What is the role of C‑reactive protein (CRP) in diagnosing and managing inflammatory and infectious conditions?

Role of C-Reactive Protein in Clinical Practice

Primary Clinical Applications

C-reactive protein (CRP) serves as a highly sensitive acute-phase reactant that rises 4-6 hours after inflammatory insult, doubles every 8 hours, and peaks at 36-50 hours, making it superior to ESR for diagnosing acute infections and monitoring rapid treatment responses. 1, 2

Diagnostic Utility in Infections

CRP demonstrates strong diagnostic performance in bacterial infections, though interpretation requires understanding specific thresholds:

• CRP >100 mg/L strongly suggests bacterial infection (median ~120 mg/L in bacterial sepsis), though it cannot reliably differentiate bacterial from viral infections at moderate elevations (10-100 mg/L) 2, 3
• Combined CRP ≥50 mg/L and procalcitonin ≥1.5 ng/mL achieves 98.5% sensitivity and 75% specificity for sepsis, making this combination superior to CRP alone 2
• In appendicitis, CRP demonstrates 93.6-96.6% sensitivity in histologically proven cases 1, 2
• For pneumonia, CRP improves severity assessment and is incorporated into NICE guidelines for diagnosis 1, 2

Monitoring Surgical Inflammation

CRP quantifies the magnitude of postoperative systemic inflammatory response:

• Only IL-6 and CRP consistently correlate with the magnitude of operative injury after elective surgery (minor/major, laparoscopic/open) 1
• The pooled negative predictive value of CRP improves daily after surgery, reaching 90% at postoperative day 3 for infectious complications (pooled CRP cutoff 159 mg/L) 1
• CRP generally returns to baseline within 2 months after surgery under normal circumstances 4

Prosthetic Joint Infection Diagnosis

When at least 2 of 3 tests (ESR >27 mm/h, CRP >0.93 mg/L, fibrinogen >432 mg/dL) are abnormal, sensitivity is 93% and specificity is 100% for prosthetic joint infection 4

• CRP alone has 73-91% sensitivity and 81-86% specificity when cutoff ≥13.5 mg/L is used 4
• The American Academy of Orthopaedic Surgeons strongly recommends ESR, CRP, and serum interleukin-6 testing for patients being assessed for periprosthetic joint infection 4

Monitoring Chronic Inflammatory Conditions

Inflammatory Bowel Disease

• CRP correlates better with disease activity in Crohn's disease than ulcerative colitis 4
• A low-level elevation <5 mg/L can rule out endoscopic inflammation in patients with known remission 4
• Measure CRP every 2-4 months during active treatment, transitioning to endoscopic evaluation 6-12 months after treatment initiation once symptoms and biomarkers normalize 4

Rheumatoid Arthritis

• CRP is incorporated into validated composite disease activity measures (DAS28-CRP) recommended by major rheumatology societies 4
• Measure CRP every 1-3 months during active disease until remission, then every 3-6 months once low disease activity or remission is maintained 4
• Rising CRP should prompt clinical reassessment, as it may signal reactivation of destructive processes 4

Critical Interpretation Thresholds

Understanding CRP reference ranges is essential for appropriate clinical decision-making:

• <3-5 mg/L: Normal range in healthy individuals 2, 3
• 5-10 mg/L: Chronic low-grade inflammation 2, 3
• 10-100 mg/L: Moderate elevation occurring in both viral and bacterial infections 2
• >100 mg/L: Strongly suggests bacterial infection 2

Key Limitations and Pitfalls

Poor Specificity for Infection

CRP has only 40-67% specificity for bacterial infection and cannot differentiate bacterial infections from non-infectious causes of inflammation 1, 2

• One-third of hospitalized patients with CRP >10 mg/L have non-infectious causes, including inflammatory diseases (median 65 mg/L), solid tumors (median 46 mg/L), and cardiovascular disease (median 6 mg/L) 2
• When CRP exceeds 10 mg/L, examine for sources of both infection AND inflammation 2

Non-Pathological Elevations

• Approximately 20% of smokers have CRP >10 mg/L from smoking alone 2, 3
• 30-40% of US adults have CRP >3 mg/L due to obesity, lifestyle factors, and chronic inflammation 2, 3
• Obesity significantly affects CRP levels, with elevated BMI consistently associated with higher baseline CRP 3

Confounding Factors

• Neutropenia, immunodeficiency, and NSAID use can suppress CRP levels 3
• Estrogen/progestogen hormone use increases CRP levels 3
• Statins, fibrates, and niacin decrease CRP levels 3

Algorithmic Approach to CRP Interpretation

For Suspected Acute Infection

1. Obtain CRP and procalcitonin simultaneously for optimal diagnostic accuracy 2
2. If CRP ≥50 mg/L AND PCT ≥1.5 ng/mL: 98.5% sensitivity for sepsis—obtain blood cultures immediately and initiate broad-spectrum antibiotics 2
3. If CRP >100 mg/L: Strongly suggests bacterial infection—evaluate for respiratory, abdominal, urinary tract, soft tissue, and bloodstream sources 2, 3
4. If CRP 10-100 mg/L: Cannot reliably differentiate bacterial from viral—interpret alongside clinical context and procalcitonin 2

For Monitoring Treatment Response

• Serial CRP measurements are more valuable than single values for diagnosis and monitoring 3
• CRP rises and falls more rapidly than ESR with inflammation onset and resolution, making it superior for detecting early treatment response 4
• Obtain CRP every 2-4 weeks during active treatment to assess response 4

When CRP is Discordant with Clinical Picture

• A single normal CRP should not rule out infection, especially in early presentation (before 6-hour rise), immunocompromised patients, or those on NSAIDs 3, 5
• Consider CRP velocity (rate of rise) rather than absolute value in equivocal cases 6
• Repeat measurement in 8-12 hours if clinical suspicion remains high despite normal initial CRP 1

Superiority Over ESR in Specific Contexts

CRP is superior to ESR for acute infections and rapid treatment monitoring because:

• CRP rises within 4-6 hours versus ESR's slower response 1
• CRP is less affected by confounding factors like anemia and azotemia that artificially elevate ESR 4
• CRP has better standardization with commercial assays and lower detection limits (0.3 mg/L for high-sensitivity CRP) 4
• CRP normalizes within weeks versus ESR remaining elevated longer after inflammation resolves 4

Cardiovascular Risk Assessment

• CRP >3 mg/L predicts future coronary events in asymptomatic individuals 3
• The American Heart Association recommends obtaining 2 measurements of CRP (optimally 2 weeks apart) and averaging the results for metabolically stable patients 4
• If CRP ≥10 mg/L, repeat the test and examine for sources of infection or inflammation 4