Disclosures: J Thomas Lamont, MD Nothing to disclose. Stephen B Calderwood, MD Patent Holder: Vaccine Technologies Inc. [Vaccines (Cholera vaccines)]. Equity Ownership/Stock Options: Pulmatrix [Inhaled antimicrobials]; PharmAthene [Anthrax (Anti-protective antigen monoclonal antibody)]. Elinor L Baron, MD, DTMH Nothing to disclose.
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INTRODUCTION — Clostridium difficile causes antibiotic-associated colitis; it colonizes the human intestinal tract after the normal gut flora has been altered by antibiotic therapy. It is one of the most common healthcare-associated infections and a significant cause of morbidity and mortality among older adult hospitalized patients.
The clinical manifestations and diagnosis of C. difficile infection will be reviewed here. The treatment, pathophysiology, and epidemiology of this disorder are discussed separately. (See "Clostridium difficile in adults: Treatment" and "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology".)
CLINICAL MANIFESTATIONS — C. difficile infection can cause a spectrum of manifestations ranging from an asymptomatic carrier state to fulminant disease with toxic megacolon (table 1) [1,2]. The basis for this range of clinical manifestations is not fully understood but may be related to various host and pathogen factors. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology".)
Diarrhea with colitis — Watery diarrhea is the cardinal symptom of C. difficile–associated diarrhea (CDAD) with colitis (≥3 loose stools in 24 hours). Other manifestations include lower abdominal pain and cramping, low-grade fever, and leukocytosis [2,3]. Fever is associated with CDAD in about 15 percent of cases; temperature >38.5°C is a sign of severe C. difficile–associated diarrhea. Leukocytosis in the setting of CDAD is common; CDAD is routinely associated with an average white blood cell count of 15,000/microL.
Symptoms of C. difficile infection typically occur in the setting of antibiotic therapy; they may begin during antibiotic therapy or 5 to 10 days following antibiotic therapy. Rarely, symptoms present as late as 10 weeks after cessation of antibiotic therapy . The antibiotics most frequently implicated in predisposition to C. difficile infection are fluoroquinolones, clindamycin, cephalosporins, and penicillins, though virtually any antibiotic can predispose to C. difficile infection (table 2).
Physical examination generally demonstrates lower abdominal tenderness. Sigmoidoscopic examination may demonstrate a spectrum of findings, from patchy mild erythema and friability to severe pseudomembranous colitis. (See 'Endoscopy' below.)
Unexplained leukocytosis in hospitalized patients (even in the absence of diarrhea) may reflect underlying C. difficile infection. In a prospective study of 60 patients with unexplained leukocytosis (white blood cell count >15,000/microL), positive stool C. difficile toxin was observed in 58 percent of cases compared with 12 percent in controls . When unexplained leukocytosis is due to CDAD, diarrhea typically develops one to two days later. (See "Causes of neutrophilia", section on 'Acute infection'.)
Fulminant colitis — Clinical manifestations of fulminant colitis include diarrhea, severe lower quadrant or diffuse abdominal pain, abdominal distention, fever, hypovolemia, lactic acidosis, hypoalbuminemia, and marked leukocytosis (up to 40,000 white blood cells/microL or higher) [5-7].
Occasionally, C. difficile infection presents acutely as ileus, with little or no diarrhea. Diarrhea may be less prominent or absent due to pooling of secretions in a dilated, atonic colon. Such patients are usually severely ill, with colonic (and possibly small bowel) dilatation, often with colonic thickening, fever, and leukocytosis. In some cases, this presentation seems benign initially but tends to progress rapidly.
Complications of fulminant colitis include toxic megacolon and bowel perforation . The diagnosis of toxic megacolon is established based on severe systemic toxicity together with radiographic evidence of colonic dilatation (>7 cm in its greatest diameter). Bowel perforation presents with abdominal rigidity, involuntary guarding, diminished bowel sounds, rebound tenderness, and severe localized tenderness in the left or right lower quadrants; abdominal radiographs may demonstrate free abdominal air. (See 'Radiographic imaging' below and "Toxic megacolon".)
Patients with fulminant colitis warrant radiographic imaging and prompt surgical evaluation. (See 'Radiographic imaging' below and "Clostridium difficile in adults: Treatment", section on 'Surgery'.)
Recurrent disease — Recurrence of symptoms after successful initial therapy for C. difficile develops in 10 to 25 percent of cases; it may be due to relapse of the initial infecting strain or reinfection with a new strain. Recurrent C. difficile infection often represents relapse rather than reinfection, regardless of the interval between episodes. Among 134 paired stool isolates from 102 patients with recurrent C. difficile infections, isolates obtained two to eight weeks apart were identical in 88 percent of cases; isolates obtained 8 weeks to 11 months apart were identical in 65 percent of cases .
