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Clinical manifestations and diagnosis of Clostridium difficile infection in adults
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2012. | This topic last updated: Jan 20, 2012.

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 "Treatment of Clostridium difficile infection in adults" and "Epidemiology, microbiology, and pathophysiology of Clostridium difficile infection in adults".)

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]. The basis for this range of symptomatic responses is not fully understood but may be related to various host and pathogen factors. (See "Epidemiology, microbiology, and pathophysiology of Clostridium difficile infection in adults".)

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 [2-4]. Although asymptomatic, these individuals serve as a reservoir for environmental contamination [3,4]. 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 "Epidemiology, microbiology, and pathophysiology of Clostridium difficile infection in adults" and "Prevention and control of Clostridium difficile in hospital and institutional settings".)

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 [5]. 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 [6].

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 [7,8]. 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 [7]. 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 [9]. 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 [8]. Colonoscopy may demonstrate pseudomembranes even if sigmoidoscopy does not [8,10].

Histopathology — The pathologic features of pseudomembranous colitis (PMC) have been classified into three distinct types [11]:

  • 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.

Imaging — Abdominal computed tomography (CT) scan in patients with pseudomembranous colitis demonstrates pronounced thickening of the colonic wall (picture 3) [12].

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 [13]. Recurrence may be related to variability in the host immune response to C. difficile infection. (See "Treatment of Clostridium difficile infection in adults", section on 'Management of initial recurrence' and "Epidemiology, microbiology, and pathophysiology of Clostridium difficile infection in adults".)

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 [14].

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, and marked leukocytosis (up to 40,000 white blood cells/microL or higher) [15,16]. 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 [17].

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 (picture 4 and picture 5). (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 [18]. (See "Treatment of Clostridium difficile infection in adults", 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 [19,20]. 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 "Treatment of Clostridium difficile infection in adults".)

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) [21,22]. Enteric infections account for about 10 percent of symptomatic relapses in patients with IBD; C. difficile accounts for about one-half of these infections [23]. Rates of C. difficile among IBD patients appear to be increasing in some institutions [24,25]. 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 [23].

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) [25]. Specific antibiotic and surgical management is discussed in detail separately. (See "Treatment of Clostridium difficile infection in adults".)

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 [26]. 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 [27]. The association may be underdiagnosed because milder cases might respond to antibiotic therapy alone.
  • Small bowel involvement with C. difficile enteritis is unusual [28-30]. 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 [29,30].
  • Rare cases of C. difficile cellulitis, soft tissue infection, and reactive arthritis have been described [28,31].

DIFFERENTIAL DIAGNOSIS — Although C. difficile is the major infectious cause of antibiotic-associated diarrhea, it 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 [32,33]. Other potential pathogens include Klebsiella oxytoca, Clostridium perfringens, Candida spp, and Salmonella [34-39].

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 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 bout of C. difficile. These patients may have up to 10 watery stools per day and are often convinced that they are suffering from a relapse of their original C. difficile infection. (See "Pathophysiology of irritable bowel syndrome".)

DIAGNOSIS — Diagnostic evaluation 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. However, some patients with C. difficile have ileus [40,41]. There is no clinical role for testing stool from asymptomatic patients or in patients on therapy for acute disease who may still have positive stool assays during or after clinical recovery.

The diagnosis should be based on results from a laboratory diagnostic test or an endoscopic evaluation that demonstrates pseudomembranes in the colon.

Laboratory diagnosis — There are two categories of laboratory tests for C. difficile: toxin assays (which evaluate for evidence of toxin), and organism detection assays (which evaluate for the presence of the organism).

The optimal approach for laboratory diagnosis of C. difficile is uncertain. Anaerobic stool culture is the most sensitive test but is not practical due to its slow turnaround time; the need to detect toxin production by the recovered isolate further slows down this approach. Cytotoxicity assay also takes too long for routine clinical use, but it is the standard against which other clinical tests should be compared.

Many laboratories use enzyme immunoassay (EIA) testing for C. difficile toxins A and B, which is rapid but less sensitive than the cytotoxicity assay. One strategy to overcome this problem is to test for glutamate dehydrogenase (GDH), an essential enzyme produced by all C. difficile isolates (in the presence or absence of toxin production). This may be used as initial screening followed by cytotoxicity testing for positive samples.

