What medications can cause worsening leukocytosis in inpatients?

Medications That Cause Worsening Leukocytosis in Inpatients

Corticosteroids, lithium, and beta-agonists are the most common medications that cause leukocytosis in hospitalized patients, with corticosteroids producing the most dramatic and dose-dependent elevations. 1, 2

Corticosteroids: The Primary Culprit

Corticosteroids cause the most significant drug-induced leukocytosis in hospitalized patients, with effects that are dose-dependent and can persist throughout therapy. 3, 4

Magnitude and Timing of Corticosteroid-Induced Leukocytosis

• High-dose corticosteroids can increase WBC counts by up to 4.84 × 10⁹/L within 48 hours of administration, with peak effects occurring at 48 hours 3
• Medium-dose corticosteroids produce mean increases of 1.7 × 10⁹/L 3
• Low-dose corticosteroids cause mean increases of only 0.3 × 10⁹/L 3
• The WBC count can surpass 20,000/mm³ as early as the first day of treatment, even with small doses administered over prolonged periods 4
• Leukocytosis reaches maximal values within two weeks in most cases, after which the WBC count may decrease but typically does not return to pretreatment levels 4

Distinguishing Corticosteroid-Induced Leukocytosis from Infection

A critical clinical pearl: increases larger than 4.84 × 10⁹/L cells, or any increase after low-dose steroids, should prompt evaluation for other causes of leukocytosis, particularly infection. 3

• Corticosteroid-induced leukocytosis is predominantly due to polymorphonuclear leukocytes, accompanied by monocytosis, eosinopenia, and variable lymphopenia 4
• A left shift (>6% band forms) and toxic granulation are rare in corticosteroid-induced leukocytosis but common in infection, making these features useful for differential diagnosis 4

Lithium

Lithium is a well-established cause of leukocytosis in hospitalized patients. 1, 2

• An encephalopathic syndrome characterized by weakness, lethargy, fever, tremulousness, confusion, extrapyramidal symptoms, and leukocytosis has been reported when lithium is combined with haloperidol 1
• Lithium is one of the three most commonly cited medications associated with leukocytosis in clinical practice 2

Beta-Agonists

Beta-agonists are recognized as a common cause of drug-induced leukocytosis. 2

• These medications are frequently used in hospitalized patients for bronchodilation and can contribute to elevated WBC counts 2

Other Medications to Consider

Chemotherapy and Immunosuppressive Agents

While the provided evidence focuses primarily on drugs causing hemolysis rather than leukocytosis, several chemotherapy agents are mentioned in the context of drug-induced hematologic effects:

• Ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, quinine/quinidine, fludarabine, ciprofloxacin, lorazepam, and diclofenac are listed as common drug causes requiring evaluation in patients with hematologic abnormalities 5

Hydroxyurea

Hydroxyurea causes severe myelosuppression rather than leukocytosis, with leukopenia being the first and most common manifestation of bone marrow suppression 6

• This medication is used for cytoreduction in patients with extreme leukocytosis (WBC >30,000/μL) from underlying hematologic conditions, not as a cause of leukocytosis 6

Clinical Algorithm for Managing Drug-Induced Leukocytosis

Step 1: Identify the Medication and Dose

• Review all current medications, particularly corticosteroids (dose and duration), lithium, and beta-agonists 3, 2

Step 2: Assess the Magnitude of Leukocytosis

• For corticosteroid users: Compare the WBC increase to expected values based on dose (up to 4.84 × 10⁹/L for high-dose) 3
• Increases exceeding expected values warrant investigation for alternative causes 3

Step 3: Evaluate for Infection

• Check for left shift (>6% bands) and toxic granulation on peripheral smear 4
• Assess for fever, localizing signs of infection, and other clinical indicators 4, 7
• The presence of left shift or toxic granulation strongly suggests infection rather than drug effect 4

Step 4: Consider Timing

• Corticosteroid-induced leukocytosis peaks at 48 hours 3
• Physical or emotional stress can cause WBC doubling within hours due to demargination 8

Step 5: Monitor and Reassess

• For patients on corticosteroids, expect WBC counts to remain elevated throughout therapy but potentially decrease after 2 weeks (though not to baseline) 4
• Any worsening leukocytosis or development of new symptoms requires immediate reassessment for infection or other causes 3, 7

Common Pitfalls to Avoid

• Do not assume all leukocytosis in steroid-treated patients is benign—increases beyond expected ranges or accompanied by left shift require infection workup 3, 4
• Do not overlook the contribution of multiple medications—patients may be on corticosteroids, beta-agonists, and lithium simultaneously 2
• Do not delay antibiotic therapy in truly infected patients due to attribution of leukocytosis to medications—use peripheral smear findings to guide decision-making 4
• Avoid prolonged empiric broad-spectrum antibiotics in patients with persistent leukocytosis without clear infection, as this leads to colonization with resistant organisms including Clostridium difficile 7