Recurrence may present within days or weeks of completing treatment; the clinical presentation may be similar to or more severe than the initial presentation . Patients may experience several episodes of recurrence.
Patients with recurrent diarrhea, cramping, and bloating following treatment of C. difficile infection may have postinfectious irritable bowel syndrome or another inflammatory colitis such as collagenous colitis, inflammatory bowel disease, or celiac disease.
Asymptomatic carriage — Asymptomatic C. difficile carriage occurs in about 20 percent of hospitalized adults; these patients shed C. difficile in stool but do not have diarrhea [11-13]. In long-term care facilities, the rate of asymptomatic colonization may approach 50 percent. These individuals serve as a reservoir for environmental contamination [12,13]. The host immune response to C. difficile may play a role in determining colonization status. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology" and "Clostridium difficile infection: Prevention and control".)
Unusual presentations — Unusual manifestations of C. difficile include protein-losing enteropathy with ascites, extracolonic involvement, and C. difficile infection in the setting of chronic inflammatory bowel disease.
Protein-losing enteropathy with ascites — Some patients with C. difficile infection develop protein-losing enteropathy with hypoalbuminemia, and a few may exhibit ascites and peripheral edema [14,15]. Inflammation of the bowel wall allows leakage of albumin into the lumen, causing colonic loss of albumin with inadequate compensatory hepatic synthesis. As a result, serum albumin levels may drop below 2.0 g/dL (20 g/L). The protein-losing enteropathy responds to appropriate medical therapy of the infection. (See "Protein-losing gastroenteropathy" and "Clostridium difficile in adults: Treatment".)
Extracolonic involvement — Rare cases of C. difficile appendicitis, small bowel enteritis, and extraintestinal involvement have been described .
●Appendicitis due to C. difficile is unusual . The association may be underdiagnosed because milder cases might respond to antibiotic therapy alone.
●Small bowel involvement with C. difficile enteritis is unusual [18-20]. Patients with C. difficile involvement of the small bowel tend to be older adults or have multiple comorbidities. In some cases, patients have had prior colectomy with ileostomy; manifestations may include increased ileostomy output, and it may be possible to visualize pseudomembranes on the ileostomy mucosa. Therefore, such patients may be at increased risk for fulminant disease with a high mortality rate [19,20].
●Rare cases of C. difficile cellulitis, soft tissue infection, bacteremia, and reactive arthritis have been described [18,21,22].
Inflammatory bowel disease and C. difficile — Infection with C. difficile may complicate the course of inflammatory bowel disease (IBD) [23,24]. Enteric infections account for about 10 percent of symptomatic relapses in patients with IBD; C. difficile accounts for about half of these infections . Rates of C. difficile among patients with IBD appear to be increasing [26,27]. The association between IBD and C. difficile may be due to a variety of factors, including antibiotic use for treatment of other gastrointestinal pathogens and frequent hospitalization for management of IBD flares. Rarely, C. difficile can trigger an initial bout of IBD .
C. difficile infection in patients with IBD requires prompt diagnosis and management, since failure to diagnose the infection can lead to inappropriate treatment with glucocorticoids or immunosuppressive therapy. Furthermore, C. difficile may be difficult to distinguish from an IBD relapse given the similar symptoms of diarrhea, abdominal pain, and low-grade fever. Thus, a high index of suspicion is required when evaluating IBD patients with apparent flares, especially those who have recently received antibiotics and/or been hospitalized.
The diagnosis requires the use of laboratory tools; endoscopy is usually not helpful because IBD patients generally do not develop pseudomembranes. Given the preexisting colonic pathology, patients with IBD who develop C. difficile colitis require colectomy more frequently (20 percent in one series) .
There is a high prevalence of C. difficile carriage in patients with IBD. This was illustrated in a study of 122 patients with longstanding IBD in which the frequency of C. difficile carriage was higher in IBD patients than in healthy volunteers (8 versus 1 percent, respectively), in the absence of recent antibiotics or hospitalization . Despite this observation, none developed symptomatic disease in the subsequent six months. The reason for this observation is not certain; possibilities include altered colonic microbial flora, mucosal inflammation, and impaired mucosal innate immunity.
Clinical approach — The diagnosis of C. difficile infection should be suspected in patients with clinically significant diarrhea (≥3 loose stools in 24 hours) or ileus, in the setting of relevant risk factors (including recent antibiotic use, hospitalization, advanced age and severe illness). (See 'Diarrhea with colitis' above and "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology", section on 'Risk factors'.)
