Clostridium Difficile Colitis - (Antibiotic-Associated Colitis, C. difficile Colitis)

Clostridium difficile diarrhea without colitis is the most common manifestation of C. difficile infection. The more serious Clostridium difficile colitis accounts for much of the morbidity and mortality associated with C. difficile. The CDC spectrum includes colitis without pseudomembrane formation, pseudomembranous colitis, and fulminant colitis. The basis for this varied response is related to host factors such as the immune response, the presence of colonic receptors for the toxins, and the concentration of antitoxin antibodies in the sera and intestinal secretions.

Patients with CDC almost always require therapeutic intervention. The illness seldom resolves spontaneously, unlike most cases of C. difficile diarrhea without colitis, which do resolve when the offending antibiotic is withdrawn. While CDC occurs mainly during or shortly after antibiotic usage, infections can occur up to six months after antibiotic exposure.

Following are key presenting characteristics of the CDC variants.

C. difficile colitis without pseudomembrane formation. These patients have 10 or more loose bowel movements per day, with only occasional occult bleeding per rectum. The diarrhea is more profuse compared to patients without colitis, and it is associated with cramping abdominal pain in the lower quadrant that is temporarily relieved with passage of loose bowel movements. Patients may have accompanying symptoms of nausea, anorexia, fever, and malaise. On physical exam, they may have signs of dehydration with abdominal distension and tenderness.

Pseudomembranous colitis. These patients have more profuse diarrhea than patients without pseudomembranes, and their systemic symptoms of nausea, anorexia, fever, and malaise are more intense. On clinical exam, they may be more dehydrated and have marked abdominal tenderness and distension.

Fulminant colitis. These patients have severe diarrhea but may also have decreased bowel movements if paralytic ileus intervenes. They are lethargic with high fever, chills, tachycardia, and profound systemic manifestations of the disease such as severe dehydration. They may present with an acute abdomen and have peritoneal signs if there is perforation. This fulminant process can lead to megacolon, ileus, perforation, and death. Patients with toxic megacolon have a dilated colon, with a diameter greater than 7 cm, accompanied by severe systemic toxicity such as marked leukocytosis, dehydration, and metabolic acidosis. Patients with bowel perforation often have abdominal rigidity, reduced bowel sounds, and in some cases, symptoms of shock.

C. difficile colitis with protein-losing enteropathy. This is an additional variant that occurs in a small number of patients, who usually have subacute CDC with low-grade, intermittent diarrhea, abdominal pain, and fever. Such patients have hypoalbuminemia secondary to the pancolitis, which causes leaking of serum albumin through the inflamed mucosa. The serum albumin may be as low as 2 g/dl or less, with accompanying ascites and peripheral edema.

Most of the manifestations of CDC are related to the colon, but infection of the small bowel and extraintestinal manifestations such as reactive arthritis can occasionally occur.

How is CDC recognizable in patients with inflammatory bowel disease?

Clostridium difficile colitis in a patient with inflammatory bowel disease may be missed because the symptoms of diarrhea, abdominal pain, and low-grade fever are attributed to a flare-up of the underlying disease process. The diagnosis, however, can be established by identifying the cytotoxin in the stool sample.

Patients with inflammatory bowel disease are at risk of acquiring CDC because they have impaired immune systems, are exposed to antibiotics, including sulfasalazine, and are frequently hospitalized due to the underlying disease process.

What is the differential diagnosis for CDC?

In addition to CDC, diagnostic considerations for patients presenting with fever, diarrhea, and abdominal pain include diverticulitis, inflammatory bowel disease (ulcerative colitis or Crohn's disease), and bacterial colitis.

While patients with diverticulitis have fever and abdominal pain, they usually will not have profuse diarrhea. On exam, there is usually left lower quadrant tenderness with a palpable mass.

Patients with ulcerative colitis usually have bloody diarrhea with fecal urgency. In severe disease, there is associated hypoalbuminemia and severe anemia. Stool cultures are negative. Patients may also have extraintestinal manifestations such as erythema nodosum, episcleritis, and oligoarthritis. In Crohn's, patients may present with intermittent diarrhea with cramping or steady right lower quadrant pain. On exam, a right lower quadrant mass may be palpable. Patients may have evidence of fistulas and abscesses in the perineum or intra-abdominally.

Besides C. difficile, bacterial colitis can be caused by Salmonella, Shigella, Campylobacter, Yersinia, and Escherichia coli. Patients with Salmonella, Shigella, or Campylobacter usually have a self-limiting diarrhea that can be differentiated from CDC by stool culture. Patients with E. coli colitis have diarrhea that may be bloody when provoked by enteroinvasive or enterohemorrhagic E. coli strains. Outbreaks of enterohemorrhagic E. coli O157:H7 that occur from consumption of undercooked hamburgers and unpasteurized apple juice can result in complications such as hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura. Isolation of E. coli O157:H7 requires identifying this strain on sorbitol-MacConkey agar and confirming it with serologic typing.

Other processes that should be considered in the differential diagnosis are viral gastroenteritis, malabsorption, and irritable bowel syndrome.

What diagnostic tests are useful in identifying CDC? Does endoscopy have a role?

Depending on the severity of the illness, patients with CDC may have leukocytosis with a left shift, electrolyte abnormalities, and even hypoalbuminemia in severe cases. Stool examination will reveal leukocytes in half the cases and may even be hemoccult positive. The diagnosis of CDC is established most often by stool bioassay, but in certain patient populations, endoscopy and abdominal CT scans are done to obtain additional information.

Stool bioassay. The stool cytotoxicity assay is the test of choice for diagnosing CDC. Diarrheal stool is diluted with buffer, then filtered and added to fibroblasts. The toxins exert a cytopathic effect on the cells that causes rounding. The test is usually reported as positive or negative and titers, if reported, are of little importance. Sensitivity is 94% to 100%, and specificity is up to 99%. Cytotoxicity assays are expensive and take two to three days to complete, so they have been largely replaced by rapid and easier-to-perform immunoassays such as ELISA, which detect toxin A. Although cytotoxicity assays and immunoassays are comparable in specificity, the sensitivity of cytotoxicity assays is greater, resulting in detection of 5% to 10% more cases. This is mainly due to negative ELISA assay results seen in patients with stool containing toxin B and mutant toxin A.

Endoscopy. Though sigmoidoscopy and colonoscopy are seldom performed in patients with classic clinical findings, they are helpful when the diagnosis is in doubt or rapid diagnostic information is required. If a patient is ill with symptoms suggestive of CDC but has a negative ELISA assay, then colonoscopy can be invaluable in providing an expeditious diagnosis. The presence of pseudomembranes is virtually diagnostic of CDC. In general, colonoscopy is superior to sigmoidoscopy because in 10% of patients, CDC is rectosigmoid-sparing. The findings with colonoscopy vary from diffuse, patchy colitis in mild cases to the characteristic raised, adherent, yellow plaques seen in pseudomembranous colitis. Other endoscopic findings include erythema, edema, friability, and erosions.

Computed tomography (CT) scan. The CT scan of the abdomen is used to evaluate for other intra-abdominal pathology. The findings of mild CDC include diffuse or patchy colitis. In pseudomembranous colitis, they include mucosal edema, thickened colon, thumbprinting, pancolitis, and even pericolonic inflammation, depending on the severity of the disease. These findings are not specific for CDC, as they may be seen in colitis from other causes. A CT scan may be helpful, however, in revealing complications of CDC such as ileus and megacolon and identifying any other intra-abdominal pathology.


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