What are the differential diagnoses for acute watery diarrhea with markedly elevated C-reactive protein and a white blood cell count of 10 × 10⁹/L?

Differential Diagnosis of Acute Watery Diarrhea with Markedly Elevated CRP and WBC 10,000/µL

The combination of watery diarrhea with very high CRP (markedly elevated) and WBC 10,000/µL most strongly suggests bacterial gastroenteritis, particularly invasive bacterial pathogens such as Salmonella, Campylobacter, or Shigella, though inflammatory bowel disease (IBD) and Clostridioides difficile infection must also be considered. 1, 2

Primary Differential Diagnoses

Bacterial Gastroenteritis (Most Likely)

• CRP >50 mg/L strongly predicts bacterial over viral gastroenteritis, with a cut-off of 3.08 mg/dL (30.8 mg/L) showing 82% sensitivity and 85% specificity for inflammatory diarrhea 2
• Invasive bacterial pathogens (Salmonella, Campylobacter, Shigella, enteroinvasive E. coli) typically produce neutrophil-predominant leukocytosis with elevated CRP 1, 3
• Mean CRP in bacterial gastroenteritis is 104 mg/L versus 38.9 mg/L in non-specific gastroenteritis 4, 5
• Obtain stool culture and blood cultures before initiating antibiotics, as positive cultures occur in approximately 31% of patients with this presentation 1, 5
• Lipopolysaccharide binding protein (LBP) >14.6 µg/mL also distinguishes bacterial from viral infection, though CRP is more readily available 4

Clostridioides difficile Infection

• C. difficile must be excluded in all patients with acute diarrhea, particularly those with recent antibiotic exposure or healthcare contact 1
• Can present with watery diarrhea and markedly elevated inflammatory markers before progressing to pseudomembranous colitis 1
• Order C. difficile toxin testing or nucleic acid amplification test (NAAT) on stool specimen 1, 3

Inflammatory Bowel Disease (IBD) - Ulcerative Colitis or Crohn's Disease

• CRP >20 mg/L with ESR >15 mm predicts active IBD with 8-fold increased risk of relapse 1
• CRP broadly correlates with clinical severity in ulcerative colitis, except in isolated proctitis 1
• However, CRP correlation is less robust for disease localized to terminal ileum (proximal Crohn's disease), with higher false-negative rates 1
• Consider IBD if patient has history of recurrent episodes, blood in stool, or extraintestinal manifestations 1
• Fecal calprotectin >30 µg/g has 100% sensitivity for distinguishing active Crohn's disease from irritable bowel syndrome 1

Viral Gastroenteritis with Severe Dehydration (Less Likely Given Very High CRP)

• Norovirus is the most common cause of acute gastroenteritis in adults 1
• Viral gastroenteritis typically produces lymphocyte-predominant differential and CRP <50 mg/L 3, 2, 4
• Very high CRP makes pure viral etiology unlikely, though viral infection with secondary bacterial translocation is possible 2

Critical Diagnostic Algorithm

Immediate Laboratory Workup

1. Obtain stool culture for bacterial pathogens (Salmonella, Shigella, Campylobacter, E. coli O157:H7) before antibiotics 1, 3
2. Test stool for C. difficile toxin or NAAT 1, 3
3. Check white blood cell differential: neutrophil predominance suggests bacterial/inflammatory cause; lymphocyte predominance suggests viral 1, 3
4. Measure fecal calprotectin or lactoferrin (more stable than fecal leukocytes) to confirm inflammatory diarrhea and guide need for endoscopy 3
5. Consider stool ova and parasites if travel history, immunosuppression, or persistent symptoms 1

Risk Stratification Based on CRP Level

• CRP >170 mg/L predicts severe diverticulitis with 87.5% sensitivity and 91.1% specificity (though this is colonic pathology, the principle applies to severe inflammatory processes) 1
• CRP >50 mg/L warrants empiric antibiotic consideration while awaiting cultures in patients with systemic toxicity 2, 4, 5
• A clinical scoring system incorporating abdominal pain (+10 points), symptom duration <5 days (0 points), and CRP >50 mg/L (+5 points) with total score ≥15 predicts bacterial gastroenteritis in 79% of cases 5

When to Pursue Endoscopy

• Persistent symptoms beyond 7-13 days despite appropriate therapy 1
• Severe symptoms with systemic toxicity, bloody diarrhea, or concern for IBD 1
• Fecal calprotectin significantly elevated (>150-250 µg/g) suggesting mucosal inflammation 1, 3
• Flexible sigmoidoscopy or colonoscopy with biopsies can distinguish IBD from infectious colitis 1

Common Pitfalls to Avoid

Do Not Rely on Fecal Leukocytes

• Fecal leukocyte examination performs poorly with significant technical limitations - morphology degrades during transport, leukocytes are intermittently present and unevenly distributed 3
• Use stool lactoferrin or calprotectin instead per American Gastroenterological Association recommendations 3

Do Not Delay Cultures for Empiric Antibiotics

• Always obtain stool and blood cultures before starting antibiotics 1
• Empiric antibiotics may be appropriate in severe cases, but cultures must be drawn first 1

Do Not Assume Normal WBC Rules Out Serious Pathology

• In bacterial sepsis from intestinal sources, WBC may be lower than expected 6
• A normal WBC does not exclude intestinal obstruction, ischemia, or early inflammatory processes 6

Consider Medication-Induced Causes

• NSAIDs may exacerbate IBD and cause inflammatory diarrhea 1
• Recent antibiotic use increases C. difficile risk 1

Additional Considerations Based on Clinical Context

If Patient Has Fever and Systemic Toxicity

• Salmonella or Yersinia bacteremia can cause sustained fever and rare complications including aortitis or mycotic aneurysms 7
• Consider blood cultures and imaging if fever persists despite appropriate therapy 7

If Patient Is Immunosuppressed

• Broader differential includes CMV colitis, opportunistic infections, and medication-related colitis 1
• IBD patients on immunosuppression have increased risk for C. difficile and CMV colitis 1

If Symptoms Persist Beyond 14 Days

• Reclassify as persistent diarrhea and consider parasitic causes (Giardia, Cryptosporidium), celiac disease, microscopic colitis, or IBD 1, 8
• Obtain anti-tissue transglutaminase IgA and total IgA to screen for celiac disease 8

In summary, this presentation most strongly suggests bacterial gastroenteritis requiring stool culture, C. difficile testing, and consideration of empiric antibiotics if systemically ill, while maintaining high suspicion for IBD if symptoms persist or recur. 1, 2, 5