What are the causes of an elevated Erythrocyte Sedimentation Rate (ESR)?

Causes of Elevated Erythrocyte Sedimentation Rate (ESR)

An elevated ESR most commonly indicates infection (33-39%), followed by autoimmune/inflammatory diseases (14-16%), malignancy (15-17%), and renal disease (8-17%), with the specific cause depending on the degree of elevation and clinical context. 1, 2

Understanding ESR Elevation by Degree

Moderate Elevation (20-100 mm/h)

• ESR >20 mm/h in men and >30 mm/h in women is considered elevated, with moderate elevations (50-100 mm/h) more likely indicating significant underlying disease 3
• Women typically have higher baseline ESR values than men, and ESR normally increases with age 3
• Anemia and azotemia can artificially elevate ESR values 3

Extreme Elevation (≥100 mm/h)

• An ESR ≥100 mm/h has a 90% predictive value for serious underlying disease, with specificity exceeding 99% as a "sickness index" 4, 2
• The most common causes in this range are:
  • Infections (33-39%): Including osteomyelitis (6.9%), tuberculosis (5.5%), sepsis (5.1%), urinary tract infections (4.7%), septic arthritis (3.1%), and abscesses (2.8%) 1, 2
  • Malignancy (15-17%): Particularly lymphoma (5.1%) and metastatic tumors 1, 2
  • Autoimmune/inflammatory diseases (14-16%): Most commonly rheumatoid arthritis (7.3%) and polymyalgia rheumatica 1, 2
  • Renal disease (8-17%) 1, 2
  • Ischemic tissue injury or trauma (8.7%) 1

Major Disease Categories

Rheumatologic/Autoimmune Conditions

• Giant cell arteritis (GCA): ESR >40 mm/h has 93.2% sensitivity, while ESR >100 mm/h has 92.2% specificity with a positive likelihood ratio of 3.11 3
• Polymyalgia rheumatica (PMR): The most common new-onset rheumatic disease causing elevated ESR (38% of new-onset rheumatic diseases), with ESR >40 mm/h associated with higher relapse rates 3, 5
• Rheumatoid arthritis: The most common individual cause of extreme ESR elevation (7.3%), with ESR incorporated into disease activity scores (DAS28-ESR) 6, 3, 1
• Seronegative rheumatoid arthritis: Second most common new-onset rheumatic disease after PMR 5
• Systemic lupus erythematosus and other connective tissue diseases 5

Infectious Causes

• Bacterial infections: Including endocarditis (obtain blood cultures if fever and heart murmurs present), osteomyelitis (ESR ≥70 mm/h has 81% sensitivity and 80% specificity for diabetes-related foot infections), and septic arthritis 3, 1
• Tuberculosis: Accounts for 5.5% of extreme ESR elevations 1
• Chronic bronchitis and respiratory infections 7
• Spine infections: Consider in patients with back pain, especially with risk factors like IV drug use, diabetes, or immunosuppression 3

Malignancies

• Lymphoma: Accounts for 5.1% of extreme ESR elevations, with ESR useful for monitoring treated Hodgkin's disease 1, 4
• Metastatic tumors: Account for 17% of extreme ESR elevations 2
• Lung cancer: Associated with increased erythrocyte turnover and eryptosis, contributing to anemia 6

Cardiovascular Conditions

• Acute pericarditis: Commonly presents with elevated inflammatory markers including ESR 3
• Ischemic tissue injury: Accounts for 8.7% of extreme ESR elevations 1

Other Causes

• Renal failure: A frequent diagnosis in elderly patients with elevated ESR 7
• Kawasaki disease: ESR often >40 mm/h and commonly ≥100 mm/h 3
• Multisystem inflammatory syndrome in children (MIS-C): Screen in pediatric patients with fever and SARS-CoV-2 exposure 3
• Pregnancy: Accounts for 2.2% of extreme ESR elevations 1
• Trauma: Accounts for 5.3% of extreme ESR elevations 1

Clinical Pitfalls and Important Considerations

Multiple Diagnoses

• 40% of elderly patients with elevated ESR have multiple contributing diagnoses, making a thorough evaluation essential 7
• In patients with previously diagnosed rheumatic disease, flare of the underlying condition is the most common cause (83%) of ESR elevation 5

CRP vs ESR Discrepancy

• Extraordinarily high CRP levels (disproportionate to ESR) should raise suspicion for infection or malignancy, even in patients with known rheumatic disease 5
• CRP tends to rise and fall more quickly than ESR, making it more responsive to acute changes 8
• CRP levels are significantly higher in infections compared to new-onset rheumatic disease or malignancies 5

False Reassurance

• Relapses of GCA and PMR may occur despite normal ESR and CRP, particularly in patients treated with IL-6 receptor blocking agents 6
• ESR lacks sensitivity: only 36% of patients with infection, 25% with malignancy, and 21% with inflammatory disorders have ESR ≥100 mm/h 2

Age-Related Considerations

• In elderly patients (>70 years), 12-18% have ESR >40 mm/h, with multifactorial etiology being common 7
• Screening asymptomatic elderly patients has little therapeutic consequence; selective use based on clinical suspicion is preferable 7, 4

Unexplained Elevation

• If no immediate explanation is apparent, repeat ESR in 2-4 weeks rather than pursuing exhaustive evaluation, as only 2.4% of patients with extreme ESR elevation have no identifiable cause 3, 1, 4
• Consider chest radiography to exclude pulmonary infections or malignancy at physician discretion 3