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 have been altered by antibiotic therapy. It is one of the most common healthcare-associated infections and a significant cause of morbidity and mortality among elderly 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 — Watery diarrhea is the cardinal clinical symptom of C. difficile infection, although it can cause a spectrum of manifestations ranging from the asymptomatic carrier state to severe fulminant disease with toxic megacolon (table 1) [1,2]. The basis for this range of symptomatic responses is not fully understood but may be related to various host and pathogen factors. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology".)
Carrier state — About 20 percent of hospitalized adults are C. difficile carriers who shed C. difficile in their stools but do not have diarrhea; in long-term care facilities, carriage rate may approach 50 percent [3-5]. Although asymptomatic, these individuals serve as a reservoir for environmental contamination [4,5]. The host immune response to C. difficile may play a role in determining an individual's carrier status. Data on treatment of asymptomatic carriers are limited and routine treatment is not recommended. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology" and "Clostridium difficile infection: Prevention and control".)
Diarrhea with colitis — Manifestations of C. difficile–associated diarrhea with colitis include watery diarrhea up to 10 or 15 times daily with lower abdominal pain and cramping, low grade fever, and leukocytosis . Fever (T>38.5) is a sign of severe C. difficile–associated diarrhea (CDAD); fever is associated with CDAD in about 15 percent of cases. Leukocytosis in the setting of CDAD is common; CDAD is reported to routinely be associated with a WBC on average of 15K. These symptoms generally occur in the setting of antibiotic administration; they may begin during antibiotic therapy or 5 to 10 days following antibiotic administration. Infrequently, symptoms present as late as 10 weeks after cessation of therapy .
The antibiotics most frequently implicated in predisposition to C. difficile infection are fluoroquinolones, clindamycin, cephalosporins, and penicillins, but virtually all antibiotics, including metronidazole and vancomycin, can predispose to C. difficile (table 2).
Physical examination generally demonstrates lower abdominal tenderness. Sigmoidoscopic or colonoscopic examination may demonstrate a spectrum of findings, from patchy mild erythema and friability to severe pseudomembranous colitis. (See 'Pseudomembranous colitis' 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), for example, 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, most often diarrhea develops in the next one to two days. (See "Causes of neutrophilia", section on 'Acute infection'.)
Pseudomembranous colitis — Patients with pseudomembranous colitis usually present with clinical manifestations of CDAD with colitis. In addition, sigmoidoscopic examination in these patients demonstrates the presence of pseudomembranes, which is sufficient to make a presumptive diagnosis of C. difficile infection.
Endoscopic findings — C. difficile toxin-induced cytoskeleton disruption manifests with gross findings of shallow ulcerations on the intestine mucosal surface . Ulcer formation allows release of serum proteins, mucus, and inflammatory cells, which manifest grossly on the colorectal mucosal surface as pseudomembranes (virtually pathognomonic for C. difficile infection; there are rare reports of Klebsiella and other pathogens also capable of causing pseudomembranous colitis).
Pseudomembranes manifest as raised yellow or off-white plaques up to 2 cm in diameter scattered over the colorectal mucosa (picture 1 and picture 2). Some patients with pseudomembranous colitis have scattered lesions with relatively normal-appearing intervening mucosa, whereas others have a confluent pseudomembrane covering the entire mucosa. Other gross findings include may include bowel wall edema, erythema, friability, and inflammation; these may be observed with or without presence of pseudomembranes.
In some cases, pseudomembranes may be absent in the rectosigmoid area but may be visualized more proximally with colonoscopy, although colonoscopy is not indicated for diagnosis of C. difficile . Colonoscopy may demonstrate pseudomembranes even if sigmoidoscopy does not [10,11].
Histopathology — The pathologic features of pseudomembranous colitis (PMC) have been classified into three distinct types :
●Type 1 PMC is the mildest form and the major inflammatory changes are confined to the superficial epithelium and immediately subjacent lamina propria. Typical pseudomembranes are present, and crypt abscesses are occasionally present.
●Type 2 PMC is characterized by more severe disruption of glands, marked mucin secretion, and more intense inflammation of basal lamina.