Polymerase chain reaction (PCR) of stool appears to be rapid, sensitive and specific. Major clinical laboratories are beginning to adopt this tool as their primary diagnostic approach; more data would be helpful to support routine use of this modality. Repeat PCR within seven days of a negative result is rarely useful, except for patients with evidence of a new infection [42].

Toxin assays — Toxin assays include cytotoxicity assay, EIA and PCR. Most strains produce both toxins A and B though some clinically relevant strains produce toxin A or B only [43-47].

  • Cytotoxin assay — Cytotoxin assay (or tissue culture assay) is the gold standard for diagnosis of C. difficile [48]. The test 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 2).

    Because only a few toxin molecules per cell are sufficient to cause rounding, the cytotoxicity assay can detect as little as 10 pg of toxin B, making it the most sensitive C. difficile test (94 to 100 percent) [49,50]. In addition, the sample is preincubated with neutralizing antibody against the toxin, allowing for high specificity (99 percent). However, most clinical laboratories do not perform this assay routinely given its relatively high cost and long turnaround time (48 hours).
  • Enzyme immunoassay (EIA) — EIA allows direct detection of C. difficile toxins in stool filtrates [51]. Commercially available reagents can detect toxin A alone or both toxins A and B. EIA for both toxins should be used because clinical cases may involve strains with a mutation in toxin A (rendering the EIA for toxin A ineffective) or strains that produce only toxin B [43-47]. In one study of 276 stool samples positive for C. difficile by EIA, for example, 19 percent were positive for toxin A alone, 48 percent for toxin B alone, and 33 percent for both toxins [52].

    EIA is the preferred diagnostic assay in most clinical laboratories because the technique is relatively simple and inexpensive compared to PCR and results are available within 24 hours. Despite good specificity (up to 99 percent), EIA is reported to have only moderate and variable sensitivity (60 to 95 percent) [53]. There is a relatively high false negative rate since 100 to 1000 pg of toxin must be present for the test to be positive [32].

    Routine repeat EIA testing does not significantly improve diagnostic yield [54,55]. Some laboratories may favor adopting a policy limiting the number of specimens tested from a given patient during a one week period; in a review of 3749 initially negative tests, only 2.5 percent were positive upon repeat testing within 10 days of the first test [56]. Supplementing negative EIA stools tests with tissue culture assay may also be useful.
  • Polymerase chain reaction (PCR) — In 2009, the United States Food and Drug Administration (FDA) approved three real-time PCR assays for the gene encoding toxin B (Cepheid Gene Xpert), BD-GeneOhn C diff assay, and IVD RT-PCR (Pro-gastro, Prodesse). These modalities are rapid, accurate diagnostic tools for C. difficile, which is important for prompt implementation of treatment and infection control measures. Subsequently the Cepheid Xpert C. difficile/Epi assay was developed; this assay detects the presence of toxin B gene [57]. The test also detects if the C. difficile is the epidemic 027/NAP1/BI strain, although this is intended for epidemiologic purposes only and should not be used to determine or monitor treatment.
  • In a study comparing the Cepheid Xpert C. difficile assay with cell cytotoxicity neutralization for diagnosis of C. difficile infection, the sensitivity and specificity of the Cepheid assay were 97 and 93 percent, respectively [58]. 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) [59]. (See "Epidemiology, microbiology, and pathophysiology of Clostridium difficile infection in adults", section on 'Hypervirulent strain'.)

Organism detection — Organism detection assays include common antigen testing and anaerobic culture. An inherent problem with detection of the organism rather than the toxin is that not all C. difficile strains are toxigenic and up to 30 percent of hospitalized patients are colonized without disease [3]. In one study of hospitalized patients colonized with C. difficile, 92 percent of patients with diarrhea were colonized with toxigenic strains, compared with 81 percent of asymptomatic carriers [60]. Some laboratories use one of these methods to screen stool samples, with subsequent cytotoxin testing for positive samples [61].

  • Common antigen testing — Common antigen testing detects GDH antigen, an essential enzyme produced constitutively by all C. difficile isolates. Some laboratories use this method to screen stool samples, with subsequent cytotoxin testing for positive samples [61-63].
  • Stool culture — Anaerobic stool culture is used infrequently for diagnosis of C. difficile. Although the test is extremely sensitive, anaerobic culture requires about three days. In addition, the assay cannot distinguish toxin-producing strains from non-toxin producing strains [50]. To address this limitation, some laboratories perform an EIA on anaerobic culture isolates to determine whether they are toxin-producing strains; this approach appears to be more sensitive than assays that use stool specimens directly [64]. (See 'Toxin assays' above.)

