Diagnosis
1) Stool testing should only be performed on diarrhea stools from at-risk patients with clinically significant diarrhea (Recommendation 1 C).
2) For patients with ileus who may be unable to produce stool specimens, polymerase chain reaction testing of perirectal swabs may be an accurate and efficient method to detect toxigenic
C. difficile
in patients with symptoms of CDI (Recommendation 2B).
Prompt and precise diagnosis is important for the effective management of CDI.
Early identification of CDI allows early treatment and can potentially improve outcomes. Rapid isolation of infected patients is important in controlling the transmission of
C. difficile [
136]
.
The diagnosis of CDI is based on the presence of a clinical picture compatible with CDI and microbiological evidence of free toxin and/or the demonstration of toxigenic
C. difficile in a diarrhea stool sample [
136]. Clinical features include: diarrhea (defined as by passage of 3 or more unformed stools in 24 h), abdominal pain and cramps, abdominal distension, ileus (signs of severely disturbed bowel function) and toxic megacolon.
Since C. difficile can colonize the intestinal tract of healthy individuals, diagnostic testing for CDI should be performed only on diarrhea stools from symptomatic patients. Testing of formed stool can result in false positive tests, which may result in unnecessary antibiotic therapy.
One limitation of the reliance on stool specimens are the patients with suspected severe CDI complicated by ileus as these patients may be unable to produce specimens for testing. For these patients testing of perirectal swabs may be an accurate and efficient method to detect toxigenic
C. difficile. In 2012 Kundrapu et al. [
137] described the results of a prospective study of 139 patients being tested for
Clostridium difficile infection by polymerase chain reaction. The sensitivity, specificity, positive predictive value, and negative predictive value of testing perirectal swabs were 95.7, 100, 100, and 99.1 %, respectively. The authors concluded that for selected patients, perirectal swabs provided an acceptable alternative to stool specimen analysis. Clinical context such as a history of recent antibiotic administration and/or residence in hospital are useful in selecting patients for testing. Other signs such as fever, abdominal pain, leukocytosis, in combination with other laboratory tests (e.g. creatinine and serum lactate) are useful for defining severity of infection.
3) Nucleic acid amplification tests (NAAT) such as polymerase chain reaction (PCR) for
C. difficile
toxin genes appear to be sensitive and specific and may be used as a standard diagnostic test for CDI. NAAT as single-step algorithm can increase detection of asymptomatic colonization therefore it should only be performed in patients with clinical suspicion for CDI (Recommendation 1 B).
4) Glutamate dehydrogenase (GDH) screening tests for
C. difficile
are sensitive but do not differentiate between toxigenic and non-toxigenic strains. They may be used in association with toxin A and B EIA testing. Algorithms involving screening with an EIA for GDH followed by a toxin assay may be used (Recommendation 1 B).
5) Enzyme immunoassay (EIA) for toxin A/B is fast and inexpensive and has high specificity but it is not recommended alone due to its relatively low sensitivity. (Recommendation 1 B).
6)
Clostridium difficile
culture is relatively slow but sensitive. It is rarely performed today as a routine diagnostic test.
C. difficile
culture is recommended for subsequent epidemiological typing and characterization of strains (Recommendation 1 C).
7) Repeat testing within 7 days should not be performed on patients who previously tested negative unless the clinical picture has changed significantly (Recommendation 1 C).
The best standard laboratory test for diagnosis of CDI has not been clearly established [
138]. In the past, toxigenic culture (TC) was accepted by many microbiologists as the method of choice for diagnosis of CDI. The procedure includes stool culture for
C. difficile on a selective differential medium (cycloserine, cefoxitin, fructose agar or CCFA) and an assay to test the colonies for the ability to produce toxins. Despite the fact that TC is considered a gold standard method, there are significant issues including slow turnaround time and it’s inability to detect the presence of toxins in stool. This may also lead to false positive results given up to 7 % of asymptomatic hospitalized patients may be colonized with toxigenic
C. difficile [
139].
However, TC can still be used as a confirmatory test in symptomatic patients with toxin positive/GDH assay(s)-negative stool samples. C. difficile culture is also necessary for subsequent epidemiological typing and characterization of strains.
The EIA for toxin A/B has been adopted by most clinical laboratories because it is fast, convenient and inexpensive [
140]. However, studies have shown that sensitivity can be low. Toxin A + B EIA tests have a described sensitivity of 32–98 % and a specificity of 84–100 % [
141].
