How do the erythrocyte sedimentation rate (ESR) and C‑reactive protein (CRP) differ in what they measure, their kinetics, and clinical utility?

ESR vs CRP: Key Differences 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 monitoring chronic inflammatory diseases like giant cell arteritis and polymyalgia rheumatica. 1, 2

What They Measure

C-Reactive Protein (CRP)

• Direct acute-phase reactant synthesized by the liver that rises and falls rapidly with active inflammation, independent of ESR 1
• More standardized measurement with commercial assays widely available and better detection limits (0.3 mg/L for high-sensitivity CRP) 1
• Less affected by confounding factors like anemia and azotemia that artificially elevate ESR 1

Erythrocyte Sedimentation Rate (ESR)

• Measures the rate at which red blood cells settle in a tube, influenced by multiple factors beyond inflammation 1
• Significantly affected by immunoglobulins, rheumatoid factor, hemoglobin levels, anemia, azotemia, and elevated immunoglobulins 1, 3
• Women typically have higher baseline ESR values than men, and ESR normally increases with age 1, 4

Kinetics: The Critical Difference

CRP Kinetics

• Rises within 12-24 hours after infection onset and peaks at 48 hours, making it ideal for acute presentations 1
• Normalizes rapidly (within weeks) during inflammation resolution, superior for detecting early treatment response 1
• Returns to baseline within 2 months after surgery under normal circumstances 1

ESR Kinetics

• Remains elevated longer than CRP after inflammation resolves, which creates discordance between the two tests 1, 5
• Slower to rise and slower to fall compared to CRP 5, 6
• This temporal difference explains why 20-33% of patients show CRP/ESR disagreements 5, 6

Clinical Utility by Condition

When CRP is Superior

Acute Infections and Sepsis:

• CRP ≥1.5 ng/mL has 100% sensitivity and 72% specificity for identifying sepsis in ICU patients 1
• CRP ≥50 mg/L has 98.5% sensitivity and 75% specificity for probable or definite sepsis 1
• Superior for diagnosing acute bacterial infections, urinary tract infections, gastrointestinal infections, pulmonary infections, and bloodstream infections 1

Inflammatory Bowel Disease:

• CRP correlates better with endoscopic activity in Crohn's disease than ESR, with a clinically relevant cutoff of 5 mg/L 2
• Normal CRP (<5 mg/L) combined with low fecal calprotectin effectively excludes active inflammation with 81% sensitivity 2
• Elevated baseline CRP predicts better response to anti-TNF therapy 2

Prosthetic Joint Infections:

• CRP has sensitivity of 73-91% and specificity of 81-86% when cutoff ≥13.5 mg/L is used 1
• 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% 1

Cardiovascular Risk Assessment:

• CRP is recommended for cardiovascular risk stratification: low risk <1.0 mg/L, average risk 1.0-3.0 mg/L, high risk >3.0 mg/L 2

When ESR is Superior or Equivalent

Giant Cell Arteritis (GCA):

• ESR >40 mm/h has 93.2% sensitivity for GCA with a negative likelihood ratio of 0.18 1, 2
• ESR >100 mm/h has highest specificity (92.2%) with positive likelihood ratio of 3.11 1
• ESR is specifically indicated for GCA diagnosis and should not be replaced by CRP alone 2

Polymyalgia Rheumatica (PMR):

• ESR is valuable for monitoring PMR, with ESR >40 mm/h predicting higher relapse rates 1, 2
• ESR should be measured at 1-3 month intervals during active disease until remission 1

Rheumatoid Arthritis:

• ESR contributes 15% of DAS28-ESR calculations for disease activity assessment 2
• Both ESR and CRP should be ordered for initial evaluation of undifferentiated inflammatory arthritis 2
• The combination of ESR and CRP yields useful information not apparent when only a single test is used 3

Osteomyelitis in Diabetic Foot:

• ESR ≥70 mm/h has 81% sensitivity and 80% specificity for diagnosing osteomyelitis in diabetes-related foot infections 1, 2

Interpretation Thresholds

CRP Reference Values

• Normal: <5 mg/L 2
• Significant inflammation: >10 mg/L (repeat test and examine for sources of infection or inflammation) 2, 4
• Risk categories: low <1.0 mg/L, average 1.0-3.0 mg/L, high >3.0 mg/L 2

ESR Reference Values

• Elevated: >20 mm/h in men, >30 mm/h in women 1, 2, 4
• Moderate elevation: 50-100 mm/h indicates greater likelihood of significant disease 1, 2
• Highly elevated: ≥70 mm/h supports specific diagnoses like osteomyelitis 1
• ESR >100 mm/h is an independent prognostic factor for mortality 1

Common Discordances and Their Causes

CRP/ESR disagreements occur in 20-33% of patients and are explained by three mechanisms: 5, 6

1. Slight fluctuations around upper limits of normal for these tests 5
2. Different time courses: CRP rises and falls faster than ESR 5, 6
3. Confounding factors affecting ESR: infection, renal insufficiency, low albumin, anemia, immunoglobulins 7, 6

Elevated ESR with Normal CRP

• Occurs in 28% of discordant cases 6
• 32% have resolving inflammatory disorders (CRP already normalized, ESR still elevated) 6
• 28% have variables interfering with ESR measurement (false-positive ESR) 6
• Infection and renal insufficiency are associated with >14-fold risk of this pattern 7
• Low serum albumin predicts this discordance 7

Elevated CRP with Normal ESR

• Occurs in 5% of discordant cases 6
• Suggests acute inflammation where ESR has not yet risen 6
• Low albumin also predicts this pattern 7

Practical Clinical Algorithm

For Acute Presentations (Suspected Infection/Acute Inflammation)

1. Order CRP as the primary marker 1, 2, 6
2. Interpret CRP as the primary marker for acute decision-making, with CRP ≥20 mg/L strongly suggesting acute inflammation 1
3. Obtain blood cultures when CRP is elevated with fever, chills, hypothermia, leukocytosis, or hemodynamic compromise 1
4. Monitor CRP every 2-4 weeks during active treatment to assess response 1

For Chronic Inflammatory Conditions

1. Order both ESR and CRP for initial evaluation of undifferentiated inflammatory arthritis 2
2. For GCA/PMR: prioritize ESR for diagnosis and monitoring 1, 2
3. For rheumatoid arthritis: use both in disease activity scores (DAS28-ESR or DAS28-CRP) 1
4. Measure ESR every 1-3 months during active disease, then every 3-6 months in remission 1

For Cardiovascular Risk Assessment

1. Use CRP exclusively 2
2. Obtain 2 measurements 2 weeks apart and average the results in metabolically stable patients 2

Critical Pitfalls to Avoid

• Do not use ESR alone in patients with infection, renal insufficiency, or low albumin as these conditions cause false elevations 7, 6
• Recent NSAID use can suppress CRP more than ESR, potentially causing discordance 1
• In immunocompromised patients or those with neutropenia, CRP may be falsely low 1
• Neither marker is sufficiently specific or sensitive when used alone as a diagnostic tool 4
• Obesity itself can cause elevated CRP and ESR without underlying inflammatory disease 1
• In hospital practice, joint measurement of ESR and CRP is often unwarranted for acute conditions—priority should be given to CRP 6