How do C‑reactive protein (CRP) and erythrocyte sedimentation rate (ESR) differ in physiology, timing, and clinical utility, and when should each be ordered?

CRP vs ESR: Physiologic Differences, Timing, and Clinical Utility

CRP should be prioritized over ESR for diagnosing acute inflammatory conditions due to its superior analyte characteristics, rapid response kinetics, and better standardization, while ESR remains valuable for specific chronic inflammatory diseases like giant cell arteritis and polymyalgia rheumatica. 1, 2

Physiologic and Kinetic Differences

CRP is a direct acute-phase reactant synthesized by the liver that rises within 12-24 hours of inflammation onset and peaks at 48 hours, then normalizes rapidly (within weeks) after inflammation resolves. 3, 2 This rapid response makes CRP ideal for diagnosing acute infections and monitoring early treatment response. 2

ESR measures the rate at which red blood cells settle in plasma and remains elevated much longer after inflammation resolves, creating potential discordance with CRP during recovery phases. 3, 4 ESR is influenced by multiple non-inflammatory factors including:

• Anemia and azotemia artificially elevate ESR independent of inflammation 3, 5
• Immunoglobulins, rheumatoid factor, and low albumin significantly affect ESR 5, 6
• Women have higher baseline ESR values than men, and ESR increases with age 3

Standardization and Measurement

CRP has superior standardization with commercial assays widely available and lower detection limits (0.3 mg/L for high-sensitivity CRP), while ESR lacks comparable standardization. 1, 2 The American Heart Association recommends:

• Obtain 2 CRP measurements optimally 2 weeks apart and average the results in metabolically stable patients 1, 2
• Express CRP results only as mg/L to 1 decimal point 1, 2
• If CRP ≥10 mg/L, repeat the test and examine for sources of infection or inflammation 1, 2

CRP risk categories are: low risk <1.0 mg/L, average risk 1.0-3.0 mg/L, high risk >3.0 mg/L. 1, 2

ESR thresholds are: elevated >20 mm/h in men and >30 mm/h in women, with moderate elevation (50-100 mm/h) indicating greater likelihood of significant disease. 3, 2

Clinical Scenarios: When to Order CRP

Order CRP as the primary inflammatory marker for:

• Acute bacterial infections and sepsis - CRP ≥1.5 ng/mL has 100% sensitivity and 72% specificity for identifying sepsis in ICU patients 3
• Suspected prosthetic joint infection - CRP ≥13.5 mg/L has 73-91% sensitivity and 81-86% specificity 3
• Crohn's disease monitoring - CRP correlates better with endoscopic activity than ESR, with clinically relevant cutoff of 5 mg/L 3, 2
• Acute cardiovascular events - myocardial infarction and venous thromboembolism preferentially elevate CRP 3, 4
• Cardiovascular risk assessment - using the risk categories above 1, 2
• Monitoring treatment response in acute settings - CRP normalizes within 2 months after surgery under normal circumstances 3

Clinical Scenarios: When to Order ESR

Order ESR specifically for:

• Giant cell arteritis (GCA) diagnosis - ESR >40 mm/h has 93.2% sensitivity with negative likelihood ratio of 0.18; ESR >100 mm/h has 92.2% specificity with positive likelihood ratio of 3.11 3, 2
• Polymyalgia rheumatica (PMR) monitoring - ESR >40 mm/h predicts higher relapse rates 3, 2
• Rheumatoid arthritis disease activity scoring - ESR contributes 15% of DAS28-ESR calculations 3, 2
• Osteomyelitis in diabetic foot infections - ESR ≥70 mm/h has 81% sensitivity and 80% specificity 3, 2
• Kawasaki disease - ESR often >40 mm/h and commonly ≥100 mm/h, though CRP may be more accurate after IVIG therapy 3

Discordance Between CRP and ESR

CRP/ESR disagreements occur in 12-33% of patients and have specific clinical patterns. 7, 8, 4

High CRP with normal ESR occurs in 5-6% of patients and indicates: 8, 4

• Acute infections - particularly urinary tract, gastrointestinal, pulmonary, and bloodstream infections (14-fold increased risk) 5, 4
• Acute cardiovascular events - myocardial infarction or venous thromboembolism 4
• Early inflammatory response - CRP rises faster than ESR 7

High ESR with normal CRP occurs in 6-28% of patients and indicates: 8, 4

• Resolving inflammatory disorders - ESR remains elevated longer after inflammation resolution (32% of cases) 8
• Connective tissue diseases - particularly systemic lupus erythematosus and lupus nephritis 7, 4
• Bone and joint infections - including osteomyelitis 4
• Ischemic stroke or transient ischemic attack 4
• Confounding factors - renal insufficiency (3-fold increased risk), anemia, low albumin 5, 8

Practical Algorithm for Test Selection

For acute presentations (symptoms <2 weeks):

• Order CRP alone - it rises and falls rapidly with active inflammation, making it superior for diagnosis and monitoring treatment response 2, 8
• CRP is less affected by confounding factors like anemia and azotemia 3

For suspected GCA or PMR (age >50, bilateral shoulder/hip pain, morning stiffness >45 minutes):

• Order ESR as the primary test - it has established diagnostic thresholds and sensitivity for these conditions 3, 2

For initial evaluation of undifferentiated inflammatory arthritis:

• Order both ESR and CRP - they provide complementary diagnostic and prognostic information 2
• 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 3

For monitoring chronic inflammatory diseases:

• Use ESR for GCA, PMR, and rheumatoid arthritis - measure every 1-3 months during active disease, then every 3-6 months in remission 3, 2
• Use CRP for Crohn's disease and acute infections - measure every 2-4 months during active treatment 3

Critical Pitfalls to Avoid

Joint measurement of ESR and CRP is unwarranted in most hospital settings - poor agreement (kappa=0.38) occurs in 67% of patients, and CRP alone is more reliable for acute inflammatory disorders. 8 The exception is initial evaluation of inflammatory arthritis and prosthetic joint infections where combined testing improves diagnostic accuracy. 3, 2

Recent NSAID use can suppress CRP more than ESR, and in immunocompromised patients or those with neutropenia, CRP may be falsely low. 3

In rheumatoid arthritis, 28% of results are discordant between ESR and CRP, explained by immunoglobulins, rheumatoid factor, and hemoglobin rather than acute phase response - when discordance occurs, CRP is the better measure of disease activity. 6