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Clostridium difficile infection in adults: Clinical manifestations and diagnosis
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Clostridium difficile infection in adults: Clinical manifestations and diagnosis
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2016. | This topic last updated: Feb 25, 2016.

INTRODUCTION — Clostridium difficile is a spore-forming, toxin-producing, gram-positive anaerobic bacterium that causes antibiotic-associated colitis. It colonizes the human intestinal tract after the normal gut flora has been altered by antibiotic therapy. C. difficile infection 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, epidemiology, and prevention of C. difficile infection are discussed separately. (See "Clostridium difficile in adults: Treatment" and "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology" and "Clostridium difficile infection: Prevention and control".)

CLINICAL MANIFESTATIONS — C. difficile infection can cause a spectrum of manifestations ranging from an asymptomatic carriage 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, nausea, anorexia, and leukocytosis [2,3]. Diarrhea may be associated with mucus or occult blood, but melena or hematochezia are rare [4]. 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, elevated creatinine, and elevated lactate in the setting of CDAD are 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 [5]. 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). Additional risk factors for C. difficile infection include age >65, recent hospitalization and use of proton pump inhibitors. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology", section on 'Risk factors'.)

Physical examination generally demonstrates lower abdominal tenderness. Lower gastrointestinal endoscopy (flexible proctoscopy, sigmoidoscopy, or colonoscopy) examination may demonstrate a spectrum of findings, from patchy mild erythema and friability to severe pseudomembranous colitis (severe inflammation of the inner lining of the bowel). (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 [6]. When unexplained leukocytosis is due to C. difficile infection, 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, lower quadrant or diffuse abdominal pain, abdominal distention, fever, hypovolemia, lactic acidosis, hypoalbuminemia, elevated creatinine, and marked leukocytosis (up to 40,000 white blood cells/microL or higher) [6-8].

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 progresses rapidly.

Complications of fulminant colitis include hypotension, sepsis, renal failure, toxic megacolon, and bowel perforation with peritonitis [9]. Severe hypotension may occur in the setting of severe C. difficile infection and/or in the setting of bowel perforation with peritonitis. In addition, C. difficile infection may develop during antibiotic treatment for septic shock caused by a separate bacterial infection.

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".)

Recurrent disease — Recurrence is defined by complete abatement of symptoms while on appropriate therapy, followed by subsequent reappearance of diarrhea and other symptoms after treatment has ended. Recurrence should be distinguished from persistent diarrhea without resolution during initial therapy, which should prompt an evaluation for other causes. In the absence of an alternative diagnosis, such patients should be considered to have refractory illness.

Recurrence of symptoms after successful initial therapy for C. difficile develops in approximately 10 to 40 percent of cases; recurrent symptoms 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 2 to 8 weeks apart were identical in 88 percent of cases; isolates obtained 8 weeks to 11 months apart were identical in 65 percent of cases [10].

Recurrence may present within days or weeks of completing treatment; the clinical presentation may be similar to or more severe than the initial presentation [11]. Patients may experience several episodes of recurrence. One study including more than 1500 patients with C. difficile infection noted 34 percent of patients with recurrent infection needed admission, 28 percent developed severe disease, and 4 percent developed a complication [12].

Patients with recurrent diarrhea, cramping, and bloating following treatment of C. difficile infection may have postinfectious irritable bowel syndrome or another inflammatory colitis. (See 'Differential diagnosis' below.)

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 or other clinical symptoms [13-15]. In long-term care facilities, the rate of asymptomatic colonization may approach 50 percent. These individuals serve as a reservoir for environmental contamination [14,15]. The host immune response to C. difficile may play a role in determining colonization status. Individuals with asymptomatic carriage of C. difficile do not warrant treatment, and there is no role for pursuing diagnostic evaluation for C. difficile infection in the absence of significant diarrhea. (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 and extracolonic involvement.

Protein-losing enteropathy – Protein-losing enteropathy with hypoalbuminemia has been described in association with acute C. difficile infection in the absence of fulminant colitis [16,17]. 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). Ascites and peripheral edema may be observed. 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 [18].

