based on the severity and the complications of the illness46:

  • Mild or moderate C difficile infection should be treated with oral metronidazole 500 mg three times per day for 10 to 14 days.
  • Severe infection, which is defined as a white blood cell count of 15.0 × 109/L or higher or a serum creatinine level greater than or equal to 1.5 times the premorbid level, should be treated with oral vancomycin 125 mg four times per day for 10 to 14 days.
  • Severe C difficile infection complicated by hypotension, shock, ileus, or megacolon should be treated with a combination of high-dose oral vancomycin (and possibly rectal vancomycin as well) at 500 mg four times per day plus intravenous metronidazole.

Additional treatment recommendations for individualized situations, recurrent C difficile infection, and comorbid conditions are discussed elsewhere.46


Colonoscopy or flexible sigmoidoscopy is the primary means by which pseudomembranous colitis is diagnosed. Lower endoscopy should be pursued as an adjunctive tool when C difficile infection remains strongly suspected despite negative testing, when presumed C difficile infection does not respond to medical therapy, and when non-C difficile diagnoses are considered. If pseudomembranes are demonstrated on lower endoscopy, obtaining biopsy samples of normal- and abnormal-appearing mucosa is recommended. Pseudomembranes are suggestive but not diagnostic of C difficile infection, and microscopic evaluation of the mucosa is warranted to explore causes of pseudomembranous colitis not related to C difficile.

The pattern and distribution of pseudomembranes may provide clues to the etiology and the degree of mucosal injury. In intestinal ischemia, for example, a localized segment of the bowel is typically involved, and mucosal changes are often well delineated from normal mucosa. On endoscopic examination, mild ischemia is characterized by granular mucosa with decreased vascularity, whereas friable, edematous, ulcerated, and at times necrotic mucosa is evident in severe cases. Punctate pseudomembrane formation is seen in early ischemia, but as injury progresses, the pseudomembranes may grow and merge. In fact, diffuse involvement of the mucosal surface of the biopsy specimen by pseudomembranes has been shown to be more closely associated with ischemic colitis than C difficile infection.47


Histologic study can differentiate the various causes of pseudomembranous colitis.

In C difficile infection and drug reaction, there is acute crypt injury and dilation. The upper lamina propria is usually involved, and affected crypts are filled with an exudate similar to that found in pseudomembranes.1 However, in drug reaction, there is also prominent apoptosis and increased intraepithelial lymphocytosis.9

In colon ischemia, hyalinization of the lamina propria is a sensitive and specific marker.47 This has been shown in a study comparing histologic characteristics of colonic biopsies in patients with pseudomembranous colitis due to either known colon ischemia or C difficile infection.47 Crypt atrophy, lamina propria hemorrhage, full-thickness mucosal necrosis, and layering of pseudomembranes would further favor the diagnosis.

In collagenous colitis, a thickened subepithelial collagen band and intraepithelial lymphocytosis are often seen.

In inflammatory bowel disease, even with secondary pseudomembranes, ulcerative colitis and Crohn disease retain the characteristics of inflammatory bowel disease with crypt architectural distortion and focal or diffuse basal lymphoplasmacytosis on microscopy.48

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