●Type 3 PMC is characterized by severe, intense necrosis of the full thickness of the mucosa with a confluent pseudomembrane.
Recurrent disease: relapse vs reinfection — Recurrence of symptoms after successful initial therapy for C. difficile, due to relapse of the initial infecting strain or due to reinfection with a new strain, develops in 10 to 25 percent of cases; patients may experience several episodes of recurrence. Recurrence may present within days or weeks of completing treatment; the clinical presentation may be similar to or more severe than the initial presentation . Recurrence may be related to variability in the host immune response to C. difficile infection. (See "Clostridium difficile in adults: Treatment", section on 'Management of initial recurrence' and "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology".)
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 .
Some patients with recurrent diarrhea, cramping, and bloating after treatment of C. difficile may have postinfectious irritable bowel syndrome or other inflammatory colitides including collagenous or microscopic colitis, concomitant ulcerative colitis or Crohn’s disease, or celiac disease (See "Pathophysiology of irritable bowel syndrome".)
Fulminant colitis — The manifestations of fulminant colitis typically include severe lower quadrant or diffuse abdominal pain, diarrhea, abdominal distention, fever, hypovolemia, lactic acidosis, hypoalbuminemia, and marked leukocytosis (up to 40,000 white blood cells/microL or higher) [8,16,17]. Diarrhea may be less prominent in patients with prolonged ileus due to pooling of secretions in the dilated, atonic colon. Other potential complications of fulminant colitis include toxic megacolon and bowel perforation .
Toxic megacolon is a clinical diagnosis based upon the finding of colonic dilatation (>7 cm in its greatest diameter) accompanied by severe systemic toxicity. Abdominal plain films may also demonstrate 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). (See "Toxic megacolon".)
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.
Aggressive diagnostic and therapeutic interventions are warranted in the setting of fulminant C. difficile infection. Bedside sigmoidoscopy or colonoscopy may be performed to make a presumptive diagnosis of C. difficile infection by evaluating for presence of pseudomembranes. Given the risk of perforation, care should be taken to introduce minimal amounts of air to avoid exacerbating ileus or distention. Prompt surgical consultation is warranted to assess the requirement for colectomy . (See "Clostridium difficile in adults: Treatment", section on 'Treatment'.)
Unusual presentations — Other manifestations of C. difficile include protein-losing enteropathy with ascites, C. difficile infection in the setting of chronic inflammatory bowel disease, and extracolonic involvement.
Protein-losing enteropathy with ascites — Many patients with C. difficile infection develop protein-losing enteropathy with hypoalbuminemia, and a few may exhibit ascites and peripheral edema [20,21]. 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".)
Clostridium difficile and inflammatory bowel disease — Infection with C. difficile (as well as other enteric pathogens) may complicate the course of inflammatory bowel disease (IBD) [22,23]. Enteric infections account for about 10 percent of symptomatic relapses in patients with IBD; C. difficile accounts for about one-half of these infections . Rates of C. difficile among IBD patients appear to be increasing in some institutions [25,26]. 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 IBD patients 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 more frequently may require colectomy (20 percent in one series) . Specific antibiotic and surgical management is discussed in detail separately. (See "Clostridium difficile in adults: Treatment".)
There is also 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.
Extracolonic involvement — Rare cases of C. difficile appendicitis, small bowel enteritis, and extraintestinal involvement have been described .
●Appendicitis due to C. difficile is unusual; three cases have been described . The association may be underdiagnosed because milder cases might respond to antibiotic therapy alone.
●Small bowel involvement with C. difficile enteritis is unusual [30-32]. Manifestations may include increased ileostomy output; in some cases, such patients have had prior colectomy with ileostomy, allowing direct visualization of pseudomembranes on the ileostomy mucosa. Patients with C. difficile involvement of the small bowel tend to be elderly or have multiple comorbidities. Therefore, such patients may be at increased risk for fulminant disease with a high mortality rate [31,32].
●Rare cases of C. difficile cellulitis, soft tissue infection, bacteremia, and reactive arthritis have been described [30,33,34].