Appendicitis due to C. difficile infection has been described in a few case reports; it may be underdiagnosed since relatively mild cases may respond to antibiotic therapy alone [19].

Small bowel involvement with C. difficile enteritis typically occurs in older adults and/or patients with multiple comorbidities [20-22]. In some cases, patients have had prior colectomy with ileostomy; manifestations may include increased ileostomy output, and it may be possible to visualize pseudomembranes (severe inflammation of the inner lining of the bowel) on the ileostomy mucosa. Therefore, such patients may be at increased risk for fulminant disease with a high mortality rate [21,22].

Rare cases of C. difficile cellulitis, soft tissue infection, bacteremia, and reactive arthritis have been described [20,23,24].

DIAGNOSIS

Overview of diagnostic 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, and advanced age). The diagnosis is established via a positive laboratory stool test for C. difficile toxins or C. difficile toxin gene. The diagnostic approach for suspected recurrent C. difficile is the same as the approach for initial infection. (See 'Diarrhea with colitis' above and "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology", section on 'Risk factors'.)

For patients with diarrhea and suspected C. difficile infection, liquid stool should be sent for C. difficile testing. Laboratory testing does not distinguish between C. difficile–associated diarrhea (CDAD) and asymptomatic carriage (which does not warrant treatment); therefore, diagnostic laboratory testing should be pursued only in patients with clinically significant diarrhea [4,25-28].

For patients with ileus and suspected C. difficile infection, laboratory diagnosis via perirectal swab for toxin assay or anaerobic culture may be performed; the sensitivity of rectal swab for C. difficile culture in the setting of ileus is high (although takes time) [4,25,29,30].

Findings of pseudomembranous colitis (severe inflammation of the inner lining of the bowel) on radiographic or endoscopic examination are highly suggestive of C. difficile infection and should prompt laboratory testing [2,31-34].

There are several diagnostic tests available for the laboratory diagnosis of C. difficile infection, each with advantages and limitations. We favor use of polymerase chain reaction (PCR) for laboratory diagnosis of C. difficile, either alone or as part of an algorithm including initial enzyme immunoassay (EIA) screening for glutamate dehydrogenase (GDH) antigen and toxins A and B (algorithm 1) [35]. 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 [36-40]. An algorithmic approach may be less expensive but take slightly longer and has lower sensitivity than PCR alone [37]. However, exclusive reliance on molecular testing may result in overdiagnosis and overtreatment, since laboratory testing cannot distinguish between CDAD and asymptomatic carriage (which does not warrant treatment) [41]. Only one stool sample is needed for diagnosis of C. difficile with PCR (either alone or as part of an algorithm).

There is no role for repeat laboratory testing or testing for cure [4,42-48]. There is also no role for laboratory testing in asymptomatic patients or in patients receiving treatment for acute C. difficile 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) to evaluate for presence of toxic megacolon, bowel perforation, or other findings warranting surgical intervention. Findings of pseudomembranous colitis on radiographic examination are highly suggestive of C. difficile infection and should prompt laboratory testing. (See 'Fulminant colitis' above and 'Radiographic imaging' below.)

Lower gastrointestinal endoscopy is not warranted in patients with classic clinical manifestations of C. difficile infection, a positive laboratory test, and/or clinical response to empiric treatment. In general, endoscopy may be pursued for circumstances in which an alternative diagnosis is suspected that requires direct visualization and/or biopsy of the bowel mucosa. It may also be helpful for patients with ileus or fulminant colitis in the absence of diarrhea since it may allow visualization of pseudomembranes (severe inflammation of the inner lining of the bowel), a finding that is highly suggestive of C. difficile infection. However, not all patients with CDAD have pseudomembranes, particularly patients with mild or partially treated infection, and absence of pseudomembranes does not rule out C. difficile infection. (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) [31]. We favor use of PCR for diagnosis of C. difficile on a single stool sample, either alone or as part of an algorithm including initial EIA screening for GDH antigen and toxins A and B (algorithm 1) [4,49-53]. A systematic review noted that single-step PCR or multistep algorithms using PCR for toxin gene(s) on liquid stool samples have the best test performance characteristics (single step testing: sensitivity 0.86 to 0.92 and specificity 0.94 to 0.97; multistep testing: sensitivity 0.68 to 1.0 and specificity 0.92 to 1.0) [2].

