What is the initial approach to a patient with leukocytosis (elevated white blood cell count)?

Initial Approach to Leukocytosis

The initial approach to a patient with leukocytosis should focus on determining the underlying cause through a complete blood count with differential, peripheral blood smear examination, and targeted diagnostic workup based on clinical presentation, rather than treating the elevated white blood cell count itself. 1

Definition and Classification

Leukocytosis is defined as an elevated white blood cell (WBC) count above the normal range of 4-10 × 10^9/L. The approach to leukocytosis requires:

• Identifying which leukocyte subpopulation is elevated (neutrophils, lymphocytes, monocytes, eosinophils, or basophils)
• Determining whether the elevation is reactive or due to a primary bone marrow disorder

Initial Diagnostic Workup

Step 1: Complete Blood Count with Differential

• Assess which WBC subpopulation is elevated
• Check for concurrent abnormalities in red blood cells or platelets
• Evaluate the maturity of white blood cells and presence of blasts 2

Step 2: Peripheral Blood Smear Examination

• Examine morphology of WBCs
• Look for:
  • Toxic granulations (suggesting infection)
  • Immature forms/blasts (suggesting leukemia)
  • Uniformity of white cells (clonal vs. reactive process)
  • Döhle bodies, cytoplasmic vacuolization 2

Step 3: Clinical Context Assessment

• Recent infections or inflammatory conditions
• Medication history (glucocorticoids, lithium, G-CSF)
• Presence of constitutional symptoms (fever, weight loss, night sweats)
• Physical examination findings (lymphadenopathy, splenomegaly, hepatomegaly)
• Recent surgery, trauma, or significant stress 2, 3

Common Causes of Leukocytosis

Reactive Causes (Most Common)

• Infections (particularly bacterial)
• Inflammation/autoimmune disorders
• Medications (corticosteroids, lithium, epinephrine)
• Physiologic stress (surgery, trauma, exercise, emotional stress)
• Smoking, obesity
• Asplenia 1, 2

Primary Bone Marrow Disorders

• Leukemias (acute or chronic)
• Myeloproliferative neoplasms
• Lymphoproliferative disorders 4

Diagnostic Algorithm Based on Differential Count

Neutrophilia (Elevated Neutrophils)

• Acute bacterial infections: Look for fever, localizing symptoms
• Inflammatory conditions: Assess for arthritis, vasculitis, tissue damage
• Physiologic stress: Recent surgery, trauma, exercise
• Medications: Corticosteroids, lithium
• Myeloproliferative disorders: Check for splenomegaly, basophilia, thrombocytosis
• Consider bone marrow examination if chronic, unexplained, or with abnormal cell morphology 2, 5

Lymphocytosis (Elevated Lymphocytes)

• Viral infections: Particularly in children (EBV, CMV, pertussis)
• Chronic infections: TB, brucellosis
• Lymphoproliferative disorders: Check for lymphadenopathy, hepatosplenomegaly
• Consider flow cytometry if persistent, significant elevation, or abnormal morphology 2

Monocytosis (Elevated Monocytes)

• Chronic infections: TB, endocarditis, fungal infections
• Inflammatory conditions: IBD, sarcoidosis
• Malignancies: Hodgkin lymphoma, solid tumors
• Myelodysplastic/myeloproliferative disorders: Chronic myelomonocytic leukemia 5

Eosinophilia (Elevated Eosinophils)

• Allergic conditions: Asthma, drug reactions, atopic dermatitis
• Parasitic infections: Stool examination, serology
• Hematologic malignancies: Particularly with other cytopenias
• Hypereosinophilic syndromes: Consider if persistent, severe elevation 2, 5

Red Flags Suggesting Malignancy

• WBC count >50,000/μL without obvious infection or inflammation
• Presence of blasts or immature cells on peripheral smear
• Concurrent anemia or thrombocytopenia
• Hepatosplenomegaly or significant lymphadenopathy
• Constitutional symptoms (fever, weight loss, night sweats)
• Progressive, unexplained leukocytosis 4, 2

Management of Severe Leukocytosis

For extreme leukocytosis (>100,000/μL), particularly with symptoms of leukostasis:

• Immediate hematology consultation
• Consider hydroxyurea (50-60 mg/kg/day) to rapidly reduce WBC count
• Maintain adequate hydration
• Monitor for and prevent tumor lysis syndrome
• Consider leukapheresis in symptomatic patients
• Avoid excessive red blood cell transfusions until WBC reduced 1, 6

When to Refer to Hematology

• WBC count >30,000/μL without clear reactive cause
• Presence of blasts or immature cells on peripheral smear
• Persistent unexplained leukocytosis
• Concurrent cytopenias
• Clinical suspicion for hematologic malignancy 2

Pitfalls to Avoid

• Treating the leukocytosis rather than the underlying cause
• Failing to recognize leukemoid reactions (extreme reactive leukocytosis)
• Missing early signs of leukostasis in hyperleukocytosis
• Overlooking medication-induced leukocytosis
• Neglecting to obtain a peripheral blood smear in significant leukocytosis 1, 6

Remember that leukocytosis is a sign, not a disease, and management should always be directed at the underlying cause rather than simply reducing the white blood cell count.