DIAGNOSIS — The diagnosis of C. difficile infection requires the presence of moderate to severe diarrhea or ileus, and either [35-39]:
●A stool test positive for C. difficile toxins or toxigenic C. difficile
●Endoscopic or histologic findings of pseudomembranous colitis
Diagnostic stool evaluation for the presence of C. difficile toxins should be pursued in the setting of clinically significant diarrhea (usually defined as three or more loose stools per day for at least two days); suspicion is warranted if many stools (10 to 15) occur with fever or nocturnal diarrhea even if only one day in duration.
In general, only loose, watery, or semiformed stool should be tested for C. difficile [40-44]. Diagnosis via swab may be warranted for patients with suspected C. difficile infection and ileus [40,41,45,46]. C. difficile toxin degrades at room temperature and may be undetectable within two hours after collection ; specimens should be kept at 4ºC if delay is anticipated. A suspected outbreak should prompt freezing of stool samples for later investigation.
Laboratory diagnosis — Laboratory diagnosis of C. difficile infection requires demonstration of C. difficile toxin(s) or detection of toxigenic C. difficile organism(s) . A number of tests are available, including [39,41,47]:
●Polymerase chain reaction (PCR)
●Enzyme immunoassay (EIA) for C. difficile glutamate dehydrogenase (GDH)
●Enzyme immunoassay (EIA) 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 that detect toxin A and B genes are highly sensitive and specific [48-51]. The sensitivity of PCR is greater than enzyme immunoassay and comparable to cytotoxicity assay [41,52-56]. In addition, PCR results can be available within as little as one hour. Given its high sensitivity and the potential, therefore, for false positive results, some favor use of PCR in an algorithm together with other assays such as EIA for GHD and EIA for toxins A and B. (See 'Clinical approach' below.)
●EIA for C. difficile GDH – GDH antigen is an essential enzyme produced constitutively by all C. difficile isolates; its detection cannot distinguish between toxigenic and nontoxigenic strains [57-59]. 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 [41,60]. GDH antigen testing is highly sensitive, 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 [61-65]. The sensitivity of EIA for toxins A and B is about 75 percent; the specificity is high (up to 99 percent) [41,66,67]. 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 .
If the initial EIA test is negative, the value of repeating the test is limited and repeat testing is generally discouraged [41,69-71]. Three studies found fewer than 10 percent more cases by repeated testing [72-74], while two others found 19 percent and 20 percent more cases with one or two further tests [69,75].
●Cell culture cytotoxicity assay – The cell culture cytotoxicity assay is the 'gold standard' test for diagnosis of C. difficile and is the standard against which other tests should be compared [76,77]. It 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 (figure 1). The cytotoxicity assay is more sensitive than enzyme immunoassays but is labor intensive and takes approximately two days [35,39,79].
A study comparing the Cepheid Xpert C. difficile PCR assay with cell culture cytotoxicity assay for diagnosis of CDAD, the sensitivity and specificity of the Cepheid assay were 97 and 93 percent, respectively . Using the PCR ribotyping as a reference for the hypervirulent 027 strain, the sensitivity and specificity were 100 and 98.1 percent, respectively. A previous study compared PCR and EIA techniques with anaerobic culture (the "most sensitive") in 618 stool samples; sensitivity and specificity were better for PCR than EIA (93 and 97 percent versus 73 and 97 percent, respectively) . PCR results may be falsely negative if stool specimen collection is delayed and the patient treated empirically for suspected C. difficile infection .
●Selective anaerobic culture – Culture on selective medium with toxin testing of isolated C. difficile is the most sensitive diagnostic method, although culture alone cannot distinguish toxin-producing strains from non-toxin–producing strains . Prior treatment with heat or alcohol to select spores is sometimes used to improve yield. Culture is useful for epidemiologic studies, but is generally too slow and labor-intensive for clinical use .
A number of multistep algorithms have been developed in an attempt to improve the accuracy of diagnostic testing for C. difficile infection [41,57-60,83].
Clinical approach — Diagnostic testing is warranted only for patients with clinically significant diarrhea. We favor use of PCR for diagnosis of C. difficile, either alone or as part of an algorithm including initial EIA screening for GDH and toxins A and B (algorithm 1). A positive result may be presumed in the setting of positive EIA for GDH and toxin, and a negative result if both EIAs are negative. Confirmatory PCR may be used if the EIA results are discordant [84-87].
