Can prednisone (corticosteroid) cause leukocytosis (elevated white blood cell count)?

Can Prednisone Cause Leukocytosis?

Yes, prednisone and other corticosteroids consistently cause leukocytosis, which is a well-established and dose-dependent effect that can occur as early as the first day of treatment and persist throughout therapy.

Mechanism and Characteristics of Corticosteroid-Induced Leukocytosis

Prednisone causes leukocytosis primarily through neutrophil demargination and increased bone marrow release, resulting in a predominantly neutrophilic pattern 1, 2. The white blood cell (WBC) elevation is accompanied by characteristic findings that help distinguish it from infectious causes:

• Monocytosis occurs alongside the neutrophilia 1
• Eosinopenia is typically present 1
• Lymphopenia develops with variable severity 1, 3
• Absence of left shift (typically <6% band forms) and lack of toxic granulation distinguish steroid-induced leukocytosis from infection 1

Dose-Response Relationship and Timing

The magnitude and timing of leukocytosis correlate directly with corticosteroid dosage 1, 4:

• Low-dose steroids (equivalent to <20 mg prednisone): Mean increase of 0.3 × 10⁹/L WBCs 4
• Medium-dose steroids: Mean increase of 1.7 × 10⁹/L WBCs 4
• High-dose steroids: Mean increase of 4.84 × 10⁹/L WBCs 4

Peak response occurs at 48 hours after steroid administration, with WBC counts potentially exceeding 20,000/mm³ even from the first day of treatment 1, 4. The leukocytosis reaches maximal values within two weeks in most cases, after which counts may decrease but typically remain above pretreatment levels for the duration of therapy 1.

Clinical Implications for Practice

Distinguishing Steroid Effect from Infection

When evaluating a patient on prednisone with leukocytosis, apply this diagnostic approach 1, 2:

1. Check the peripheral smear for left shift (>6% bands) and toxic granulation—their presence suggests infection rather than steroid effect 1
2. Consider the magnitude of increase: Increases >4.84 × 10⁹/L after high-dose steroids, or any significant increase after low-dose steroids, should prompt investigation for alternative causes 4
3. Assess clinical context: Physical stress, emotional stress, and disease activity (particularly in rheumatoid arthritis) can contribute to leukocytosis independent of steroids 2, 5

Chronic Low-Dose Therapy

Even small doses of prednisone administered over prolonged periods can induce extreme and persistent leukocytosis 1, 5. In rheumatoid arthritis patients receiving chronic low-dose corticosteroids (mean 7 mg prednisone daily), the prevalence of leukocytosis was 40% compared to 7.5% in those not receiving steroids 5.

Alternate-Day Dosing

With alternate-day prednisone therapy, the leukocytosis is maximal at 6 hours post-dose but returns to control levels by 24 hours 3. This transient pattern includes dose-dependent lymphopenia affecting T-cells, B-cells, and null cells, with T-cells most severely affected 3.

Critical Pitfalls to Avoid

• Do not automatically attribute all leukocytosis to steroids in immunocompromised patients—maintain vigilance for occult infection, particularly when WBC increases exceed expected steroid-induced elevations 1, 5
• Recognize that corticosteroids are listed among medications commonly associated with leukocytosis alongside lithium and beta agonists 2
• Be aware that the ASCO guideline specifically identifies corticosteroids as lymphocyte-depleting therapy when evaluating hematologic abnormalities 6