What causes a mildly low white blood cell (WBC) count?

Causes of Mildly Low White Blood Cell Count

A mildly low WBC count most commonly results from viral infections (particularly influenza), medications, nutritional deficiencies, or benign ethnic neutropenia, though primary immunodeficiency and early hematologic disorders must be excluded in specific clinical contexts. 1, 2

Most Common Causes

Viral Infections

• Influenza is the most frequent infectious cause, with 8-27% of influenza A cases presenting with WBC <4.0 × 10⁹/L 1, 2
• H5N1 influenza demonstrates particularly severe leukopenia, with mean WBC of 2.44 × 10⁹/L in all documented pediatric cases 1
• Other viral respiratory infections commonly produce transient leukopenia that resolves with clinical recovery 3

Medications

• Numerous drugs can suppress WBC production, including chemotherapy agents, immunosuppressants, antithyroid medications, and certain antibiotics 4, 5
• Lithium therapy paradoxically causes leukocytosis rather than leukopenia—WBC counts below 4,000/mm³ would be highly unusual in lithium-treated patients 2

Nutritional Deficiencies

• Vitamin B12 and folate deficiency can present with leukopenia, often accompanied by macrocytic anemia 6
• Severe iron deficiency may occasionally contribute to mild leukopenia 6

Less Common but Important Causes

Primary Immunodeficiency Disorders

• Phagocytic cell defects can present with neutropenia as the predominant laboratory finding 6
• Combined immunodeficiencies may show leukopenia before other immune abnormalities become apparent 6
• These disorders typically present with recurrent severe infections, particularly pyogenic bacterial and fungal infections of respiratory tract, skin, and viscera 6

Early Hematologic Malignancies

• Chronic lymphocytic leukemia (CLL) may initially present with leukopenia before the characteristic lymphocytosis develops 6, 1
• Early myelodysplastic syndromes can manifest as isolated cytopenias 6
• Primary bone marrow disorders should be suspected when leukopenia occurs with concurrent red blood cell or platelet abnormalities 5

Autoimmune and Inflammatory Conditions

• Systemic lupus erythematosus and other autoimmune disorders frequently cause leukopenia 4
• Hemophagocytic syndromes present with cytopenias, often triggered by viral infections 6

Diagnostic Approach

Initial Evaluation

• Repeat CBC with manual differential to confirm persistent leukopenia and assess cell morphology 1
• Review medication list for potential causative agents 4, 5
• Assess for viral infection symptoms (fever, respiratory symptoms, myalgias) 1, 2
• Examine peripheral blood smear for morphologic abnormalities, cellular fragmentation, or dysplastic features 1

Red Flags Requiring Further Investigation

• Recurrent or severe infections suggest primary immunodeficiency or functional neutrophil defects 6
• Progressive decline in WBC over serial measurements is more concerning than stable low counts 1
• Concurrent cytopenias (anemia or thrombocytopenia) raise suspicion for bone marrow disorders 5
• Lymphadenopathy, hepatosplenomegaly, or unexplained weight loss warrant hematologic evaluation 5

Extended Workup When Indicated

• Immunoglobulin levels and specific antibody responses if recurrent infections present 6
• Lymphocyte subset enumeration (CD4, CD8, B cells, NK cells) for suspected immunodeficiency 6
• Vitamin B12, folate, and iron studies to exclude nutritional causes 6
• Bone marrow examination if primary marrow disorder suspected or unexplained persistent leukopenia 6, 5

Clinical Significance and Management

When to Observe

• Isolated mild leukopenia with normal differentials is less concerning than leukopenia with abnormal differential counts 1
• Stable low counts without infectious complications may represent benign ethnic neutropenia or constitutional variation 1
• Post-viral leukopenia typically resolves within 2-4 weeks 3

When to Act Urgently

• Absolute neutrophil count <500/mm³ represents severe neutropenia requiring infection precautions and prompt evaluation for fever 4
• Development of fever in neutropenic patients mandates immediate empiric antibiotic therapy 4
• Suspected primary immunodeficiency, particularly SCID, requires urgent referral as outcomes improve dramatically with earliest intervention 6

Common Pitfalls to Avoid

• Do not dismiss mild leukopenia in patients with recurrent infections—this combination warrants immunologic evaluation even when WBC is only mildly reduced 6
• Do not assume all leukopenia is benign—serial monitoring is essential to detect progressive decline 1
• Do not overlook medication review—drug-induced leukopenia is common and reversible 4, 5
• Do not ignore accompanying symptoms—unexplained fever, weight loss, or organomegaly with leukopenia requires hematologic consultation 5