Elevated ESR with Normal WBC: Differential Diagnosis
An ESR of 65 mm/h with a normal white blood cell count most commonly indicates chronic inflammatory conditions, connective tissue diseases, malignancies, or certain infections where the acute phase response is dissociated from leukocytosis.
Primary Diagnostic Considerations
Chronic Inflammatory and Autoimmune Conditions
Adult-onset Still's disease presents with markedly elevated ESR (virtually all patients show elevation), often accompanied by fever, rash, and arthralgia, while WBC may be normal or elevated 1, 2.
Temporal arteritis is the condition where ESR has the highest diagnostic utility, with values typically >60 mm/h, and the test is most useful for both diagnosis and monitoring treatment response 2, 3.
Inflammatory bowel disease (particularly ulcerative colitis) shows ESR elevation that correlates with disease activity, though sensitivity ranges only 54-78% 2.
Rheumatic fever characteristically presents with ESR >60 mm/h as a minor diagnostic criterion, often with normal WBC in early stages 2.
Infectious Etiologies
Chronic infections including osteomyelitis and certain viral infections (such as COVID-19) can produce elevated ESR with normal WBC 1, 2.
In the COVID-19 case series, patients demonstrated elevated ESR (mean 29.3 mm/h, range 8-67) with normal WBC counts (mean 5.45 × 10⁹/L) 1.
Diabetic foot osteomyelitis shows ESR >70 mm/h increases likelihood of bone infection, often without leukocytosis 2.
Malignancy
Occult malignancies can elevate ESR without affecting WBC count, though ESR alone has sensitivity not exceeding 0.85 and should not be used as a sole screening tool 4, 3.
ESR is often normal in many cancers, limiting its utility for exclusion 3.
Clinical Approach Algorithm
Immediate Assessment
Evaluate for temporal arteritis if patient is >50 years old with headache, jaw claudication, or visual symptoms—this requires urgent treatment 2, 3.
Screen for infection markers: Check fever, localized pain/swelling, and measure CRP alongside ESR 1, 5.
Assess for systemic symptoms: Fever patterns, rash (salmon-colored in Still's disease), joint pain, weight loss, night sweats 1, 2.
Laboratory Correlation
CRP measurement is essential as it provides complementary information and rises/falls more quickly than ESR, making discordance between the two markers clinically informative 2, 4, 5.
ESR and CRP can be discrepant in the same patient, reflecting different aspects of inflammatory response 4, 5.
Additional markers to consider: Fibrinogen (elevated in chronic inflammation), platelet count (reactive thrombocytosis common in inflammatory states), and anemia of chronic disease 1, 5.
Specific Disease Patterns
Still's disease pattern: ESR elevated, possible normal WBC (though 50% have WBC >15 × 10⁹/L), elevated ferritin, liver enzyme abnormalities 1.
Infection pattern: If CRP is also elevated with normal WBC, consider chronic osteomyelitis, fracture-related infection, or atypical infections 1, 2.
Malignancy pattern: Persistently elevated ESR with normal WBC, anemia, and constitutional symptoms warrants age-appropriate cancer screening 4, 3.
Critical Pitfalls to Avoid
Do not use ESR as a screening test in asymptomatic patients—it is seldom the sole clue to disease and unexplained elevation is often transitory 3.
Do not rely on ESR alone to exclude serious disease, as it is often normal in cancer, infection, and connective tissue disease 3.
Recognize that ESR has limited diagnostic value when used in isolation—always combine with clinical history, physical examination, and complementary inflammatory markers 3, 5.
Monitor for evolving infection: In postoperative or trauma patients, renewed elevation of inflammatory markers after initial decline (days 4-11) may indicate developing infection even with normal WBC 6.