Anaerobic culture is not a routinely used diagnostic tool in most clinical laboratories since it is relatively slow and labor intensive. However, it remains an important tool for epidemiologic surveillance [53].

Endoscopy — Colonoscopy or sigmoidoscopy 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 [10,38]

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.)

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SUMMARY

  • 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 Cd strains or an endoscopic evaluation that demonstrates pseudomembranes in the colon. (See 'Diagnosis' above.)
  • The optimal approach for laboratory diagnosis of C. difficile is uncertain. Anaerobic stool culture is the most sensitive test but is not practical due to its slow turnaround time. Cytotoxicity assay also takes too long for routine clinical use but is the standard against which other clinical tests should be compared. (See 'Laboratory diagnosis' above.)
  • Many laboratories use enzyme immunoassay (EIA) testing for C. difficile toxins A and B, which is rapid but less sensitive than the cytotoxicity assay. One strategy to overcome this problem is a two-step method using common antigen detection for glutamate dehydrogenase (GDH) in stool as initial screening followed by followed by cytotoxicity testing for positive samples. Polymerase chain reaction (PCR) of stool appears to be rapid, sensitive, and specific; major clinical laboratories are beginning to adopt this tool as their primary diagnostic approach. (See 'Laboratory diagnosis' above.)

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REFERENCES

  1. Kelly CP, LaMont JT. Clostridium difficile--more difficult than ever. N Engl J Med 2008; 359:1932.
  2. Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 2000; 342:390.
  3. McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989; 320:204.
  4. Riggs MM, Sethi AK, Zabarsky TF, et al. Asymptomatic carriers are a potential source for transmission of epidemic and nonepidemic Clostridium difficile strains among long-term care facility residents. Clin Infect Dis 2007; 45:992.
  5. Wanahita A, Goldsmith EA, Musher DM. Conditions associated with leukocytosis in a tertiary care hospital, with particular attention to the role of infection caused by clostridium difficile. Clin Infect Dis 2002; 34:1585.
  6. Tedesco FJ. Pseudomembranous colitis: pathogenesis and therapy. Med Clin North Am 1982; 66:655.
  7. Rao SS, Edwards CA, Austen CJ, et al. Impaired colonic fermentation of carbohydrate after ampicillin. Gastroenterology 1988; 94:928.
  8. Seppälä K, Hjelt L, Sipponen P. Colonoscopy in the diagnosis of antibiotic-associated colitis. A prospective study. Scand J Gastroenterol 1981; 16:465.
  9. Riegler M, Sedivy R, Pothoulakis C, et al. Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro. J Clin Invest 1995; 95:2004.
  10. Tedesco FJ. Antibiotic associated pseudomembranous colitis with negative proctosigmoidoscopy examination. Gastroenterology 1979; 77:295.
  11. Price AB, Davies DR. Pseudomembranous colitis. J Clin Pathol 1977; 30:1.
  12. Valiquette L, Pépin J, Do XV, et al. Prediction of complicated Clostridium difficile infection by pleural effusion and increased wall thickness on computed tomography. Clin Infect Dis 2009; 49:554.
  13. Fekety R, McFarland LV, Surawicz CM, et al. Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial. Clin Infect Dis 1997; 24:324.
  14. Kamboj M, Khosa P, Kaltsas A, et al. Relapse versus reinfection: surveillance of Clostridium difficile infection. Clin Infect Dis 2011; 53:1003.
  15. Wanahita A, Goldsmith EA, Marino BJ, Musher DM. Clostridium difficile infection in patients with unexplained leukocytosis. Am J Med 2003; 115:543.
  16. Bulusu M, Narayan S, Shetler K, Triadafilopoulos G. Leukocytosis as a harbinger and surrogate marker of Clostridium difficile infection in hospitalized patients with diarrhea. Am J Gastroenterol 2000; 95:3137.
  17. Rubin MS, Bodenstein LE, Kent KC. Severe Clostridium difficile colitis. Dis Colon Rectum 1995; 38:350.