A number of laboratory stool tests are available, including [4,54]:

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 [55-59]. The sensitivity of PCR is greater than EIA and comparable with cytotoxicity assay [4,60-64]. 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 stool sample should be tested. PCR results can be available within as little as one hour. Given its high sensitivity and its inability to distinguish C. difficile infection from asymptomatic carriage, 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 [65]. (See 'Overview of diagnostic approach' above.)

EIA for C. difficile GDH antigen – GDH antigen is an essential enzyme produced constitutively by all C. difficile isolates; however, its detection cannot distinguish between toxigenic and nontoxigenic strains [51-53]. 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 toxin A and B EIA or PCR on specimens that are GDH antigen positive [4,50]. 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 [66-70]. Toxin B is the clinically important toxin; no CDAD due to toxin A alone has been reported. However, testing for both toxins by EIA gives a higher sensitivity than testing for toxin B alone. The sensitivity of EIA for toxins A and B is about 75 percent; the specificity is high (up to 99 percent) [4,71,72]. There is a relatively high false-negative rate since 100 to 1000 pg of toxin must be present for the test to be positive [73]. A number of inexpensive assays are commercially available, and test results are available within hours [4]. More than one stool sample may be tested.

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 [74]. Use of a second test (EIA, PCR) is required to detect toxin production by cultured C. difficile strains. Culture followed by strain testing for toxin 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 [71]. Perirectal swab for toxin assay or anaerobic culture can be a useful diagnostic tool for patients with ileus and suspected C. difficile infection.

Cell culture cytotoxicity assay – The cell culture cytotoxicity assay was developed contemporaneously with the discovery of C. difficile and has been used as a gold standard test for diagnosis of C. difficile; it is more sensitive than enzyme immunoassay, although it is limited by lack of standardization and slow turnaround time (approximately two days) [74,75]. The cell culture cytotoxicity assay is performed by adding a prepared stool sample (diluted, buffered, and filtered) to a monolayer of cultured cells [31,76,77]. 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 of the cytopathic effect with specific antiserum.

It is important to note that C. difficile toxin degrades at room temperature and may be undetectable within two hours after collection; therefore, specimens for testing based on toxin detection (EIA for C. difficile toxins and cell culture cytotoxicity assay) should be kept at 4ºC if delay in laboratory testing is anticipated. In addition, a suspected outbreak should prompt freezing of stool samples for later investigation.

Fecal leukocyte testing is not helpful for diagnosis of C. difficile infection [78].

Adjunctive diagnostic tools — Adjunctive diagnostic tools for evaluating patients with suspected C. difficile infection include radiographic imaging and endoscopy.

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), to evaluate for presence of toxic megacolon, bowel perforation, or other findings warranting surgical intervention. Computed tomography (CT) of the abdomen and pelvis with oral and intravenous contrast is the preferred imaging modality; plain films may be useful for circumstances in which CT is not readily available.

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 1 and image 2). In the setting of bowel perforation, free abdominal air may be observed. (See "Toxic megacolon".)

Other radiographic findings associated with C. difficile colitis include pronounced colonic wall thickening (image 3) and low-attenuation mural thickening, corresponding with mucosal and submucosal edema (which may be visible as a "target sign" or "double halo sign" consisting of two or three concentric rings of different attenuation) [79]. Pericolonic stranding and ascites may be seen but are not specific for C. difficile infection.

