What are the possible causes of a mildly reduced white‑blood‑cell count (mild leukopenia)?

Causes of Mild Leukopenia

Mild leukopenia (slightly reduced white blood cell count) most commonly results from viral infections, certain medications, nutritional deficiencies, autoimmune conditions, or benign ethnic neutropenia, though bone marrow disorders and chronic infections must be excluded in persistent cases. 1

Infectious Causes

Viral infections are among the most frequent causes of transient mild leukopenia:

• Acute viral illnesses (including common respiratory viruses, EBV, CMV, parvovirus B19) typically produce lymphopenia or mild neutropenia that resolves spontaneously within weeks 2, 1
• HIV infection causes progressive leukopenia and should be tested in all adults with unexplained persistent leukopenia 1, 3
• Hepatitis C virus can produce chronic mild leukopenia, often years before other manifestations appear 1, 3
• Tickborne rickettsial diseases (ehrlichiosis, anaplasmosis) characteristically present with leukopenia (up to 53% of patients) alongside thrombocytopenia and fever 2
• Q fever typically shows normal white blood cell counts despite prolonged fever, though mild leukopenia can occur 2

Important diagnostic pitfall: In Kawasaki disease, leukopenia and lymphocyte predominance suggest an alternative diagnosis rather than KD, which typically presents with leukocytosis 2. Similarly, in tickborne illnesses, the combination of leukopenia plus thrombocytopenia is highly suggestive and should prompt specific serologic testing 2.

Medication-Induced Causes

Numerous medications cause dose-dependent or idiosyncratic bone marrow suppression:

• Chemotherapy agents are the most common iatrogenic cause, producing predictable dose-dependent myelosuppression 1
• Immunosuppressive drugs (azathioprine, 6-mercaptopurine) cause leukopenia in approximately 3.2% of patients overall, with severe leukopenia occurring in 5.3% of rheumatoid arthritis patients 1
• Patients with TPMT or NUDT15 deficiency face dramatically increased risk of life-threatening myelosuppression from thiopurines, though normal TPMT testing does not exclude risk (only 27% of leukopenia cases are explained by common TPMT variants) 1
• Immune checkpoint inhibitors can induce hematologic immune-related adverse events including leukopenia 1
• Clozapine requires routine monitoring because of the risk of clozapine-induced agranulocytosis, though mild leukopenia from lymphopenia (e.g., during COVID-19) may allow continuation with increased monitoring 4
• Other implicated agents include certain antibiotics, anticonvulsants, antithyroid drugs, and NSAIDs 1, 5

Critical caveat: Profound leukopenia can develop suddenly and unpredictably between blood tests in patients on thiopurines, occurring in around 3% of cases 1. A comprehensive medication history—including over-the-counter products, herbal supplements, and recent antibiotic courses—is mandatory 1, 3.

Hematologic Malignancies and Bone Marrow Disorders

Bone marrow infiltration or dysfunction produces persistent leukopenia:

• Myelodysplastic syndromes (MDS) impair normal blood cell production and require stable cytopenia for at least 6 months (or 2 months if specific karyotype or bilineage dysplasia present) plus exclusion of other causes 2, 1
• Chronic lymphocytic leukemia (CLL) causes cytopenias through bone marrow infiltration or autoimmune mechanisms; autoimmune granulocytopenia is less common than autoimmune hemolytic anemia or immune thrombocytopenia in CLL 1
• Aplastic anemia produces pancytopenia including leukopenia, with mortality up to 80% in severe cases 1
• Hairy cell leukemia presents with varying degrees of pancytopenia; 39% of patients have absolute neutrophil count <0.5 × 10⁹/L at presentation, and 17% have active infection at diagnosis 2

When to suspect malignancy: Constitutional symptoms (fever, unexplained weight loss, night sweats, bone pain), splenomegaly, hepatomegaly, lymphadenopathy, or additional cytopenias beyond isolated leukopenia mandate bone marrow examination 2, 1, 3.

