Agranulocytosis: Definition and Management
Agranulocytosis is a life-threatening condition characterized by a severe reduction in neutrophil count (<0.5 × 10^9/L) that requires immediate discontinuation of the offending agent, prompt initiation of broad-spectrum antibiotics, and consideration of granulocyte colony-stimulating factors in high-risk patients. 1
Definition and Pathophysiology
Agranulocytosis is defined as:
- Severe neutropenia with absolute neutrophil count below 0.5 × 10^9/L
- A potentially fatal condition with mortality rates of approximately 5% with modern treatment 2
- Most commonly drug-induced (>70% of cases) 2
The pathophysiology appears to be two-fold:
- Direct toxicity to myeloid cell lines
- Immune-mediated destruction of neutrophils 1
Common Causes
Medications
High-risk medications include:
- Antithyroid drugs
- Clozapine
- Ticlopidine
- Sulfasalazine
- Dipyrone
- Trimethoprim/sulfamethoxazole
- Carbamazepine
- Rituximab 2
Other Causes
- Infections (bacterial, viral, fungal)
- Autoimmune disorders
- Hematologic malignancies
- Congenital neutropenia syndromes 3
Clinical Presentation
Patients may present with:
- Asymptomatic neutropenia discovered on routine blood work
- Severe sore throat
- Isolated fever
- Pneumonia
- Septicemia 2
Diagnostic Approach
- Complete blood count with differential showing neutrophil count <0.5 × 10^9/L
- Peripheral blood smear examination
- Bone marrow examination (may show maturation arrest of myeloid series)
- Blood cultures and site-specific cultures in febrile patients 2
- Medication history to identify potential culprits
Management
Immediate Actions
- Discontinue all suspected medications immediately 1, 2
- Obtain blood cultures and site-specific cultures as indicated 2
- Start empiric broad-spectrum antibiotics promptly in febrile patients 2
Supportive Care
- Isolation precautions for severely neutropenic patients
- Aggressive treatment of infections
- Nutritional support
Specific Treatments
Granulocyte colony-stimulating factors (G-CSF) should be considered in:
Granulocyte transfusions may be considered for:
- Neutropenic patients with severe infections that have failed standard therapy
- Patients with severe infections including invasive aspergillosis and other mold infections
- When neutrophil recovery is anticipated 4
Monitoring
- Daily complete blood counts to monitor neutrophil recovery
- Close monitoring for signs of infection
- Repeat bone marrow examination if no recovery within expected timeframe
Prognosis
- Case fatality has decreased to approximately 5% in recent years 2
- Most cases are self-limiting with complete resolution within two weeks after withdrawal of the offending agent 5
- Recovery may be accelerated with G-CSF therapy
Special Considerations
Granulocyte Transfusions
- Separate administration of amphotericin B and granulocyte infusions by several hours to avoid acute lung injury 4
- Use CMV-seronegative granulocyte donors for CMV-seronegative recipients 4
Recurrence Prevention
- Document the causative agent
- Avoid rechallenge with the suspected medication
- Provide patient education regarding medications to avoid
Pitfalls and Caveats
- Failure to promptly discontinue the offending agent can lead to prolonged neutropenia
- Delayed initiation of antibiotics in febrile neutropenic patients significantly increases mortality
- Not all patients with agranulocytosis present with fever or obvious infection
- Granulocyte transfusions carry risks including acute lung injury, alloimmunization, and CMV transmission 4
- Some medications (like clozapine) require regular monitoring of neutrophil counts to detect early neutropenia before it progresses to agranulocytosis 4
By following this algorithmic approach to diagnosis and management, clinicians can effectively address this potentially life-threatening condition while minimizing complications and improving outcomes.