What causes a low White Blood Cell (WBC) count with normal differentials?

Causes of Low White Blood Cell Count with Normal Differentials

A low white blood cell (WBC) count with normal differentials is most commonly due to benign genetic predisposition, viral infections, or medication effects, and rarely indicates serious underlying pathology when other clinical parameters are normal.

Common Causes

Viral Infections

• Viral infections, particularly influenza, can cause a low total WBC count while maintaining normal differential proportions 1, 2
• In influenza A infections, a low WBC count is common in children, with studies showing WBC <4 in 8-27% of cases 1
• H5N1 influenza cases have demonstrated particularly severe leukopenia, with all seven children in one study having WBC <4.0 (mean 2.44) 1

Medication-Related Causes

• Certain medications can cause isolated leukopenia without affecting the relative proportions of cell types 3
• Chemotherapeutic agents and immunosuppressants are common culprits, with individuals genetically predisposed to lower WBC counts being at higher risk (hazard ratio=0.78 for chemotherapeutics and 0.61 for immunosuppressants) 3
• Filgrastim (G-CSF) withdrawal can cause temporary leukopenia as the stimulated neutrophil production returns to baseline, typically within 4 days of discontinuation 4

Genetic Factors

• Polygenic variation unrelated to disease contributes to interindividual variation in baseline WBC counts 3
• A genetic predisposition to lower WBC counts is associated with decreased risk of identifying pathology on bone marrow biopsies performed for low WBC counts (odds-ratio=0.55) 3
• These benign genetic variants can lead to what appears clinically as leukopenia but represents a normal variant for that individual 3

Less Common Causes

Early Stages of Bone Marrow Disorders

• Early stages of certain hematologic disorders may present with isolated leukopenia before differential abnormalities become apparent 1
• In chronic lymphocytic leukemia (CLL), while lymphocytosis is typical, some patients may initially present with leukopenia 1

Redistribution of White Blood Cells

• Redistribution among body neutrophil pools can cause temporary changes in circulating WBC counts without affecting the differential percentages 5
• This can occur during acute stress, infection, or inflammation 5

Diagnostic Approach

Laboratory Assessment

• Complete blood count with differential should be repeated to confirm persistent leukopenia 1
• Normal differentials in the setting of leukopenia are defined as normal relative proportions of neutrophils, lymphocytes, monocytes, eosinophils, and basophils 1
• Assessment of peripheral blood smear for morphologic abnormalities is important to rule out cellular fragmentation or abnormal cell morphology 1

Additional Testing Based on Clinical Context

• If viral infection is suspected, specific viral testing may be warranted 1, 2
• In cases of persistent unexplained leukopenia, bone marrow examination may be considered, though the yield is lower in those with genetic predisposition to low counts 3
• Monitoring trends in WBC counts over time is more informative than a single measurement 1

Clinical Implications and Management

When to Be Concerned

• Isolated leukopenia with normal differentials is less concerning than leukopenia with abnormal differential counts 1
• Development of symptoms such as recurrent infections, unexplained fever, or other cytopenias warrants further investigation 1
• Progressive decline in WBC count over time is more concerning than stable low counts 1

Management Approach

• For asymptomatic patients with mildly low WBC counts and normal differentials, observation with periodic monitoring is often sufficient 3
• For medication-induced leukopenia, dose adjustment or medication change may be necessary, particularly in those with genetic predisposition to lower counts 3
• G-CSF (filgrastim) therapy may be considered in cases of severe symptomatic leukopenia, but is not indicated for asymptomatic mild leukopenia 4

Common Pitfalls to Avoid

• Overinvestigation of mildly low WBC counts in otherwise healthy individuals can lead to unnecessary testing and anxiety 3
• Failure to consider genetic predisposition to lower WBC counts can result in inappropriate discontinuation of necessary medications 3
• Not accounting for normal age-related and population variations in WBC count reference ranges 6
• Interpreting a single low WBC count without clinical context or trend data 1

Remember that a low WBC count with normal differentials is often benign, especially in the absence of symptoms or other abnormal findings. However, persistent or progressive leukopenia warrants appropriate clinical follow-up to rule out underlying pathology.