The diagnosis is established via a positive laboratory stool test for C. difficile toxins or toxin gene or findings of pseudomembranous colitis (on endoscopic or radiographic examination) [2,29-32]. The diagnostic approach for suspected recurrent C. difficile is the same as the approach for initial infection.
Diagnostic laboratory testing should be pursued only in patients with clinically significant diarrhea, and only liquid stool should be sent for C. difficile testing [33-37]. Laboratory testing does not distinguish between asymptomatic colonization and C. difficile–associated diarrhea (CDAD). For patients with ileus and suspected C. difficile infection, laboratory diagnosis via swab for enzyme immunoassay (EIA), polymerase chain reaction (PCR) or culture may be performed; the sensitivity of rectal swab for C. difficile culture in the setting of ileus is high (although takes time) [33,34,38,39].
We favor use of PCR for laboratory diagnosis of C. difficile, either alone or as part of an algorithm including initial EIA screening for glutamate dehydrogenase (GDH) antigen and toxins A and B (the clinically important toxin for testing is toxin B) (algorithm 1) . A positive test result for C. difficile infection may be presumed in the setting of positive EIA for GDH antigen and toxin A or B, a negative result may be presumed if both EIAs are negative, and confirmatory PCR may be used if the EIA results are discordant [41-45]. An algorithmic approach may be less expensive but take slightly longer and have lower sensitivity than PCR alone .
There is no role for repeat laboratory testing or testing for cure [34,46-52]. There is also no role for laboratory testing in asymptomatic patients or in patients being treated for acute infection; stool assays may remain positive during or after clinical recovery.
Radiographic imaging of the abdomen and pelvis is warranted for patients with clinical manifestations of severe illness or fulminant colitis (severe abdominal pain, abdominal distention with apparent ileus, fever, hypovolemia, lactic acidosis, hypoalbuminemia, and/or marked leukocytosis). (See 'Fulminant colitis' above and 'Radiographic imaging' below.)
Lower gastrointestinal endoscopy is warranted for patients with ileus or fulminant colitis in the absence of diarrhea; it may be used to establish a presumptive diagnosis of C. difficile infection by visualization of pseudomembranes. (See 'Endoscopy' below.)
Laboratory assays — Laboratory diagnosis of C. difficile infection requires demonstration of C. difficile toxin(s) or detection of toxigenic C. difficile organism(s) . We favor use of PCR for diagnosis of C. difficile, either alone or as part of an algorithm including initial EIA screening for GDH antigen and toxins A and B (algorithm 1) [34,53-57]. A number of laboratory stool tests are available, including [34,58]:
●Polymerase chain reaction
●Enzyme immunoassay for C. difficile glutamate dehydrogenase
●Enzyme immunoassay for C. difficile toxins A and B
●Cell culture cytotoxicity assay
●Selective anaerobic culture
These tests are discussed in further detail below.
●PCR testing – Real-time PCR tests detect one or more genes specific to toxigenic strains; the critical gene is tcdB, which encodes for toxin B; PCR is highly sensitive and specific [59-63]. The sensitivity of PCR is greater than EIA and comparable with cytotoxicity assay [34,64-68]. PCR is specific for toxigenic strains but does not test for active toxin production and is capable of detecting asymptomatic carriers of C. difficile; therefore, only liquid stool samples from patients with ≥3 loose stools in 24 hours should be tested. Only a single sample should be tested. PCR results can be available within as little as one hour. Given its high sensitivity and the potential for false-positive results, some favor use of PCR in an algorithm together with other assays such as EIA for GDH and EIA for toxins A and B. PCR results may be falsely negative if stool specimen collection is delayed and the patient treated empirically for suspected C. difficile infection . (See 'Clinical approach' above.)
●EIA for C. difficile GDH antigen – GDH antigen is an essential enzyme produced constitutively by all C. difficile isolates; its detection cannot distinguish between toxigenic and nontoxigenic strains [55-57]. Therefore, testing for GDH antigen is useful as an initial screening step in a multistep approach, which also consists of subsequent testing with more specific assays such as PCR on specimens that are GDH antigen positive [34,54]. GDH antigen testing has good sensitivity, and results are available in less than one hour.
●EIA for C. difficile toxins A and B – Most C. difficile strains produce both toxins A and B, although some strains produce toxin A or B only [70-74]. Toxin B is the clinically important toxin; no CDAD due to toxin A alone has been reported. The sensitivity of EIA for toxins A and B is about 75 percent; the specificity is high (up to 99 percent) [34,75,76]. There is a relatively high false-negative rate since 100 to 1000 pg of toxin must be present for the test to be positive . A number of inexpensive assays are commercially available, and test results are available within hours .
