Clostridium difficile

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics
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Indications for Testing

  • Severe or persistent diarrhea in patients with risk factors (eg, recent antibiotic use, immunosuppression, age >65 years, chronic disease, hospital stay)
  • Hospitalized patients with >72 hours diarrhea (or sooner with clinical indications present)
  • Unexplained leukocytosis in hospitalized patients

Laboratory Testing

  • Current accepted practice
    • PCR testing for C. difficile toxin
      • PCR testing alone may be too sensitive and overdiagnose C. difficile infection – only patients with high pretest probability should be evaluated using this method
    • Enzyme immunoassay (EIA) for glutamate dehydrogenase antigen
    • Two-step process (refer to Clostridium difficile-associated disease (CDAD) testing algorithm)
  • Clostridium difficile-specific testing
    • Test diarrheal stools only – asymptomatic carrier state possible (American College of Gastroenterology [ACG], 2013)
    • C. difficile toxin B gene (tcdB) by PCR
      • Recommended initial test (ACG, 2013)
      • High sensitivity and specificity
      • Rapid platforms available
    • Glutamate dehydrogenase EIA
      • Initial rapid test, but sensitivity depends on strain
      • Does not identify toxin production (only presence of clostridium); therefore, test must be followed by toxin testing (so-called two-step test)
        • Most sensitive confirmatory test is tcdB PCR
    • Cytotoxin cell test –  gold standard, but time intensive
      • Requires specialized equipment and trained personnel
      • Sensitive and specific
      • May require >48 hours for results
    • Stool culture for C. difficile with cytotoxin cell assay
      • Reference method
    • Strain typing (eg,  NAP1) can be done for epidemiologic purposes only, using a variety of methods
    • Pulsed-field gel electrophoresis (PFGE) – laboratory test method for gram negative bacteria
    • PCR ribotyping – (eg, 027, 001, or 014 ribotype)
  • Molecular testing
    • Multilocus variable-number tandem repeat analysis
    • Multilocus sequence typing
    • Whole gene sequencing

Imaging Studies

  • Radiographic evidence of inflammation, ileus, or toxic megacolon
  • Lower GI endoscopy
    • Classic exam demonstrates pseudomembranous colitis on colonic histopathology
    • Test is invasive
    • Sensitivity is low – 50% for disease
    • Recommended for recurrent disease to rule out alternative diagnoses

Differential Diagnosis

Clostridium difficile is a major healthcare-associated infection (HAI) and causes significant morbidity and mortality. Severity ranges from mild to severe (requiring ICU admission).

Criteria for severity generally recognized to include

  • WBC >15,000,
  • Albumin <2.5 or 3.0,
  • Elevated creatinine (>1.5 % baseline)
  • Fever

Epidemiology

  • 435,000 cases yearly in the U.S. (Lessa, 2015)
    • 65% healthcare associated
    • 83,000 recurrences
    • 29,000 deaths

Organism

  • Gram-positive, spore-forming, anaerobic rod
    • Spores are resistant to heat, acid, and antibiotics
    • Found in environment, and in this form may be responsible for recurrent disease
  • Produces toxins – A, B, and binary
  • Higher virulence – associated with antibiotic resistance, more efficient spore production, and increased toxin production
  • BI/NAP1/027 – epidemic strain, emerged in 2000
  • Disease is associated with host risk factors
  • Bacteria is cultured in the stools of up to 50% of healthy neonates (<1 year), 3% of healthy adults, and 35% of hospitalized patients without disease (asymptomatic carrier state)

Risk Factors

  • Previous antimicrobial administration – from 10 days up to 10 weeks
  • Age >65 years
  • Previous history of C. difficile disease
  • Prior or current hospitalization
  • Residence in long-term care center
  • Severe underlying illness
  • Antineoplastic chemotherapy

Clinical Presentation

  • Watery diarrhea
  • Abdominal cramping
  • Anorexia
  • Nausea
  • Fever
  • Hypovolemia
  • Peritoneal signs
  • Rare presentation – ileus
  • Complications may include
    • Toxic megacolon
    • Bowel perforation with peritonitis
    • Need for colectomy
    • Shock
    • Renal failure
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Clostridium difficile toxin B gene (tcdB) by PCR 2002838
Method: Qualitative Polymerase Chain Reaction

Clostridium difficile Cytotoxin Cell Assay 0060851
Method: Cell Culture/Neutralization

Limitations 

May take up to 48 hours to get results

Clostridium difficile Culture with Reflex to Cytotoxin Cell Assay 0060140
Method: Culture/Identification

