Prednisone Typically Causes Leukocytosis, Not Leukopenia
If you are observing true leukopenia (low WBC) in a patient on prednisone, this is NOT an expected effect of the corticosteroid and warrants immediate investigation for alternative causes such as infection, bone marrow suppression, drug interactions, or underlying autoimmune disease.
Understanding the Expected Effect: Corticosteroid-Induced Leukocytosis
Prednisone reliably causes leukocytosis (elevated WBC), not leukopenia:
Corticosteroids are lymphocyte-depleting agents that paradoxically increase total WBC count through neutrophilia, with leukocytosis appearing as early as the first day of treatment and persisting throughout therapy 1, 2.
The magnitude is dose-dependent: Low-dose prednisone increases WBC by approximately 0.3 × 10⁹/L, medium doses by 1.7 × 10⁹/L, and high doses by up to 4.84 × 10⁹/L within 48 hours 3.
Even small doses administered over prolonged periods can induce extreme and persistent leukocytosis, with WBC counts exceeding 20,000/mm³ in some patients 2.
The pattern is predominantly neutrophilic, accompanied by monocytosis, eosinopenia, and variable lymphopenia, but the total WBC count rises 1, 2.
Diagnostic Approach When Finding Low WBC on Prednisone
Immediate Workup Required
Stop and investigate—this is NOT a prednisone effect. Obtain:
Complete blood count with differential to characterize which cell lines are affected (neutropenia vs. lymphopenia vs. pancytopenia) 4.
Peripheral blood smear to evaluate for left shift, toxic granulation, dysplastic changes, or evidence of bone marrow failure 4.
Medication review for other drugs causing leukopenia: chemotherapy agents, antimetabolites (azathioprine, mycophenolate), valproate, antibiotics (especially beta-lactams), or other immunosuppressants 5, 6.
Infection workup including blood cultures, viral studies (CMV, EBV, HIV), and assessment for sepsis, as infection can cause leukopenia despite concurrent steroid use 5, 7.
Autoimmune serology if not already performed, as the underlying condition (not the prednisone) may be causing cytopenias 4.
Consider bone marrow biopsy if pancytopenia or unexplained persistent leukopenia, to evaluate for myelodysplastic syndromes, aplastic anemia, or marrow infiltration 4.
Critical Distinction: Infection in Steroid-Treated Patients
Prednisone increases infection susceptibility while simultaneously causing leukocytosis, creating diagnostic confusion:
Investigate for infection if WBC >14,000/mm³ with left shift (>6% bands), regardless of steroid dose 1.
In patients on chronic steroids, leukocytosis may be blunted or absent when infection develops, making leukopenia a particularly concerning finding 1.
Prednisolone increases susceptibility to serious infections and infection-related mortality, with infections developing in up to 23% of treated patients 7.
Serial WBC monitoring with differential is necessary if infection is suspected, rather than relying on a single value 1.
Management Algorithm for Leukopenia on Prednisone
Step 1: Confirm True Leukopenia
- Repeat CBC immediately to exclude laboratory error.
- Define severity: Mild (3.0-4.0 × 10⁹/L), Moderate (2.0-3.0 × 10⁹/L), Severe (<2.0 × 10⁹/L) or neutropenic (<1.5 × 10⁹/L neutrophils).
Step 2: Identify the Actual Cause
- Review all concurrent medications for myelosuppressive agents 5, 6.
- Assess for infection with appropriate cultures and imaging 5, 7.
- Consider the underlying disease being treated with prednisone as the cause of cytopenias 4.
- Evaluate for drug-induced immune cytopenias (drug-dependent antibodies) 4.
Step 3: Adjust Management Based on Severity
For severe leukopenia (<2.0 × 10⁹/L) or neutropenia (<1.5 × 10⁹/L):
- Hold or reduce prednisone dose only if another cause is identified and steroid continuation is not critical 4.
- Initiate broad-spectrum antibiotics if febrile or signs of infection 5.
- Consider hematology consultation for persistent or unexplained cytopenias 4.
- Implement neutropenic precautions if absolute neutrophil count <1.0 × 10⁹/L 5.
For mild-moderate leukopenia without neutropenia:
- Continue prednisone if clinically indicated, as this is likely unrelated to the steroid 1, 2.
- Monitor CBC weekly until etiology clarified and counts stabilize 4.
- Address identified alternative causes (discontinue offending drugs, treat infection, etc.) 5, 6.
Step 4: Infection Prophylaxis Considerations
If continuing moderate-to-high dose prednisone (≥15-30 mg daily) for ≥4 weeks:
- Consider Pneumocystis jirovecii pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole, especially if leukopenia suggests additional immunosuppression 5.
- Screen for latent tuberculosis, hepatitis B, and Strongyloides before prolonged high-dose therapy 5.
- Maintain heightened vigilance for opportunistic infections given dual risk from steroids and leukopenia 1, 5.
Common Pitfalls to Avoid
Do not attribute leukopenia to prednisone—this represents a fundamental misunderstanding of corticosteroid pharmacology 1, 2, 3.
Do not assume infection is absent because WBC is low—immunocompromised patients on steroids may have blunted leukocytosis despite serious infection 1, 7.
Do not overlook drug interactions—patients on prednisone often receive multiple medications, and combinations (e.g., cyclophosphamide + corticosteroids) significantly increase myelosuppression risk 5.
Do not delay workup—unexplained leukopenia in an immunosuppressed patient requires urgent evaluation to exclude life-threatening causes 4, 5.