Findings consistent with pseudomembranous colitis (severe inflammation of the inner lining of the bowel) on radiographic examination are highly suggestive of C. difficile infection and should prompt laboratory testing if not already performed. The "accordion sign" is highly suggestive of pseudomembranous colitis; it consists of mucosal edema and inflammation involving the large bowel and is seen when orally administered contrast material becomes trapped between thickened haustral folds, giving the appearance of alternating bands of high attenuation (contrast material) and low attenuation (edematous haustra) [79-81]. (See 'Overview of diagnostic approach' above.)

Endoscopy — Lower gastrointestinal endoscopy is not warranted in patients with classic clinical manifestations of C. difficile infection, a positive laboratory test and/or clinical response to empiric treatment. In general, endoscopy may be pursued for circumstances in which an alternative diagnosis is suspected that requires direct visualization and/or biopsy of the bowel mucosa. It may also be helpful for patients with ileus or fulminant colitis in the absence of diarrhea since it may allow visualization of pseudomembranes (severe inflammation of the inner lining of the bowel), a finding that is highly suggestive of C. difficile infection. The decision to proceed with endoscopy should be made carefully; if pursued, flexible proctoscopy is preferred since insufflation with sigmoidoscopy and colonoscopy may damage potentially friable bowel tissue with increased risk for perforation.

Findings on lower gastrointestinal endoscopy in the setting of C. difficile infection include bowel wall edema, erythema, friability, and inflammation. When visible, findings of pseudomembranous colitis are highly suggestive of C. difficile infection and should prompt diagnostic laboratory confirmation if not already performed (via stool assay or, in the setting of ileus, a perirectal swab for toxin assay or anaerobic culture) [82]. However, not all patients with CDAD have pseudomembranes, particularly patients with mild or partially treated infection, and absence of pseudomembranes does not rule out C. difficile infection. Pseudomembranes are rarely observed in the setting of recurrent C. difficile infection or inflammatory bowel disease [83,84]. There are rare reports of other pathogens also capable of causing pseudomembranous colitis (see 'Differential diagnosis' below).

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 [85]. 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 given potential bowel tissue friability and risk of perforation [82,86].

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. Most antibiotic-associated diarrhea is not attributable to C. difficile infection (but rather to osmotic mechanisms), whereas antibiotic-associated diarrhea associated with colitis is nearly always C. difficile–associated diarrhea (CDAD).

Acute abdomen – C. difficile may present as abdominal distension mimicking small bowel ileus, Ogilvie's syndrome, volvulus, or ischemia [87]. The approach to diagnosis varies by age, gender and condition; tools include history and physical examination, surgical consultation, and radiographic imaging. (See "Evaluation of the adult with abdominal pain in the emergency department".)

Shock – Severe hypotension may occur in the setting of severe C. difficile infection and/or in the setting of bowel perforation with peritonitis. In addition, C. difficile infection may develop during antibiotic treatment for septic shock caused by a separate bacterial infection. Shock due to other causes (such as septic shock or cardiogenic shock) must be distinguished from severe hypotension due to C. difficile infection via cardiac and hemodynamic assessment. (See "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock".)

Infectious diarrhea – Other organisms that have been implicated as causes of antibiotic-associated diarrhea include Staphylococcus aureus [88], Klebsiella oxytoca [89], Clostridium perfringens [90], and possibly Candida albicans [73]. Salmonella can present as a pseudomembranous colitis (severe inflammation of the inner lining of the bowel) [91]. The clinical manifestations are similar to that of C. difficile infection; the diagnosis is distinguished by stool culture.

Noninfectious diarrhea – Causes of noninfectious diarrhea that may mimic C. difficile infection include postinfectious irritable bowel syndrome, inflammatory bowel disease, celiac disease, and collagenous colitis. Differentiation of noninfectious antibiotic-associated diarrhea from C. difficile infection 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 favors C. difficile or other infectious etiology. (See "Approach to the adult with chronic diarrhea in developed countries".)

Postinfectious irritable bowel syndrome – 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".)