The high sensitivity and specificity of PCR, together with its rapid turnaround time, allow prompt isolation and treatment of patients with C. difficile infection, likely reducing opportunity for nosocomial spread and improving patient outcomes. An algorithmic approach may be less expensive but take slightly longer and may have reduced sensitivity compared with PCR alone . Repeat testing and test for cure are not warranted.
The diagnostic approach for suspected recurrent C. difficile is the same as the approach for initial infection. There is no clinical role for laboratory diagnosis among asymptomatic patients or among patients on treatment for acute disease, whose stool assays may remain positive during or after clinical recovery.
Endoscopy — Colonoscopy or sigmoidoscopy and biopsy (in the setting of diagnostic uncertainty) can be a useful adjunctive tool for diagnosis of C. difficile in the following settings:
●High clinical suspicion for C. difficile with negative laboratory assay(s)
●Prompt C. difficile diagnosis needed before laboratory results can be obtained
●Failure of C. difficile infection to respond to antibiotic therapy
●Atypical presentation with ileus or minimal diarrhea [11,88]
In the appropriate clinical setting, visualization of pseudomembranes on sigmoidoscopy nearly always reflects C. difficile infection. However, pseudomembranes are not observed in 10 to 20 percent of patients with C. difficile, particularly in the setting of recurrent infection; in such cases, biopsy is useful for diagnosis of C. difficile infection [89,90]. In addition, pseudomembranes may not be observed in the setting of other forms of colitis. For example, pseudomembranes are rarely seen in patients with inflammatory bowel disease and superimposed C. difficile infection; in such cases, biopsy is also useful for diagnosis of C. difficile infection.
Endoscopy is not warranted in patients with classic clinical findings and a positive stool toxin assay. In the setting of fulminant colitis, care should be taken to introduce minimal amounts of air given the risk of perforation. Gross and histologic findings obtained by endoscopic evaluation are discussed in detail above. (See 'Endoscopic findings' above and 'Pseudomembranous colitis' above.)
DIFFERENTIAL DIAGNOSIS — C. difficile must be distinguished from other infectious and noninfectious causes of diarrhea. Staphylococcus aureus was previously implicated as an important cause of antibiotic-associated pseudomembranous colitis [68,91]. Other potential pathogens include Klebsiella oxytoca, Clostridium perfringens, Candida spp, and Salmonella [88,92-96].
Among noninfectious causes, antibiotic-associated diarrhea may be attributable to osmotic mechanisms rather than C. difficile infection. Differentiation of this noninfectious form of antibiotic-associated diarrhea may be difficult, especially in patients who also may be asymptomatic C. difficile carriers. Cessation of symptoms with discontinuation of oral intake is a distinguishing feature of osmotic diarrhea (figure 2). 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 bout of C. difficile. These patients may have up to 10 watery stools per day and this must be distinguished from a relapse of the original C. difficile infection. (See "Pathophysiology of irritable bowel syndrome".)
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 have been altered by antibiotic therapy and causes antibiotic-associated colitis; a spectrum of manifestations is observed (table 1). (See 'Clinical manifestations' above.)
●Manifestations of C. difficile–associated diarrhea (CDAD) with colitis include watery diarrhea up to 10 or 15 times daily 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, cephalosporins, and penicillins (table 2). (See 'Diarrhea with 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: relapse vs reinfection' above.)
●Manifestations of fulminant colitis include severe lower quadrant or diffuse abdominal pain, diarrhea, abdominal distention, fever, hypovolemia, lactic acidosis, and marked leukocytosis. Diarrhea may be less prominent 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.)
●The diagnosis should be based on results from a laboratory diagnostic test detecting toxin-producing strains (via enzyme immunoassay or polymerase chain reaction) or an endoscopic evaluation that demonstrates pseudomembranes in the colon. (See 'Diagnosis' above.)
●We favor use of polymerase chain reaction (PCR) for diagnosis of C. difficile, either alone or as part of an algorithm (See 'Clinical approach' above.)
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