GDH-Positive/Toxin-Negative/NAAT-Positive Result Interpretation
What This Result Pattern Means
A patient who tests negative for C. difficile toxin but positive on nucleic acid testing most likely represents colonization rather than active infection, and generally should NOT be treated unless high-risk clinical features are present. 1
This discordant result occurs because:
- The NAAT/PCR detects the genetic material of C. difficile bacteria with 93-94% sensitivity but cannot distinguish between active infection producing toxins and harmless colonization. 1
- Approximately 44-55% of patients who test positive by PCR will be negative for toxins, representing colonization rather than true infection. 1
- The absence of detectable free toxin in stool (despite presence of toxigenic organisms) indicates the bacteria are present but not actively producing sufficient toxin to cause disease. 2
Clinical Significance and Outcomes
The presence or absence of toxin dramatically affects patient outcomes:
- Patients who are gene-positive AND toxin-positive have significantly worse outcomes: 7.6% complication rate, 8.4% mortality, and longer duration of diarrhea. 1
- Patients who are gene-positive but toxin-negative have minimal complications: 0% complication rate in the largest study, 0.6% mortality, and outcomes similar to patients without C. difficile at all. 1
- Toxin-negative patients had 9.7% mortality versus 16.6% in toxin-positive patients (P = .022), with the toxin-negative group not significantly different from controls at 8.6%. 3
- Only one toxin-negative patient out of 6,121 (0.02%) was diagnosed with pseudomembranous colitis, with no complications such as megacolon or colectomy. 4
Management Algorithm
Step 1: Assess Clinical Features
Evaluate for high-risk features that might warrant treatment despite negative toxin:
- Severe diarrhea (≥3 unformed stools in 24 hours that conform to container shape) 1
- Significant leukocytosis 3
- Rising serum creatinine 3
- High fever 1
- Severe abdominal pain 1
- Recent antibiotic exposure 1
Step 2: Treatment Decision
For most patients (LOW-RISK features):
- Do NOT treat with antibiotics, as these patients likely represent "excretors" who may present an infection control risk but generally do not require treatment. 1, 3
- Implement contact precautions to prevent transmission regardless of treatment decision. 3
- Consider alternative causes of diarrhea. 3
For patients with HIGH-RISK features:
- Consider empiric treatment with oral vancomycin 125 mg four times daily while awaiting additional evaluation. 1, 3
- Discontinue inciting antibiotics if possible. 3
Step 3: Additional Considerations
- Do NOT repeat testing within 7 days of the initial test during the same diarrheal episode—this increases false-positive results and has only 2% diagnostic yield. 1
- Maintain contact precautions regardless of treatment decision to prevent transmission. 3
- Consider that over half (63.2%) of GDH-positive/toxin-negative patients may harbor toxigenic C. difficile on culture, but this does not necessarily indicate need for treatment. 5
Common Pitfalls to Avoid
- Do not automatically treat all NAAT-positive results—this leads to overtreatment of colonized patients. 1
- Do not use NAAT alone as a stand-alone test in endemic settings due to low positive predictive value. 1
- Do not test asymptomatic patients, as up to 7% of hospitalized patients are colonized without disease. 3
- Do not perform test of cure, as >60% of patients may remain C. difficile positive even after successful treatment. 1
Why Multi-Step Algorithms Are Recommended
The IDSA/SHEA 2018 guidelines recommend using NAAT to arbitrate discordant results in a three-step algorithm: GDH plus toxin, arbitrated by NAAT when results are discordant. 1 This approach provides results for approximately 85-92% of samples on the day of receipt, with only 8-15% requiring further testing. 1