Glutamate dehydrogenase (GDH) is an enzyme produced by
C. difficile in relatively large amounts compared with toxins A and B [
142,
143]. A positive GDH assay only documents the presence of
C. difficile but it does not discriminate between toxigenic and non-toxigenic strains (about 20 % of the
C. difficile population). Therefore, a second test for toxin production is necessary for confirmation. GDH screening tests for
C. difficile used in association to toxin A + B EIA testing gives an accurate test result quickly [
140,
141] even if the sensitivity of such strategy is lower than nucleic acid amplification tests (NAATs).
NAATs such as PCR for CD toxin genes have a high sensitivity and specificity, but not all laboratories routinely perform this assay [
143]. A current topic of debate is whether a stool sample that was positive by a molecular assay needs to be tested with a confirmatory toxin assay [
144] given it can also identify toxigenic
C difficile in asymptomatic patients. This underscores the importance of only testing patients with symptoms. There is no evidence suggesting that surgical patients should be diagnosed any differently than general medical patients.
8) Immunocompromised patients (including patients in chemotherapy, chronic corticosteroid therapy, or immunosuppressive agents, and post-transplant patients) should be always tested for CDI if they have a diarrheal illness (Recommendation 1 C).
It has already been highlighted that immunocompromised patients including those on glucocorticoids, or chemotherapy and post-transplant patients are at increased risk for CDI.
9) CT imaging is suggested for suspected severe-complicated
C. difficile
colitis, however its sensitivity is not satisfactory for screening purposes (Recommendation 2 B).
CT has been studied as an imaging modality for diagnosing
C. difficile colitis [
145‐
148]. Typical CT findings of CDC include colonic wall thickening, dilation, pericolonic stranding, “accordion sign” (high-attenuation oral contrast in the colonic lumen alternating with low-attenuation inflamed mucosa), “double-halo sign, target sign” (intravenous contrast displaying varying degrees of attenuation caused by submucosal inflammation and hyperemia), and ascites [
149]. However, the most common finding, colonic wall thickening is non-specific and can be found in other forms of colitis, although it may be more pronounced in that caused by
C. difficile.
In the Kirkpatrick et al. study [
150], CT diagnosis of CDC was made with a sensitivity of 52 %, a specificity of 93 %, and positive and negative predictive valued 88 %, and 67 % respectively. Sensitivity would have been increased to 70 % with no change in specificity if a colon wall thickness of greater than 4 mm had been used, in conjunction with the presence of colon wall nodularity, accordion sign, peri-colonic stranding, or otherwise unexplained ascites.
10) Ultrasound may be useful in critically ill patients suspected to have pseudomembranous colitis who cannot be transported for CT scan (Recommendation 2 C).
Point-of-care ultrasound may be useful in diagnosing and managing critically ill patients who cannot be moved to the radiology department [
151].
Ultrasound findings of pseudomembranous colitis in severe cases include a thickened colonic wall with heterogeneous echogenity and narrowing of the colonic lumen [
152]. Pseudomembranes can also be visualised as hyperechoic lines covering the mucosa [
152‐
155].
In the early stages of pseudomembranous colitis, the texture of the colonic wall is preserved. The hypoechoic edematous mucosa and muscularis propria may be thickened with the echogenic submucosa sandwiched between them. The presence of submucosal gaps may indicate extension of tissue damage into deeper structures. Intraperitoneal free fluid is seen in more than 70 % of cases [
153‐
155].
11) Flexible sigmoidoscopy may be helpful for the diagnosis of
C. difficile
colitis (CDC) when there is a high level of clinical suspicion for
C. difficile
despite repeated negative laboratory assays (Recommendation 2 B).
Endoscopy should be used sparingly to confirm the diagnosis of
C. difficile colitis since the diagnosis can be usually made by laboratory tests, clinical findings and imaging. Moreover colonoscopy may be hazardous in the setting of fulminant colitis where there may be increased risk of perforation [
156].
A study by Johal et al. [
157] described the use of flexible sigmoidoscopy as a tool for the diagnosis of
C. difficile colitis when stool assays were negative. Of 136 patients with
C. difficile associated diarrhea (CDAD) 56 patients had pseudomembranous colitis at sigmoidoscopy. The stool
C. difficile cytotoxin test was negative in 29 (52 %) but toxigenic
C. difficile was isolated from all of nine stool samples cultured. Of patients with pseudomembranous colitis, 30.4 % relapsed over the subsequent 57.7 days. The authors concluded that sigmoidoscopy should be considered in all hospitalised patients with diarrhea in whom the stool tests for
C. difficile cytotoxin and enteric pathogens are negative.
Emergency colonoscopy or sigmoidoscopy may also reveal pseudomembranous colitis in patients too ill to wait for laboratory results.