In a symptomatic Clostridioides difficile (C. diff) screen, should you follow up with C. difficile toxin testing?

C. difficile Testing in Symptomatic Patients: Multi-step Algorithm Approach

In symptomatic patients with suspected C. difficile infection (CDI), a multi-step algorithm that includes C. difficile toxin testing following an initial positive screen is the recommended diagnostic approach to optimize both sensitivity and specificity. 1

Diagnostic Testing Strategy

The optimal testing approach for symptomatic patients involves:

1. Initial screening test:

   • Nucleic Acid Amplification Test (NAAT) or Glutamate Dehydrogenase (GDH) assay
   • Both have high sensitivity but cannot distinguish between colonization and active infection

2. Follow-up toxin testing:

   • For positive initial screens, follow with toxin A/B detection by EIA
   • Confirms active toxin production, which correlates with clinical disease

This multi-step algorithm significantly improves positive predictive value compared to single-step testing, with sensitivity of 0.68-1.00 and specificity of 0.92-1.00 1.

Rationale for Multi-step Approach

• Single NAAT testing alone: High sensitivity (80-100%) but may detect asymptomatic colonization 2
• Toxin EIA alone: Variable sensitivity (32-98%) but high specificity (84-100%) 2
• Combined approach: Balances detection of the organism with confirmation of active toxin production

The IDSA/SHEA guidelines strongly support this approach, noting that "a highly sensitive test such as a NAAT alone or multi-step algorithm (i.e., GDH plus toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin) may be best" for symptomatic patients 1.

Clinical Application

• Only test patients with clinically significant diarrhea (≥3 loose stools in 24 hours)
• Limit testing to patients with risk factors (antibiotic exposure, hospitalization)
• Do not test asymptomatic patients or perform "test of cure" after treatment 1

Important Caveats

• Avoid repeat testing within 7 days during the same diarrheal episode (diagnostic yield only ~2%) 1
• Exception: Consider repeat testing if symptoms worsen despite a negative initial test
• Recurrent symptoms: After successful treatment and symptom resolution, new diarrhea should prompt repeat testing including toxin detection 1

Special Populations

• Infants ≤12 months: Testing is not recommended due to high asymptomatic colonization rates (>40%) 1
• Children 1-2 years: Test only after excluding other causes of diarrhea 1
• Children ≥2 years: Test when there are risk factors or prolonged/worsening diarrhea 1

The multi-step algorithm approach optimizes diagnostic accuracy, reduces unnecessary treatment, and improves patient outcomes by correctly identifying patients with true CDI who require intervention while avoiding overtreatment of colonized patients without active disease.