Approach Considerations
Leukocytosis is common in C difficile infection (CDI) and the white blood cell (WBC) count levels may be quite elevated, a finding that portends a worse prognosis. Patients with C difficile are also prone to acute kidney injury. Therefore, white blood cell counts and serum creatinine should be measured in patients with C difficile. Because the presence of leukocytosis and renal impairment are indicators of severe infection, patients with these findings should be treated initially with oral vancomycin instead of metronidazole. [5]
In severe disease, electrolyte imbalance, dehydration, hypoalbuminemia, and anasarca may occur, and patients should be monitored periodically. If surgical intervention is being considered, serum lactate levels and white blood cell counts may aid clinicians in their decision making.
The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) recommend testing for C difficile and its toxins in symptomatic patients only on diarrheal stool, unless there is suspicion of ileus due to C difficile. [5, 42] When individuals are asymptomatic, stool testing is not recommended unless for epidemiologic studies, in which case stool cultures are the most sensitive studies. [5, 42]
C difficile testing is not recommended in asymptomatic patients due to the difficulty in distinguishing asymptomatic carriage from infection in this setting. In addition, repeat testing for C difficile is not recommended following successful treatment in a patient recently treated for CDI. [5, 42]
Retesting for C difficile is not recommended, particularly for molecular studies, as detection rates and results do not improve, and there is an associated increase in healthcare costs and the likelihood of false-positive findings. [42]
Stool Examination and Stool Assays
In symptomatic patients, stool testing for C difficile should be performed only on diarrheal samples, [5, 42] and perirectal swabs are not accepted for testing, unless there is suspicion for ileus due to this organism. Stool testing is not recommended for asymptomatic patients, as the results are not clinically useful; if such testing is used for epidemiologic purposes, stool culture is required. [5, 42]
Stool may be positive for blood in the presence of severe colitis, but grossly bloody stools are unusual. Fecal leukocytes are present in about half of the C difficile colitis cases.
Stool cultures are the most sensitive tests for detecting C difficile and its toxins. [5] Moreover, results of the stool cultures followed by the identification of a toxigenic culture from an experienced laboratory are the standard used for comparison with other diagnostic testing. [5] However, despite their role as the gold standard test in patients with suspected C difficile infection (CDI), stool cultures have a long turnaround time and are resource intensive. Such factors make them too slow for practical clinical decision making (to treat or not to treat) in affected patients. Consequently, in clinical practice, enzyme immunoassay (EIA) for C difficile toxin A and B is used more often.
However, although EIA is a rapid test for C difficile toxin A and B, it is not an ideal alternative test for diagnosing CDI, due to it having a lesser sensitivity than the cell cytotoxin assay (see below). Nonetheless, the poor sensitivity of EIA can be overcome by obtaining repeat stool specimens or by combining EIA with polymerase chain reaction (PCR) assay or C difficile antigen (glutamate dehydrogenase [GDH]) EIA.
The following are stool assays for C difficile, from the most sensitive to the least sensitive:
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Stool culture is the most sensitive (sensitivity 90-100% and specificity 84-100%), but results are slow and may lead to delay in diagnosis if used alone
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GDH EIA is very sensitive (sensitivity 85-100% and specificity 87-98%); this test detects the presence of GDH produced by C difficile; positive test results need to be rerun by another assay to verify
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Real-time PCR assay may be used to detect C difficile gene toxin as an alternative “gold standard” to stool culture, with some studies demonstrating excellent sensitivity and specificity, as well as test-retest reliability [3, 43] ; in a study that used toxigenic culture as the gold standard, the sensitivity was 86%, the specificity was 97%, the positive predictive value (PPV) was 90%, and the negative predictive value (NPV) was 96%, for C difficile [3] (the PCR test is also inexpensive and has a fast turnaround time)
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The stool cytotoxin test has a sensitivity of 70-100% and a specificity of 90-100%; the diarrheal stool is filtered and then added to cultured fibroblasts; a positive test result is the demonstration of a cytopathic effect that is neutralized by specific antiserum; however, this test result is reported only as positive or negative, it is expensive, and it requires overnight incubation and a tissue culture facility
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EIA for detecting toxins A and B is used in most laboratories; it has moderate sensitivity (79-80%) but excellent specificity (98%); repeat testing is needed if the initial test is negative; EIA for toxin A is available, but it has come to be used less frequently because of the availability of EIA for toxins A and B
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Latex agglutination technique can also be used to detect GDH; however, the sensitivity of this test is poor (48-59%), although the specificity is 95-96%
Toxin testing has the most important clinical relevance, but its lack of sensitivity is an issue. The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) suggest an interim strategy; ie, a 2-step method that has the potential to overcome the sensitivity concern. [5] It would be carried out as follows:
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For the initial screening, use EIA detection of GDH
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This would be followed by a confirmatory test only for GDH-positive stool specimens by cell cytotoxic assay or toxigenic culture
In addition, the SHEA and IDSA note that although PCR assay testing appears to be rapid, sensitive, and specific, further research is needed before it can be recommended for routine testing in cases of suspected CDI. [5]
Biomarkers
A study by El Feghaly et al indicated that fecal inflammatory cytokines may be useful as biomarkers for distinguishing between C difficile colonization and actual disease. They may also be helpful in determining whether a child with C difficile infection is at a high risk for prolonged diarrhea. The study involved 65 children who were known to be C difficile positive, as well as symptomatic and asymptomatic controls. Results included the following [44] :
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Fecal cytokines: Elevated in symptomatic children (cases and controls); also elevated at diagnosis in patients with a significantly greater time to resolution of diarrhea (TTROD)
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Fecal chemokine ligand (CXCL)–5 messenger ribonucleic acid (mRNA): Correlation found between abundance at diagnosis and persistent diarrhea
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Phosphorylated p38: Lacks sensitivity, although specific for C difficile infection
Endoscopy
Although endoscopy is not routinely recommended for the diagnosis or management of C difficile infection (CDI), this procedure may demonstrate the presence of raised, yellowish white, 2- to 10-mm plaques overlying an erythematous, edematous mucosa. These plaques are termed pseudomembranes (see the following images). Pseudomembranes are observed in 14-25% of patients with mild C difficile disease and 87% of patients with fulminant disease.