Limitations 

Culture alone does not distinguish toxin-producing strains

Requires up to 72 hours for report

Guidelines

Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald C, Pepin J, Wilcox MH, Society for Healthcare Epidemiology of America, Infectious Diseases Society of America. 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(5): 431-55. PubMed

Crobach MJ, Dekkers OM, Wilcox MH, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): data review and recommendations for diagnosing Clostridium difficile-infection (CDI). Clin Microbiol Infect. 2009; 15(12): 1053-66. PubMed

Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, McFarland LV, Mellow M, Zuckerbraun BS. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013; 108(4): 478-98; quiz 499. PubMed

General References

Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015; 313(4): 398-408. PubMed

Bartlett JG, Gerding DN. Clinical recognition and diagnosis of Clostridium difficile infection. Clin Infect Dis. 2008; 46 Suppl 1: S12-8. PubMed

Burnham CD, Carroll KC. Diagnosis of Clostridium difficile infection: an ongoing conundrum for clinicians and for clinical laboratories. Clin Microbiol Rev. 2013; 26(3): 604-30. PubMed

Eckert C, Jones G, Barbut F. Diagnosis of Clostridium difficile infection: the molecular approach. Future Microbiol. 2013; 8(12): 1587-98. PubMed

Gupta A, Patel R, Baddour LM, Pardi DS, Khanna S. Extraintestinal Clostridium difficile infections: a single-center experience. Mayo Clin Proc. 2014; 89(11): 1525-36. PubMed

Hessen MT. In the clinic. Clostridium difficile Infection. Ann Intern Med. 2010; 153(7): ITC41-15; quiz ITC416. PubMed

Larson AM, Fung AM, Fang FC. Evaluation of tcdB real-time PCR in a three-step diagnostic algorithm for detection of toxigenic Clostridium difficile. J Clin Microbiol. 2010; 48(1): 124-30. PubMed

Leffler DA, Lamont T. Clostridium difficile infection. N Engl J Med. 2015; 372(16): 1539-48. PubMed

Lessa FC, Winston LG, McDonald C, Emerging Infections Program C. difficile Surveillance Team. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015; 372(24): 2369-70. PubMed

Novak-Weekley SM, Marlowe EM, Miller JM, Cumpio J, Nomura JH, Vance PH, Weissfeld A. Clostridium difficile testing in the clinical laboratory by use of multiple testing algorithms. J Clin Microbiol. 2010; 48(3): 889-93. PubMed

O'Horo JC, Jones A, Sternke M, Harper C, Safdar N. Molecular techniques for diagnosis of Clostridium difficile infection: systematic review and meta-analysis. Mayo Clin Proc. 2012; 87(7): 643-51. PubMed

Pawlowski SW, Warren CA, Guerrant R. Diagnosis and treatment of acute or persistent diarrhea. Gastroenterology. 2009; 136(6): 1874-86. PubMed

Planche T, Aghaizu A, Holliman R, Riley P, Poloniecki J, Breathnach A, Krishna S. Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review. Lancet Infect Dis. 2008; 8(12): 777-84. PubMed

Pollock NR. Ultrasensitive Detection and Quantification of Toxins for Optimized Diagnosis of Clostridium difficile Infection. J Clin Microbiol. 2016; 54(2): 259-64. PubMed

Winslow BT, Onysko M, Thompson KA, Caldwell K, Ehlers GH. Common questions about Clostridium difficile infection. Am Fam Physician. 2014; 89(6): 437-42. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Couturier B, Schlaberg R, Konzak C, Nicholes J, Law C, She RC. tcdA As a diagnostic target in a loop-mediated amplification assay for detecting toxigenic Clostridium difficile. J Clin Lab Anal. 2013; 27(3): 171-6. PubMed

Schlaberg R, Mitchell MJ, Taggart EW, She RC, Microbiology Resource Committee of the College of American Pathologists. Verification of performance specifications for a US Food and Drug Administration-approved molecular microbiology test: Clostridium difficile cytotoxin B using the Becton, Dickinson and Company GeneOhm Cdiff assay. Arch Pathol Lab Med. 2012; 136(1): 20-5. PubMed

She RC, Durrant RJ, Petti CA. Evaluation of enzyme immunoassays to detect Clostridium difficile toxin from anaerobic stool culture. Am J Clin Pathol. 2009; 131(1): 81-4. PubMed

Medical Reviewers

Last Update: January 2017