Clostridium difficile

Diagnosis

Indications for testing

• Severe or persistent diarrhea in patients with risk factors (predominantly previous antibiotic use); may also occur several months after antibiotic use
• Hospitalized patients with >72 hours diarrhea (or sooner for clinical indications)

Laboratory testing

• CDC testing recommendations
• Initial testing
  • CBC – often demonstrates leukocytosis; if leukocytosis not present, consider testing to rule out other organisms as the cause of diarrhea
  • Culture stool for Campylobacter, Salmonella, Shigella, E. coli (Shiga toxin producing strains)
• Testing for presence of toxins A and B on unformed stool (multiple repeats in 24-hour period are not recommended); should not be used to monitor therapy
  • Glutamate dehydrogenase enzyme immunoassay (EIA) – initial rapid test but must be followed by toxin testing (so-called two-step test)
  • EIA – rapid but less sensitive than cytotoxin cell assay (sensitivity ~80% for stool specimen)
  • PCR of stool for presence of toxin B gene
    • Emerging gold standard with high sensitivity and specificity
    • Rapid platforms available
  • Cytotoxin cell assay – highly sensitive and most specific test; may require 48 hours for results
  • Stool culture for C. difficile with cytotoxin cell assay
    • Gold standard 
    • Requires up to 96 hours
    • Does not distinguish toxin-producing strains; toxin testing of isolates delays final results
    • Individuals without disease may have positive culture; perform only in symptomatic patients
• Endoscopy – classic exam effectively demonstrates pseudomembranous colitis, but sensitivity is low (50%) for CDAD
• Strain typing can be done for epidemiologic purposes using a variety of methods (eg, PCR ribotyping, pulsed field gel electrophoresis) but has no proven clinical utility and is not routinely performed by clinical laboratories

Differential Diagnosis

• Other bacterial diarrhea
• Diarrhea, viral
• Diarrhea, parasitic
• Inflammatory bowel disease
• Irritable bowel syndrome
• Malabsorption

Clinical Background

Clostridium difficile causes 15-25% of all antibiotic-associated diarrhea (AAD) and >90% of antibiotic-associated pseudomembranous colitis (PMC).

Epidemiology

• Incidence – 112/100,000 in the U.S. for adult C. difficile-associated disease (CDAD) hospitalizations (CDC, 2005)

Organism

• Gram-positive, spore-forming rod
• Obligate anaerobe
• Produces toxins – A, B and binary
  • Toxin production is necessary to produce disease
  • A and B activate cytokines
  • Binary toxin is less well understood – produced by NAP1 strain (NAP1/B1/027)
    • Strain also produces A and B toxins in much higher quantities than other strains
    • May be a hyper-virulent strain
    • Testing of patient specimens to identify NAP1 has no proven clinical utility; used mainly for epidemiologic purposes
• Cultured in the stools of up to 50% of healthy neonates (<1 year), 3% of healthy adults, and 35% of hospitalized patients

Risk Factors

• Antimicrobial administration within previous 60 days – >90% of cases have this risk factor
• Age >65 years
• Previous history of C. difficile disease
• Prior or current hospitalization
• Residence in long-term care center
• Severe underlying illness

Clinical Presentation

• Asymptomatic carrier state
• Mild – non-bloody diarrhea (bacterial, parasitic, viral), abdominal cramping, >3 stools/day
• Severe – abdominal pain, severe diarrhea, fulminant disease (toxic megacolon and paralytic ileus) with fever, anorexia, nausea and malaise
• Recurrent disease (15-25% of patients) – typically occurs within 4 weeks of completion of therapy

Treatment

• Treatment usually necessary in symptomatic patients
• Often difficult to eradicate

Indications for Laboratory Testing

• 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
CBC with Platelet Count and Automated Differential 0040003 Method: Automated Cell Count/Differential	Aid in determining cause of diarrhea; leukocytosis suggests bacterial etiology
Stool Culture and E. coli Shiga-like Toxin by EIA 0060134 Method: Culture/Identification	Rule out other organisms as cause of diarrhea Routine stool culture includes culture for Salmonella, Shigella, Campylobacter, and E. coli 0157 as well as EIA for Shiga-like toxin from E. coli

Diagnostic Algorithm

  Clostridium difficile-Associated Disease (CDAD) Testing Algorithm