Clostridioides (Clostridium) Difficile Colitis. Gross pathology specimen from a case of pseudomembranous colitis revealing the characteristic yellowish plaques.
Clostridioides (Clostridium) Difficile Colitis. Gross pathology specimen from a case of pseudomembranous colitis, again demonstrating the characteristic yellowish plaques.
Clostridioides (Clostridium) Difficile Colitis. Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M Osgard, MD.
Histologic findings
Biopsy of pseudomembranous plaques reveals an inflammatory exudate composed of mucinous debris, fibrin, necrotic epithelial cells and polymorphonuclear cells. The underlying crypts show disruption by mucous and inflammatory debris. The intervening mucosa shows edema but is otherwise unremarkable.
Things to consider
Most patients have disease throughout the colon. However, sigmoidoscopy alone may not reveal any abnormality if the disease is confined to the right colon. Typical pseudomembranes are beyond the limit of flexible sigmoidoscopy in 10% of patients. Therefore, colonoscopy is more useful.
Endoscopic examination findings may be normal in patients with mild disease or may demonstrate nonspecific colitis in moderate cases. Endoscopy is the least sensitive means of diagnosing C difficile relative to stool assays.
Sigmoidoscopy and colonoscopy in patients with fulminant colitis may be contraindicated because of the risk of perforation. Limited proctoscopy, with minimal air insufflation, may be a useful diagnostic tool in case of a diagnostic dilemma.
Computed Tomography Scanning
The American College of Radiology (ACR) recommends abdominal computed tomography (CT) scanning as the imaging modality of choice for C difficile colitis when pseudomembranous colitis, other complications of C difficile infection (CDI), or other intra-abdominal pathology is suspected. [4] Marked colonic wall thickening is the most common finding (see the following images). Other features may include ascites, irregularity of the bowel wall, and pericolonic stranding. In patients with sepsis due to suspected megacolon, abdominal radiography may be performed instead of CT scanning to establish the presence of megacolon in a timely manner.
Clostridioides (Clostridium) Difficile Colitis. Axial computed tomography scan of pseudomembranous colitis.
Clostridioides (Clostridium) Difficile Colitis. Computed tomography scan depicting pseudomembranous colitis.
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Clostridioides (Clostridium) Difficile Colitis. Endoscopic visualization of pseudomembranous colitis, a characteristic manifestation of full-blown <i>C difficile</i> colitis. Classic pseudomembranes are visible as raised, yellow plaques ranging from 2 to 10 mm in diameter and scattered over the colorectal mucosa. Courtesy of Gregory Ginsberg, MD, University of Pennsylvania.
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Clostridioides (Clostridium) Difficile Colitis. Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M Osgard, MD.
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Clostridioides (Clostridium) Difficile Colitis. Gross pathology specimen from a case of pseudomembranous colitis revealing the characteristic yellowish plaques.
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Clostridioides (Clostridium) Difficile Colitis. Gross pathology specimen from a case of pseudomembranous colitis, again demonstrating the characteristic yellowish plaques.
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Clostridioides (Clostridium) Difficile Colitis. Frontal abdominal radiograph in a patient with proven pseudomembranous colitis. Note the nodular haustral thickening, most pronounced in the transverse colon.
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Clostridioides (Clostridium) Difficile Colitis. Barium enema demonstrating the typical serrated appearance of the barium column (resulting from trapped barium between the edematous mucosal folds and the plaquelike membranes of pseudomembranous colitis).
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Clostridioides (Clostridium) Difficile Colitis. Axial computed tomography scan of pseudomembranous colitis.
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Clostridioides (Clostridium) Difficile Colitis. Computed tomography scan depicting pseudomembranous colitis.
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Clostridioides (Clostridium) Difficile Colitis. Ultrasonographic image of pseudomembranous colitis.