C. difficile toxin degrades at room temperature and may be undetectable within two hours after collection; specimens should be kept at 4ºC if delay in laboratory testing is anticipated. A suspected outbreak should prompt freezing of stool samples for later investigation.
●Selective anaerobic culture – Culture on selective medium with toxin testing of isolated C. difficile is the most sensitive diagnostic method, although culture cannot distinguish toxin-producing strains from non–toxin-producing strains . Use of a second test (EIA, PCR) is required to detect toxin B production by cultured C. difficile strains. Culture with strain testing for toxin B is considered by most to be the gold standard for diagnosis of C. difficile. Treatment of stool with heat or alcohol to shock spores (to increase vegetative growth) is sometimes used to improve yield. Culture is useful for epidemiologic studies but is generally too slow and labor intensive for routine clinical use .
●Cell culture cytotoxicity assay – Cell culture cytotoxicity assay is performed by adding a prepared stool sample (diluted, buffered, and filtered) to a monolayer of cultured cells . If C. difficile toxin is present, it exerts a cytopathic effect characterized by rounding of fibroblasts in tissue culture; specificity of the cytotoxicity is then demonstrated by neutralization with specific antiserum. The cell culture cytotoxicity assay has been used as a gold standard test for diagnosis of C. difficile [78,80]. The cytotoxicity assay is more sensitive than enzyme immunoassays but limitations include lack of standardization as well as being labor intensive with slow turnaround time (approximately two days) [29,81].
Radiographic imaging — Radiographic imaging of the abdomen and pelvis is warranted for patients with clinical manifestations of severe illness or fulminant colitis (severe abdominal pain, abdominal distention with apparent ileus, fever, hypovolemia, lactic acidosis, hypoalbuminemia, and/or marked leukocytosis).
Computed tomography (CT) of the abdomen and pelvis is the preferred imaging modality for evaluation of patients with known or suspected C. difficile infection. Pronounced thickening of the colonic wall may be observed, although this finding is not specific for pseudomembranous colitis (image 1) . Mucosal edema and inflammation involving the large bowel (the "accordion sign") is pathognomonic of pseudomembranous colitis .
Radiographic evidence of colonic dilatation (>7 cm in diameter) is diagnostic of toxic megacolon. Other radiographic findings consistent with toxic megacolon include small bowel dilatation, air-fluid levels (mimicking an intestinal obstruction or ischemia), and "thumb printing" (scalloping of the bowel wall) due to submucosal edema (image 2 and image 3). In the setting of bowel perforation, free abdominal air may be observed.
Plain films may be useful for circumstances in which CT is not readily available.
Endoscopy — Lower gastrointestinal endoscopy is warranted for patients with ileus or fulminant colitis in the absence of diarrhea; it may be used to establish a presumptive diagnosis of C. difficile infection by visualization of pseudomembranes (severe inflammation of the inner lining of the colon) [84,85]. The decision to proceed with endoscopy should be made carefully; endoscopy is not warranted in patients with classic clinical findings and a positive stool assay and may not be necessary for patients who respond clinically to empiric treatment for C difficile infection. For circumstances in which endoscopy is warranted, care should be taken to minimize the amount of air introduced into the colon given the risk of perforation. Endoscopic visualization of pseudomembranes is considered strong evidence for presence of CDAD; a perirectal swab for anaerobic culture could be used for diagnostic confirmation. (See 'Clinical approach' above.)
Formation of pseudomembranes occurs following C difficile toxin-induced ulcer formation on the mucosal surface of the intestine, which facilitates release of serum proteins, mucus, and inflammatory cells . Pseudomembranes manifest as raised yellow or off-white plaques up to 2 cm in diameter scattered over the colonic mucosa (picture 1 and picture 2). Some patients with pseudomembranous colitis have scattered lesions with relatively normal-appearing intervening mucosa, while others have a confluent pseudomembrane covering the entire mucosa. Pseudomembranes may be absent in the rectosigmoid area but present more proximally, although colonoscopy for proximal evaluation of the colon is not warranted for diagnosis of C. difficile [84,87].
Not all patients with CDAD have pseudomembranes, particularly patients with mild or partially treated infection. The absence of pseudomembranes does not rule out C. difficile infection; pseudomembranes are rarely observed in the setting of recurrent infection or inflammatory bowel disease [88,89].
