What are the common causes of mild leukopenia (a mildly low white blood cell count)?

Common Causes of Mild Leukopenia

Mild leukopenia with a normal absolute neutrophil count (ANC ≥1.5 × 10³/μL) in an otherwise healthy adult is clinically insignificant and requires only repeat testing in 4-6 weeks to confirm stability. 1

Primary Etiologic Categories

The most common causes of mild leukopenia can be organized into several key categories:

Medication-Related Causes

• Chemotherapy agents represent the most frequent iatrogenic cause through direct bone marrow suppression, affecting granulocyte production. 2
• Corticosteroids, lithium, and beta agonists can paradoxically cause changes in white blood cell counts. 3
• A thorough medication history focusing on chemotherapy, immunosuppressants, and other marrow-toxic drugs is crucial in diagnosing leukopenia. 2

Infectious Causes

• Bacterial infections, especially overwhelming sepsis, cause leukopenia through increased white blood cell utilization and destruction rather than decreased production. 2
• Viral infections commonly cause transient leukopenia. 4
• The combination of fever plus leukopenia suggests severe bacterial infection with poor prognosis. 1

Nutritional and Metabolic Causes

• Vitamin B12 or folate deficiency can cause leukopenia in patients with nutritional deficiencies. 2
• Megaloblastosis is responsible for many cases of neutropenia. 4

Hematologic Disorders

• Myelodysplastic syndromes cause ineffective hematopoiesis with stable cytopenia (≥6 months duration, or 2 months with specific karyotype abnormalities). 2
• Leukemias and lymphomas can present with paradoxical leukopenia despite being proliferative disorders. 2
• Aplastic anemia can cause pancytopenia and leukopenia in patients with bone marrow disorders. 2

Other Causes

• Hypersplenism leads to increased sequestration and destruction of white blood cells. 4
• Immunoneutropenia and autoimmune processes can cause selective white blood cell destruction. 4
• Primary immunodeficiency disorders, including Wiskott-Aldrich syndrome, present with T-cell lymphopenia and neutropenia variants. 2
• Familial Mediterranean fever can cause episodic leukopenia due to autophagy and apoptosis processes. 5

Critical Diagnostic Thresholds

Understanding when mild leukopenia becomes clinically significant:

• A WBC <3.0 × 10³/μL is considered a red flag threshold requiring closer monitoring. 1
• A normal ANC (≥1.5 × 10³/μL) indicates adequate infection-fighting capacity is preserved. 1
• An ANC <0.5 × 10³/μL is associated with severe neutropenia and substantial infection risk. 1

Essential Diagnostic Workup

Obtain a manual differential count immediately to calculate absolute neutrophil count (ANC) and assess for left shift, immature forms, or dysplasia. 1, 6

Key diagnostic steps include:

• Complete blood count with differential is essential to characterize the specific white blood cell lineage affected and identify other cytopenias. 2
• Peripheral blood smear review is necessary to assess for dysplasia, blast cells, and abnormal cell morphology. 2, 6
• Check previous blood counts to assess the dynamic development of the leukopenia. 6
• Assess red blood cell count and platelet count; a bi- or pancytopenia usually implies insufficient production in the bone marrow. 6

Reassuring Features in Mild Leukopenia

• Normal lymphocyte count and all other cell lines normal argue against bone marrow pathology and immune suppression. 1
• Stable counts over time without progressive decline suggest benign etiology. 1

Red Flags Requiring Further Investigation

• Progressive decline over serial measurements indicates evolving bone marrow disorder. 1
• Recurrent infections suggest functional immune deficiency despite cell counts. 1
• Splenomegaly or lymphadenopathy suggests hematologic malignancy. 1
• Weight loss, bleeding or bruising, or liver/spleen/lymph node enlargement increase suspicion for a marrow disorder. 3

Management Approach for Mild Leukopenia

For mild leukopenia (WBC 3.0-4.0 × 10³/μL) with normal ANC, repeat CBC in 4-6 weeks to assess trend and provide patient education on infection warning signs. 1

• Bone marrow aspiration and biopsy with cytogenetics may be required for persistent unexplained leukopenia, particularly when neutrophil count <1500/μL or when dysplasia is suspected. 2
• For severe neutropenia (ANC <1.0 × 10³/μL), hematology referral is mandatory and bone marrow biopsy is often indicated. 1

Common Pitfalls to Avoid

• Do not assume all leukopenia is clinically significant; the ANC and differential are more important than the total WBC alone. 1
• Leukopenia can be life-threatening if the patient presents with agranulocytosis and fever; in this case admission is mandatory with immediate broad-spectrum antibiotics. 6
• Do not overlook medication history, as drug-induced leukopenia is the most common iatrogenic cause. 2
• Consider episodic causes like familial Mediterranean fever in patients with recurrent, self-limited leukopenia. 5