What is the appropriate management for a patient with elevated calprotectin (fecal calprotectin) levels in the absence of a rise in inflammatory markers, such as C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), and a history of gastrointestinal symptoms or inflammatory bowel disease (IBD)?

Management of Elevated Fecal Calprotectin with Normal Systemic Inflammatory Markers

In patients with elevated fecal calprotectin but normal CRP/ESR, proceed with management based on the calprotectin level and symptom severity, as fecal calprotectin is a superior marker of intestinal mucosal inflammation compared to systemic inflammatory markers and frequently remains elevated even when CRP/ESR are normal. 1, 2

Understanding the Discordance

The absence of elevated systemic inflammatory markers (CRP, ESR) does not exclude active intestinal inflammation when fecal calprotectin is elevated:

• Fecal calprotectin directly measures intestinal neutrophilic inflammation and correlates strongly with endoscopic disease activity (r=0.847 in Crohn's disease, r=0.798 in ulcerative colitis), whereas CRP shows weaker correlation (r=-0.44 in Crohn's, r=0.463 in UC) 3

• Systemic inflammatory markers can remain normal in IBD, particularly in patients with isolated mucosal inflammation without significant transmural or systemic involvement 3, 4

• This discordance is common and does not diminish the clinical significance of elevated calprotectin 5, 3

Management Algorithm Based on Calprotectin Level and Symptoms

For Calprotectin >250 μg/g:

• Strongly indicates active inflammatory disease requiring treatment intensification regardless of normal CRP/ESR 2

• Proceed with endoscopic evaluation to assess disease extent and severity 2

• Consider treatment adjustment based on endoscopic findings without delay 6

For Calprotectin 150-250 μg/g:

With moderate to severe symptoms:

• The false positive rate is only 4.6%, meaning 95.4% of patients have true moderate-to-severe endoscopic inflammation 2, 7
• Proceed directly to treatment adjustment without requiring endoscopic assessment first 2, 6
• Repeat calprotectin at 2-4 months to assess treatment response 6

With mild symptoms:

• Perform endoscopic assessment before treatment adjustment, as the false positive rate increases to 15.5% in this scenario 2, 7
• Obtain stool studies to exclude C. difficile and other enteric pathogens 2

Asymptomatic patients with known IBD:

• Consider endoscopic evaluation, as the false positive rate is 22.4% 2
• Alternatively, repeat calprotectin in 3-6 months if clinical suspicion is lower 2

For Calprotectin 50-150 μg/g:

• This range has intermediate specificity and requires clinical correlation 1, 2

• In patients under 50 years with new lower GI symptoms, the negative predictive value for significant luminal pathology (IBD, advanced adenoma, colorectal cancer) is 97.5% 8

• Consider repeat testing in 3-6 months rather than immediate invasive investigation if symptoms are mild 8

• Exclude NSAID use, as this can elevate calprotectin without true IBD 8

For Calprotectin <50 μg/g:

• Rules out active inflammation with high negative predictive value 2, 6
• No intervention needed in asymptomatic patients 6

Critical Diagnostic Considerations

Before proceeding with treatment:

• Exclude infectious causes first: Obtain stool cultures and C. difficile testing, as enteric infections markedly elevate calprotectin 2, 7

• Review medication history: NSAIDs used within the past 6 weeks can elevate calprotectin 7, 8

• Consider other non-IBD causes: Colorectal neoplasia, celiac disease, and ischemic colitis can also elevate calprotectin 2

Monitoring After Treatment Initiation

• Repeat fecal calprotectin at 2-4 months after initiating or adjusting therapy to assess biochemical response 2, 6, 7

• Target calprotectin <150 μg/g indicates adequate treatment response 2

• Perform follow-up endoscopy at 6-12 months to confirm mucosal healing, as calprotectin normalization correlates with but does not guarantee endoscopic remission 2, 6

Common Pitfalls to Avoid

• Do not dismiss elevated calprotectin simply because CRP/ESR are normal - fecal calprotectin has superior diagnostic accuracy for intestinal inflammation (AUC=1.0) compared to CRP (AUC=0.849) or ESR (AUC=0.846) 3

• Do not over-investigate patients with calprotectin 100-200 μg/g and mild symptoms - the negative predictive value is high (86.7% for any pathology), and excessive testing has low yield 8

• Do not delay treatment in symptomatic patients with calprotectin >150 μg/g waiting for CRP/ESR to rise - the intestinal inflammation is already documented 2, 6