What is the likely diagnosis and management for an adult patient with persistent diarrhea, elevated fecal calprotectin (indicating inflammation), and negative results for other stool tests, colonoscopy, endoscopy, biopsies, celiac panel, and allergy panel?

Likely Diagnosis: Microscopic Colitis or Post-Infectious IBS

The most likely diagnosis in this patient with persistent diarrhea, mildly elevated fecal calprotectin (85.9 μg/g), and negative endoscopic/histologic evaluation is microscopic colitis, which requires targeted biopsies for diagnosis, or post-infectious IBS if there was a preceding infectious gastroenteritis. 1, 2

Interpretation of the Fecal Calprotectin Level

Your patient's calprotectin of 85.9 μg/g falls into a challenging intermediate zone:

• Levels <100 μg/g have high negative predictive value for IBD and typically suggest IBS is the likely diagnosis 2
• However, this level is above the optimal 50 μg/g threshold that provides 90.6% sensitivity for detecting endoscopic inflammation 1, 2
• The British Society of Gastroenterology notes that calprotectin 50-100 μg/g represents a gray zone where mild non-specific inflammation may be present 2

Critical Diagnostic Consideration: Microscopic Colitis

The most important missed diagnosis in your case is microscopic colitis, which presents exactly as your patient does:

• Persistent watery diarrhea with normal-appearing mucosa on colonoscopy 1
• Mildly elevated calprotectin (typically 50-150 μg/g range) 3
• Requires specific histologic evaluation of random colonic biopsies even when mucosa appears normal 1
• Two subtypes: collagenous colitis (thickened subepithelial collagen band) and lymphocytic colitis (increased intraepithelial lymphocytes) 1

If biopsies were not specifically examined for microscopic colitis features, request pathology review or repeat colonoscopy with targeted biopsies from multiple colonic segments. 1

Additional Diagnostic Workup Required

Infectious Causes to Exclude

Despite negative initial stool tests, several pathogens require specific testing:

• Giardia lamblia: Standard ova and parasite exam has only 60-90% sensitivity; order Giardia stool ELISA (92% sensitivity, 98% specificity) 1
• Cryptosporidium: Requires specific staining or antigen testing, not detected on routine culture 1
• Clostridium difficile: Use two-stage testing approach - glutamate dehydrogenase EIA or PCR to detect organism, followed by toxin EIA to confirm active toxin production 1
  • Critical pitfall: PCR alone without toxin confirmation can lead to overdiagnosis, especially in post-infectious IBS where colonization without active infection occurs 1

Medication History

NSAID use within the past 6 weeks can elevate calprotectin through direct mucosal injury and must be excluded before attributing the elevation to other causes 2, 4

Post-Infectious IBS Consideration

If there was preceding acute gastroenteritis 2-6 months prior to symptom onset:

• Post-infectious IBS typically shows calprotectin <100 μg/g due to altered immune responses rather than active neutrophilic inflammation 5
• Your patient's level of 85.9 μg/g is compatible with post-infectious IBS 5
• However, levels persistently >100 μg/g warrant repeat testing or further investigation to exclude occult IBD 2, 5

Management Algorithm

Step 1: Complete Infectious Workup

• Order Giardia stool ELISA (not just O&P) 1
• Order two-stage C. difficile testing (GDH/PCR + toxin EIA) 1
• Consider Cryptosporidium antigen testing if immunocompromised or travel history 1

Step 2: Review Pathology

• Request pathology review specifically for microscopic colitis if not already done 1
• If biopsies inadequate, repeat colonoscopy with random biopsies from ascending, transverse, descending, and sigmoid colon 1

Step 3: Repeat Calprotectin in 2-3 Weeks

• Use first morning stool, analyze within 3 days at room temperature 1, 2
• If repeat value <50 μg/g and symptoms mild, IBS is likely 2
• If repeat value >100 μg/g, consider gastroenterology re-referral for small bowel imaging 2

Step 4: Consider Small Bowel Evaluation

If above workup negative and symptoms persist:

• MR enterography or CT enterography to evaluate for small bowel Crohn's disease not visible on colonoscopy 2
• Video capsule endoscopy if cross-sectional imaging negative but suspicion remains high 1

Treatment Considerations Based on Final Diagnosis

If Microscopic Colitis Confirmed:

• First-line: Budesonide 9 mg daily for 6-8 weeks (highly effective for induction of remission) 1
• Avoid NSAIDs and consider discontinuing PPIs if possible (both associated with microscopic colitis) 1

If Post-Infectious IBS:

• Symptomatic management: loperamide for diarrhea, dietary modification 5
• Reassurance that condition typically improves over 6-12 months 5

If Giardiasis Confirmed:

• Metronidazole 250 mg TID for 5-7 days or tinidazole 2 g single dose 1

Key Pitfalls to Avoid

• Do not assume normal-appearing mucosa excludes organic disease - microscopic colitis requires histologic diagnosis 1
• Do not rely on C. difficile PCR alone - requires toxin confirmation to avoid treating colonization 1
• Do not accept "negative O&P" as excluding Giardia - requires specific ELISA testing 1
• Do not ignore NSAID use - can cause both symptoms and calprotectin elevation 2, 4
• Do not assume calprotectin <100 μg/g completely excludes IBD - 10% of active Crohn's patients have normal calprotectin 2