  18. Lamontagne F, Labbé AC, Haeck O, et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg 2007; 245:267.
  19. Dansinger ML, Johnson S, Jansen PC, et al. Protein-losing enteropathy is associated with Clostridium difficile diarrhea but not with asymptomatic colonization: a prospective, case-control study. Clin Infect Dis 1996; 22:932.
  20. Rybolt AH, Bennett RG, Laughon BE, et al. Protein-losing enteropathy associated with Clostridium difficile infection. Lancet 1989; 1:1353.
  21. LaMont JT, Trnka YM. Therapeutic implications of Clostridium difficile toxin during relapse of chronic inflammatory bowel disease. Lancet 1980; 1:381.
  22. Greenfield C, Aguilar Ramirez JR, Pounder RE, et al. Clostridium difficile and inflammatory bowel disease. Gut 1983; 24:713.
  23. Mylonaki M, Langmead L, Pantes A, et al. Enteric infection in relapse of inflammatory bowel disease: importance of microbiological examination of stool. Eur J Gastroenterol Hepatol 2004; 16:775.
  24. Rodemann JF, Dubberke ER, Reske KA, et al. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin Gastroenterol Hepatol 2007; 5:339.
  25. Issa M, Vijayapal A, Graham MB, et al. Impact of Clostridium difficile on inflammatory bowel disease. Clin Gastroenterol Hepatol 2007; 5:345.
  26. Clayton EM, Rea MC, Shanahan F, et al. The vexed relationship between Clostridium difficile and inflammatory bowel disease: an assessment of carriage in an outpatient setting among patients in remission. Am J Gastroenterol 2009; 104:1162.
  27. Brown TA, Rajappannair L, Dalton AB, et al. Acute appendicitis in the setting of Clostridium difficile colitis: case report and review of the literature. Clin Gastroenterol Hepatol 2007; 5:969.
  28. Jacobs A, Barnard K, Fishel R, Gradon JD. Extracolonic manifestations of Clostridium difficile infections. Presentation of 2 cases and review of the literature. Medicine (Baltimore) 2001; 80:88.
  29. Hayetian FD, Read TE, Brozovich M, et al. Ileal perforation secondary to Clostridium difficile enteritis: report of 2 cases. Arch Surg 2006; 141:97.
  30. Vesoulis Z, Williams G, Matthews B. Pseudomembranous enteritis after proctocolectomy: report of a case. Dis Colon Rectum 2000; 43:551.
  31. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 19-1998. A 70-year-old man with diarrhea, polyarthritis, and a history of Reiter's syndrome. N Engl J Med 1998; 338:1830.
  32. Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med 2002; 346:334.
  33. Gravet A, Rondeau M, Harf-Monteil C, et al. Predominant Staphylococcus aureus isolated from antibiotic-associated diarrhea is clinically relevant and produces enterotoxin A and the bicomponent toxin LukE-lukD. J Clin Microbiol 1999; 37:4012.
  34. Högenauer C, Langner C, Beubler E, et al. Klebsiella oxytoca as a causative organism of antibiotic-associated hemorrhagic colitis. N Engl J Med 2006; 355:2418.
  35. Sparks SG, Carman RJ, Sarker MR, McClane BA. Genotyping of enterotoxigenic Clostridium perfringens fecal isolates associated with antibiotic-associated diarrhea and food poisoning in North America. J Clin Microbiol 2001; 39:883.
  36. Forbes D, Ee L, Camer-Pesci P, Ward PB. Faecal candida and diarrhoea. Arch Dis Child 2001; 84:328.
  37. Hovius SE, Rietra PJ. Salmonella colitis clinically presenting as a pseudomembranous colitis. Neth J Surg 1982; 34:81.
  38. Triadafilopoulos G, Hallstone AE. Acute abdomen as the first presentation of pseudomembranous colitis. Gastroenterology 1991; 101:685.
  39. Bauer TM, Lalvani A, Fehrenbach J, et al. Derivation and validation of guidelines for stool cultures for enteropathogenic bacteria other than Clostridium difficile in hospitalized adults. JAMA 2001; 285:313.
  40. Peterson LR, Robicsek A. Does my patient have Clostridium difficile infection? Ann Intern Med 2009; 151:176.
  41. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31:431.
  42. Luo RF, Banaei N. Is repeat PCR needed for diagnosis of Clostridium difficile infection? J Clin Microbiol 2010; 48:3738.
