What is agranulocytosis?

Agranulocytosis: Definition, Causes, and Management

Agranulocytosis is a potentially life-threatening condition characterized by a severe reduction in neutrophil count to less than 0.5 × 10^9/L, which significantly increases the risk of serious infections and can lead to mortality if not promptly treated.

Definition and Pathophysiology

Agranulocytosis represents the most severe form of neutropenia and can develop through several mechanisms:

• Direct toxicity to bone marrow cells
• Immune-mediated destruction of neutrophils
• Decreased production of granulocyte precursors
• Increased peripheral destruction of mature granulocytes

Common Causes

Drugs account for more than 70% of agranulocytosis cases 1. High-risk medications include:

• Antithyroid drugs (methimazole, propylthiouracil)
• Clozapine
• Ticlopidine
• Sulfasalazine
• Dipyrone
• Trimethoprim/sulfamethoxazole
• Carbamazepine
• Rituximab

Other causes include:

• Viral infections
• Autoimmune disorders
• Hematologic malignancies
• Congenital disorders

Clinical Presentation

Patients with agranulocytosis typically present with:

• Severe sore throat
• High fever
• Signs of infection (pneumonia, cellulitis)
• Septicemia in severe cases

Diagnostic Approach

The diagnosis is established when:

• Absolute neutrophil count is <0.5 × 10^9/L
• Patient has history of exposure to high-risk medications
• Other causes of neutropenia have been excluded

Management Algorithm

1. Immediate discontinuation of suspected causative drugs 1, 2

   • This is crucial to prevent further damage to bone marrow

2. Infection management:

   • Obtain blood cultures and site-specific cultures when indicated
   • Start empiric broad-spectrum antibiotics immediately 1
   • Consider combination therapy with an anti-pseudomonal β-lactam plus an aminoglycoside for severe cases 3

3. Supportive care:

   • Consider granulocyte colony-stimulating factors (G-CSF) for:
     • Neutrophil count <0.1 × 10^9/L
     • Presence of severe clinical infection
     • Underlying comorbidities
     • Prolonged expected duration of neutropenia 1, 3

4. Monitoring:

   • Daily complete blood counts to track neutrophil recovery
   • Clinical monitoring for signs of infection or sepsis
   • Typically, hematologic recovery occurs within 7-14 days after stopping the offending agent 2

Special Considerations

Antithyroid Drug-Induced Agranulocytosis

This typically occurs within the first three months of treatment and requires:

• Immediate drug discontinuation
• Broad-spectrum antibiotics
• G-CSF in selected patients
• Later definitive treatment for hyperthyroidism with radioactive iodine or surgery 2

Granulocyte Transfusions

May be considered for neutropenic patients with severe infections that have failed or are unlikely to respond to standard therapy 3. However:

• The overall benefit vs. risk remains unclear
• Acute lung injury is a major risk
• Should be separated from amphotericin B administration by several hours if both are needed 3

Prognosis

With modern management including broad-spectrum antibiotics and hematopoietic growth factors, case fatality has decreased to approximately 5% in recent years 1. Factors associated with poor prognosis include:

• Severe neutropenia (<0.1 × 10^9/L)
• Presence of sepsis or septic shock
• Advanced age
• Significant comorbidities

Prevention

Patient education is crucial for early recognition, particularly for those taking high-risk medications. Patients should be instructed to:

• Report fever, sore throat, or other signs of infection immediately
• Undergo regular blood count monitoring when taking high-risk drugs
• Understand the early warning signs that require medical attention