Does a positive result for both antigen and toxins A and B indicate an active Clostridioides (C.) difficile infection?

Positive Antigen and Toxin A/B Results Indicate Active C. difficile Infection

A positive result for both glutamate dehydrogenase (GDH) antigen and toxins A and B strongly indicates an active Clostridioides difficile infection that requires treatment. 1

Diagnostic Significance of Combined Positive Results

The diagnosis of C. difficile infection (CDI) relies on laboratory testing that typically follows one of several approaches:

1. GDH antigen detection: Screens for the presence of C. difficile bacteria (both toxigenic and non-toxigenic strains)
2. Toxin A/B detection: Identifies the presence of toxins produced by pathogenic C. difficile
3. Nucleic acid amplification tests (NAATs): Detect genes encoding toxins

When both GDH antigen and toxins A/B are positive, this represents a high-specificity scenario with excellent positive predictive value (PPV), especially in symptomatic patients. According to European guidelines, this combination has a PPV of 0.84-0.91 in populations with 20% CDI prevalence 1.

Clinical Interpretation of Results

The clinical significance of positive results should be interpreted as follows:

• GDH+/Toxin A/B+: Active CDI requiring treatment
• GDH+/Toxin A/B-: Potential CDI requiring confirmatory testing (toxigenic culture or NAAT)
• GDH-/Toxin-: No CDI present

The IDSA/SHEA guidelines emphasize that patients with positive results for both tests have significantly higher rates of complications (39% vs 3%) compared to those positive by NAAT alone, including higher 30-day mortality, colectomy, ICU admission, and recurrence 1.

Importance of Both Toxins

Both toxins A and B are important virulence factors in C. difficile infection:

• Toxin A is primarily enterotoxic
• Toxin B is cytotoxic
• Both toxins contribute to the pathogenesis of CDI 2

It's worth noting that toxin A-negative, toxin B-positive strains can cause clinically significant disease, highlighting the importance of tests that detect both toxins 3.

Testing Algorithms and Recommendations

Current guidelines recommend multi-step testing algorithms for optimal diagnosis:

1. Two-step approach: Initial GDH screening followed by toxin A/B testing for GDH-positive specimens
2. Three-step approach: GDH screening → toxin A/B testing → confirmatory NAAT for discordant results

The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommends screening for C. difficile at every flare in patients with colonic disease 1. This approach allows for:

• Rapid results (85-92% available same day)
• Reduced need for more expensive reference testing
• High diagnostic accuracy

Pitfalls and Caveats

Several important considerations should be kept in mind:

1. False positives: Can occur in asymptomatic carriers or with certain testing methods
2. Clinical correlation: Test results must be interpreted in the context of clinical symptoms (≥3 loose/liquid stools in <24 hours)
3. Test limitations: No single test is perfect; sensitivity and specificity vary by method
4. Repeat testing: Not recommended in endemic settings due to high negative predictive values of initial tests 1
5. Low BMI: Patients with lower BMI may be at higher risk for toxigenic C. difficile when GDH+/toxin- results are obtained 4

Immune Response and Recurrence Risk

Patients with lower serum IgG antibodies against toxins A and B have higher risk of CDI and recurrence. A robust immune response to toxin A during an initial episode is associated with protection against recurrence 5, 6. This underscores the clinical significance of toxin detection in stool samples.

In conclusion, the combination of positive GDH antigen and positive toxins A/B represents a high-specificity diagnostic scenario that strongly indicates active C. difficile infection requiring appropriate treatment and infection control measures.