  43. Limaye AP, Turgeon DK, Cookson BT, Fritsche TR. Pseudomembranous colitis caused by a toxin A(-) B(+) strain of Clostridium difficile. J Clin Microbiol 2000; 38:1696.
  44. Barbut F, Lalande V, Burghoffer B, et al. Prevalence and genetic characterization of toxin A variant strains of Clostridium difficile among adults and children with diarrhea in France. J Clin Microbiol 2002; 40:2079.
  45. Johnson S, Kent SA, O'Leary KJ, et al. Fatal pseudomembranous colitis associated with a variant clostridium difficile strain not detected by toxin A immunoassay. Ann Intern Med 2001; 135:434.
  46. Knapp CC, Sandin RL, Hall GS, et al. Comparison of vidas Clostridium difficile toxin-A assay and premier C. difficile toxin-A assay to cytotoxin-B tissue culture assay for the detection of toxins of C. difficile. Diagn Microbiol Infect Dis 1993; 17:7.
  47. Lyras D, O'Connor JR, Howarth PM, et al. Toxin B is essential for virulence of Clostridium difficile. Nature 2009; 458:1176.
  48. Bartlett JG, Chang TW, Gurwith M, et al. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med 1978; 298:531.
  49. Laughon BE, Viscidi RP, Gdovin SL, et al. Enzyme immunoassays for detection of Clostridium difficile toxins A and B in fecal specimens. J Infect Dis 1984; 149:781.
  50. Shanholtzer CJ, Willard KE, Holter JJ, et al. Comparison of the VIDAS Clostridium difficile toxin A immunoassay with C. difficile culture and cytotoxin and latex tests. J Clin Microbiol 1992; 30:1837.
  51. Gerding DN, Johnson S, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol 1995; 16:459.
  52. Kader HA, Piccoli DA, Jawad AF, et al. Single toxin detection is inadequate to diagnose Clostridium difficile diarrhea in pediatric patients. Gastroenterology 1998; 115:1329.
  53. Blossom DB, McDonald LC. The challenges posed by reemerging Clostridium difficile infection. Clin Infect Dis 2007; 45:222.
  54. Manabe YC, Vinetz JM, Moore RD, et al. Clostridium difficile colitis: an efficient clinical approach to diagnosis. Ann Intern Med 1995; 123:835.
  55. Deshpande A, Pasupuleti V, Patel P, et al. Repeat stool testing to diagnose Clostridium difficile infection using enzyme immunoassay does not increase diagnostic yield. Clin Gastroenterol Hepatol 2011; 9:665.
  56. Cardona DM, Rand KH. Evaluation of repeat Clostridium difficile enzyme immunoassay testing. J Clin Microbiol 2008; 46:3686.
  57. Babady NE, Stiles J, Ruggiero P, et al. Evaluation of the Cepheid Xpert Clostridium difficile Epi assay for diagnosis of Clostridium difficile infection and typing of the NAP1 strain at a cancer hospital. J Clin Microbiol 2010; 48:4519.
  58. Huang H, Weintraub A, Fang H, Nord CE. Comparison of a commercial multiplex real-time PCR to the cell cytotoxicity neutralization assay for diagnosis of clostridium difficile infections. J Clin Microbiol 2009; 47:3729.
  59. Peterson LR, Manson RU, Paule SM, et al. Detection of toxigenic Clostridium difficile in stool samples by real-time polymerase chain reaction for the diagnosis of C. difficile-associated diarrhea. Clin Infect Dis 2007; 45:1152.
  60. McFarland LV, Elmer GW, Stamm WE, Mulligan ME. Correlation of immunoblot type, enterotoxin production, and cytotoxin production with clinical manifestations of Clostridium difficile infection in a cohort of hospitalized patients. Infect Immun 1991; 59:2456.
  61. Ticehurst JR, Aird DZ, Dam LM, et al. Effective detection of toxigenic Clostridium difficile by a two-step algorithm including tests for antigen and cytotoxin. J Clin Microbiol 2006; 44:1145.
  62. Reller ME, Lema CA, Perl TM, et al. Yield of stool culture with isolate toxin testing versus a two-step algorithm including stool toxin testing for detection of toxigenic Clostridium difficile. J Clin Microbiol 2007; 45:3601.
  63. Fenner L, Widmer AF, Goy G, et al. Rapid and reliable diagnostic algorithm for detection of Clostridium difficile. J Clin Microbiol 2008; 46:328.
  64. Delmée M, Van Broeck J, Simon A, et al. Laboratory diagnosis of Clostridium difficile-associated diarrhoea: a plea for culture. J Med Microbiol 2005; 54:187.
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