Inflammatory bowel disease – Infection with C. difficile may complicate the course of inflammatory bowel disease (IBD) [92,93]. Enteric infections account for about 10 percent of symptomatic relapses in patients with IBD; C. difficile accounts for about half of these infections [94]. Rates of C. difficile among patients with IBD appear to be increasing [95,96]. 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 [94].

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 laboratory testing; endoscopy is usually not helpful because IBD patients generally do not develop pseudomembranes. Given preexisting colonic pathology, patients with IBD who develop C. difficile colitis require colectomy more frequently (20 percent in one series) [96].

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 [97]. 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.

Collagenous colitis – Collagenous colitis is a chronic inflammatory disease of the colon characterized by chronic, watery diarrhea. The diagnosis is established via colonoscopy with biopsy. (See "Lymphocytic and collagenous colitis (microscopic colitis): Clinical manifestations, diagnosis, and management".)

Celiac disease – Celiac disease is a small bowel disease associated with dietary gluten exposure; gastrointestinal symptoms including chronic or recurrent diarrhea, malabsorption, weight loss, and abdominal distension or bloating. The diagnosis is established via serology and/or biopsy. (See "Diagnosis of celiac disease in adults".)

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.)

Basics topics (see "Patient information: Antibiotic-associated diarrhea (C. difficile infection) (The Basics)")

Beyond the Basics topics (see "Patient information: Antibiotic-associated diarrhea caused by Clostridium difficile (Beyond the Basics)")

SUMMARY

Clostridium difficile colonizes the human intestinal tract after the normal gut flora has been altered by antibiotic therapy and causes antibiotic-associated colitis. The antibiotics most frequently implicated in predisposition to C. difficile infection are fluoroquinolones, clindamycin, cephalosporins, and penicillins (table 2). Additional risk factors include age >65 and recent hospitalization. (See 'Diarrhea with colitis' above.)

A spectrum of clinical manifestations is observed (table 1). (See 'Clinical manifestations' above.)

Clinical manifestations of C. difficile–associated diarrhea (CDAD) with colitis include watery diarrhea (≥3 loose stools in 24 hours) with lower abdominal pain and cramping, low-grade fever, and leukocytosis. (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.)

Recurrence C. difficile infection is defined by complete abatement of symptoms while on appropriate therapy, followed by subsequent reappearance of diarrhea and other symptoms after treatment has ended. 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 infection is established via a positive stool test for C. difficile toxins or C. difficile toxin gene. 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). The diagnostic approach for suspected recurrent C. difficile is the same as the approach for initial infection. (See 'Overview of diagnostic approach' above.)

Laboratory testing should be pursued only in patients with clinically significant diarrhea, since testing cannot distinguish between CDAD and asymptomatic carriage (which does not warrant treatment). For patients with ileus, laboratory diagnosis via perirectal swab for toxin assay or anaerobic culture may be performed. (See 'Overview of diagnostic approach' above.)

Radiographic imaging of the abdomen and pelvis is warranted for patients with clinical manifestations of severe illness or fulminant colitis to evaluate for presence of toxic megacolon, bowel perforation, or other findings warranting surgical intervention. (See 'Overview of diagnostic approach' above and 'Radiographic imaging' above.)

Lower gastrointestinal endoscopy is not warranted in patients with classic clinical manifestations of C. difficile infection, a positive laboratory test, and/or clinical response to empiric treatment. In general, endoscopy may be pursued for circumstances in which an alternative diagnosis is suspected that requires direct visualization and/or biopsy of the bowel mucosa. It may also be helpful for patients with ileus or fulminant colitis in the absence of diarrhea since it may allow visualization of pseudomembranes (severe inflammation of the inner lining of the bowel), a finding that is highly suggestive of C. difficile infection. (See 'Endoscopy' above.)

Findings of pseudomembranous colitis (severe inflammation of the inner lining of the bowel) on radiographic or endoscopic examination are highly suggestive of C. difficile infection and should prompt laboratory testing if not already performed. (See 'Radiographic imaging' above and 'Endoscopy' above.)

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