What is the differential diagnosis of a leucemoid (leukocyte disorder) reaction in adults?

Differential Diagnosis of Leukemoid Reaction

A leukemoid reaction is defined as reactive leukocytosis exceeding 40-50 × 10⁹/L with significant increase in early neutrophil precursors, and the differential diagnosis must systematically exclude chronic myelogenous leukemia (CML) and chronic neutrophilic leukemia (CNL) before identifying the underlying reactive cause. 1, 2

Primary Exclusions Required

Before diagnosing a leukemoid reaction, you must rule out:

• Chronic myelogenous leukemia (CML) - This is the critical first step, as CML can present identically with marked leukocytosis and left shift 1
• Chronic neutrophilic leukemia (CNL) - A rare myeloproliferative neoplasm that closely mimics leukemoid reaction and requires bone marrow evaluation and molecular testing to distinguish 1, 3
• Acute myeloid leukemia (AML) - Particularly when hyperleukocytosis (WBC >100 × 10⁹/L) is present, as this represents a medical emergency requiring immediate cytoreduction 4, 5
• Other myeloproliferative neoplasms - Including polycythemia vera, essential thrombocythemia, and primary myelofibrosis 4

Major Causes of True Leukemoid Reaction

Once malignancy is excluded, the differential includes:

Infectious Causes (Most Common)

• Severe bacterial infections - The most frequent cause, involving multiple organisms including gram-positive and gram-negative bacteria 2, 6
• Tuberculosis - Particularly in patients with travel exposure to endemic areas 7
• Endocarditis - Should be considered with recurrent infections and monocytosis 7
• Ehrlichiosis - Look for morulae in monocytes on peripheral smear 7
• Parasitic infections - Consider with appropriate travel history 7

Malignancy-Related (Second Most Common)

• Paraneoplastic syndrome from solid tumors - Particularly sarcomatoid renal cell carcinoma, poorly differentiated carcinomas, and other nonhematopoietic malignancies 2, 8, 3
• This carries an extremely poor prognosis with high mortality 2, 8

Other Causes

• Severe hemorrhage - Acute blood loss can trigger marked reactive leukocytosis 1
• Acute hemolysis - Massive hemolytic episodes 1
• Drug intoxications - Various medications and toxic exposures 1
• Adult-onset Still's disease - Presents with fever spikes, sore throat, salmon-colored rash, and monocytosis in 51-87% of cases 7
• Autoimmune disorders - Including systemic lupus erythematosus and rheumatoid arthritis 7

Diagnostic Algorithm

Step 1: Confirm the Count and Review Peripheral Smear

• Calculate absolute counts - Don't rely solely on automated differentials 7
• Manual differential is mandatory - Automated analyzers miss critical morphologic features 7, 6
• Look for activated neutrophil changes - These suggest reactive process rather than malignancy 6
• Identify dysplasia - Pseudo-Pelger-Huët anomaly, hypogranulation suggest myelodysplastic syndrome or CMML 7
• Count blasts and blast equivalents precisely - >1% blasts or promonocytes raises concern for CMML 7

Step 2: Exclude Hematologic Malignancy

• Bone marrow aspirate and biopsy - Required when absolute monocyte count ≥1 × 10⁹/L persists >3 months without identified reactive cause, or when concurrent cytopenias, dysplastic features, or constitutional symptoms are present 7
• Cytogenetic analysis - Conventional karyotyping to exclude CML and other myeloid neoplasms 5, 7
• Molecular testing - BCR-ABL for CML, JAK2 mutations for other myeloproliferative neoplasms 5
• Flow cytometry - To characterize cell populations and exclude lymphoproliferative disorders 5, 6

Step 3: Identify Underlying Reactive Cause

• Targeted infectious workup - Blood cultures, imaging for occult infections, tuberculosis testing, HIV, hepatitis C 7
• Imaging for solid tumors - CT chest/abdomen/pelvis if paraneoplastic syndrome suspected 7
• Inflammatory markers - ESR and CRP (virtually always elevated in Adult-onset Still's disease and CMML) 7
• Autoimmune serologies - If constitutional symptoms or physical findings suggest autoimmune disease 7

Critical Pitfalls to Avoid

• Don't confuse relative and absolute monocytosis - Always calculate absolute monocyte count from total WBC and differential percentage 7
• Don't attribute persistent monocytosis to inflammation without excluding infection - Tuberculosis, endocarditis, and parasitic infections require specific treatment 7
• Don't delay bone marrow evaluation beyond 3 months in unexplained monocytosis - CMML has poor prognosis and early identification allows consideration of allogeneic stem cell transplantation 7
• Don't miss hyperleukocytosis (WBC >100 × 10⁹/L) as a medical emergency - This requires immediate cytoreduction with hydroxyurea 50-60 mg/kg/day and measures to prevent tumor lysis syndrome 4, 5
• Don't give excessive red blood cell transfusions in hyperleukocytosis - This increases blood viscosity and worsens symptoms 5

Prognostic Implications

Leukemoid reaction carries a poor prognosis regardless of etiology, with high mortality rates. 2 Lower hemoglobin, older age, and increased segmented neutrophil count are associated with increased risk of death 2. Paraneoplastic leukemoid reaction is particularly ominous and may serve as a predictor of poor prognosis in patients with solid tumors 8, 3.