Autoimmune and Immune-Mediated Causes

Autoimmune destruction of leukocytes occurs in several conditions:

• Autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis) can produce immune-mediated leukopenia, particularly when patients are also receiving immunosuppressive therapy 1
• Common variable immune deficiency (CVID) may present initially with leukopenia; immunoglobulin measurement should be considered 3
• In CLL, autoimmune cytopenias not responding to conventional therapy are indications for CLL-directed treatment 1

Nutritional Deficiencies

Megaloblastic causes impair normal cell maturation:

• Vitamin B12 or folate deficiency produces macrocytic anemia with associated leukopenia and thrombocytopenia 2
• Copper deficiency (often from zinc supplementation or malabsorption) can cause cytopenias mimicking MDS 1

Hypersplenism and Sequestration

Splenic pooling reduces circulating leukocyte counts:

• Portal hypertension from cirrhosis induces hypersplenism with platelet and leukocyte sequestration; the degree correlates with splenomegaly magnitude 3
• Chronic liver disease also causes direct bone marrow suppression (from alcohol, viral hepatitis) beyond the effect of reduced thrombopoietin 3

Benign Ethnic Neutropenia

Benign ethnic neutropenia (BEN) is a common, benign variant:

• Occurs in individuals of African, Middle Eastern, or West Indian descent with chronically lower neutrophil counts (typically 1.0–1.5 × 10⁹/L) but normal bone marrow reserves and no increased infection risk 6
• Diagnosis requires exclusion of other causes and demonstration of chronically stable counts without clinical consequences 6

Diagnostic Algorithm for Mild Leukopenia

Step 1: Confirm true leukopenia

• Repeat complete blood count to verify persistent reduction 1, 6
• Review peripheral blood smear to assess which white cell lines are affected and identify morphologic abnormalities 1

Step 2: Determine acuteness and severity

• Transient leukopenia (days to weeks) with recent viral illness suggests self-limited viral suppression; observe with repeat CBC in 2–4 weeks 1, 6
• Chronic leukopenia (>3 months) or absolute neutrophil count <1.0 × 10⁹/L requires systematic evaluation 6

Step 3: Exclude secondary causes

• Comprehensive medication review including recent additions or dose changes 1
• HIV and hepatitis C serology in all adults with unexplained leukopenia 1, 3
• Vitamin B12, folate, and copper levels if macrocytosis or other cytopenias present 2, 1
• Antinuclear antibodies and rheumatoid factor if autoimmune features exist 1

Step 4: Assess for red flags requiring bone marrow examination

• Age ≥60 years (to exclude MDS, leukemia) 2, 1
• Constitutional symptoms (fever, weight loss, night sweats, bone pain) 2, 1
• Splenomegaly, hepatomegaly, or lymphadenopathy 2, 1
• Additional unexplained cytopenias (anemia, thrombocytopenia) 2, 1
• Abnormal peripheral smear (immature cells, dysplastic features) 2, 1
• Persistent leukopenia despite removal of potential offending agents 1, 6

Step 5: Risk stratification for infection

• Absolute neutrophil count <0.5 × 10⁹/L confers high infection risk (10–20% when <0.1 × 10⁹/L) 1
• Patients with cancer, HIV, or on immunosuppression face particularly elevated infectious complications 1
• Antimicrobial prophylaxis may be indicated in severe neutropenia, especially in cancer patients 1

Management Principles

For medication-induced leukopenia:

• Consider dose reduction or discontinuation of the offending agent 1
• In thiopurine-induced cases, TPMT/NUDT15 genotyping guides future dosing, though normal results do not exclude risk 1
• Transition to alternative immunosuppression (methotrexate, biologic DMARDs, JAK inhibitors) once counts recover 1

For autoimmune-mediated leukopenia:

• Corticosteroids are first-line treatment for warm-antibody autoimmune cytopenias 1
• In CLL with autoimmune cytopenias refractory to conventional therapy, initiate CLL-directed treatment 1

For infection-related leukopenia:

• Treat underlying infection (HIV antiretroviral therapy, HCV direct-acting antivirals, H. pylori eradication) 1
• In febrile neutropenia, prompt empiric broad-spectrum antibiotics are essential 1

For benign ethnic neutropenia:

• No treatment required; provide patient education and document baseline to avoid unnecessary future workup 6

Monitoring frequency should be based on severity of leukopenia, underlying condition, and infection risk; patients on myelosuppressive agents require more frequent surveillance 1, 6.