What is the approach to a patient with a positive Erythrocyte Sedimentation Rate (ESR) and a negative C-Reactive Protein (CRP)?

Approach to Elevated ESR with Normal CRP

When ESR is elevated but CRP is normal, prioritize CRP as the more reliable indicator of active inflammation and investigate non-inflammatory causes of ESR elevation, particularly anemia, renal insufficiency, hypergammaglobulinemia, and resolving inflammatory conditions. 1, 2

Understanding the Discordance

This pattern (elevated ESR/normal CRP) occurs in approximately 28% of hospitalized patients when both tests are ordered simultaneously and represents poor agreement between these markers (kappa coefficient 0.38). 1 The discordance has specific clinical significance:

Most Common Explanations for Elevated ESR with Normal CRP

Non-inflammatory factors artificially elevating ESR:

• Anemia - directly increases ESR independent of inflammation 3, 2
• Renal insufficiency/azotemia - associated with >3-fold increased risk of this discordance pattern 3, 2
• Low serum albumin - predicts both types of ESR/CRP discordance 2
• Elevated immunoglobulins or rheumatoid factor - substantially contribute to ESR elevation without reflecting acute inflammation 4

Resolving inflammatory conditions:

• ESR remains elevated for weeks after CRP normalizes due to slower kinetics 1
• In chart review, 32% of patients with elevated ESR/normal CRP had resolving inflammatory disorders 1

Active infection (paradoxically):

• Underlying infection was associated with >14-fold increased risk of elevated ESR/low CRP discordance 2
• This counterintuitive finding suggests ESR may be less reliable in infectious contexts 2

Clinical Approach Algorithm

Step 1: Verify the CRP is Truly Normal

• Confirm CRP threshold used (typically <5-6 mg/L is normal) 5
• CRP is the preferred marker for active inflammation because it rises and falls more rapidly with disease activity 6, 1

Step 2: Evaluate for Non-Inflammatory ESR Elevators

Check complete blood count:

• Assess hemoglobin/hematocrit for anemia 3, 2

Check renal function:

• Measure serum creatinine and calculate GFR 3, 2

Check serum albumin:

• Low albumin strongly predicts ESR/CRP discordance 2

If rheumatic disease suspected, check:

• Immunoglobulin levels (IgG, IgA, IgM) 4
• Rheumatoid factor 4

Step 3: Consider Timing of Inflammatory Process

Recent treatment or resolving inflammation:

• ESR may remain elevated 2-4 weeks after CRP normalizes 1
• If patient recently completed antibiotics or anti-inflammatory treatment, elevated ESR likely represents lag phenomenon 1

Monitor trend:

• Repeat ESR and CRP in 2-4 weeks to determine if elevation is persistent or transitory 3

Step 4: Age and Gender Considerations

Normal ESR increases with age:

• Women have higher baseline ESR values than men 3
• ESR normally increases with advancing age 3
• Consider age-adjusted reference ranges (>20 mm/h in men, >30 mm/h in women for general screening) 3

When to Pursue Further Workup

Do NOT pursue extensive inflammatory workup if:

• Patient is clinically well without symptoms 1
• Clear non-inflammatory explanation exists (anemia, renal disease, low albumin) 2
• Recent resolution of known inflammatory condition 1

Consider targeted evaluation only if:

• Patient has specific symptoms suggesting giant cell arteritis (new headache, jaw claudication, visual symptoms) - ESR >40 mm/h has 93.2% sensitivity 3
• Bilateral shoulder/hip girdle pain with morning stiffness >45 minutes suggesting polymyalgia rheumatica 3
• Constitutional symptoms (fever, weight loss, night sweats) suggesting occult malignancy or infection 3

Key Clinical Pitfalls

Avoid these common errors:

• Do not order both ESR and CRP routinely - joint measurement is unwarranted in hospital practice 1
• Do not assume elevated ESR always means active inflammation - 28% of false-positive ESR results are due to confounding variables 1
• Do not rely on ESR in patients with renal disease - ESR has limited utility as inflammation marker in this population 2
• Do not use ESR to screen for IBD - both ESR and CRP have poor sensitivity (54-78% for ESR, 73% for CRP) and are not recommended for this purpose 5

Bottom Line for Clinical Practice

In 74 patients with elevated ESR and normal CRP reviewed by chart analysis: 32% had resolving inflammation, 28% had variables interfering with ESR measurement (false-positive), 32% had unexplained discordance, and only 8% had active inflammatory disease with false-negative CRP. 1 This distribution strongly favors a conservative approach focused on identifying non-inflammatory causes rather than pursuing extensive inflammatory workup when CRP is reassuringly normal.