Other endoscopic findings in the setting of C difficile infection include bowel wall edema, erythema, friability, and inflammation; these may be observed with or without pseudomembranes. Visualization of pseudomembranes is virtually pathognomonic for C. difficile infection; there are rare reports of other pathogens also capable of causing pseudomembranous colitis (see 'Differential diagnosis' below).
Biopsy is not needed for diagnosis of C. difficile. Biopsy may be warranted to establish an alternative diagnosis, particularly for patients who are not responding clinically to appropriate therapy for presumed C. difficile infection. (See 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS — C. difficile must be distinguished from other infectious and noninfectious causes of diarrhea.
Other organisms that have been implicated as causes of antibiotic-associated diarrhea include Staphylococcus aureus , Klebsiella oxytoca , Clostridium perfringens , and possibly Candida albicans . Salmonella can present as a pseudomembranous colitis . The clinical manifestations are similar to that of C. difficile infection; the diagnosis is distinguished by stool culture.
Among noninfectious causes of diarrhea, most antibiotic-associated diarrhea is not attributable to C. difficile infection (but rather to osmotic mechanisms), whereas colitis associated with antibiotic-associated diarrhea is nearly always C. difficile–associated diarrhea (CDAD). Differentiation of noninfectious form of antibiotic-associated diarrhea may be difficult, especially in patients who are asymptomatic C. difficile carriers; this is most relevant among patients in nursing homes or hospitals where the rate of asymptomatic carriage is 10 to 50 percent (in community populations, the rate of asymptomatic carriage is ≤5 percent). Cessation of symptoms with discontinuation of oral intake is a distinguishing feature of osmotic diarrhea (figure 1). The presence of fever and leukocytosis favor C. difficile or other infectious etiology. (See "Approach to the adult with chronic diarrhea in developed countries".)
Postinfectious irritable bowel syndrome occurs in about 10 percent of patients who have been successfully treated for an initial episode of C. difficile. These patients may have up to 10 watery stools per day; this must be distinguished from a relapse of the original C. difficile infection based on established criteria (table 3). (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults".)
Issues related to inflammatory bowel disease are discussed above. (See 'Inflammatory bowel disease and C. difficile' above.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient information: Antibiotic-associated diarrhea caused by Clostridium difficile (Beyond the Basics)")
●Clostridium difficile colonizes the human intestinal tract after the normal gut flora has been altered by antibiotic therapy and causes antibiotic-associated colitis; a spectrum of clinical manifestations is observed (table 1). (See 'Clinical manifestations' above.)
●Manifestations of C. difficile–associated diarrhea (CDAD) with colitis include watery diarrhea with lower abdominal pain and cramping, low-grade fever, and leukocytosis. The antibiotics most frequently implicated in predisposition to C. difficile infection are fluoroquinolones, clindamycin, and cephalosporins (table 2). (See 'Diarrhea with colitis' above.)
●Clinical manifestations of fulminant colitis include diarrhea, severe lower quadrant or diffuse abdominal pain, abdominal distention, fever, hypovolemia, lactic acidosis, hypoalbuminemia, and marked leukocytosis. Diarrhea may be less prominent or absent in patients with prolonged ileus due to pooling of secretions in the dilated, atonic colon. Potential complications include toxic megacolon and bowel perforation. (See 'Fulminant colitis' above.)
●Relapse or reinfection develops in 10 to 25 percent of treated C. difficile cases, and patients may experience several episodes of relapsing colitis. Relapse may present within days or weeks of completing treatment for C. difficile; the clinical presentation may be similar to or more severe than the initial presentation. (See 'Recurrent disease' above.)
●The diagnosis of C. difficile is established via a positive laboratory stool test for C. difficile toxins or toxin gene or findings of pseudomembranous colitis on endoscopic examination. (See 'Clinical approach' above.)
●We favor use of polymerase chain reaction for laboratory diagnosis of C. difficile, either alone or as part of an algorithm including initial enzyme immunoassay screening for glutamate dehydrogenase antigen and toxins A and B (algorithm 1). (See 'Clinical approach' above.)
●Radiographic imaging of the abdomen and pelvis is warranted for patients with clinical manifestations of fulminant colitis, including severe abdominal pain, abdominal distention, hypovolemia, lactic acidosis, hypoalbuminemia, and/or marked leukocytosis. (See 'Clinical approach' above and 'Radiographic imaging' above.)
●Lower gastrointestinal endoscopy is warranted for patients with ileus or fulminant colitis in the absence of diarrhea; it may be used to establish a presumptive diagnosis of C. difficile infection by visualization of pseudomembranes (severe inflammation of the inner lining of the colon). (See 'Endoscopy' above.)
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