What is agranulocytosis?

Agranulocytosis: Definition, Causes, and Management

Agranulocytosis is a 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 be fatal if not promptly recognized and treated.

Definition and Pathophysiology

Agranulocytosis is a severe form of neutropenia where the absolute neutrophil count falls below 500 cells/mm³ (0.5 × 10^9/L). This condition can develop through two primary mechanisms:

• Direct toxicity to myeloid cell lines in the bone marrow
• Immune-mediated destruction of neutrophils, often triggered by drug-dependent antibodies 1

Causes

Medication-Induced (Most Common)

Medications account for more than 70% of agranulocytosis cases 2. High-risk medications include:

• Antithyroid drugs (e.g., methimazole, propylthiouracil) 3, 2
• Antipsychotics (particularly clozapine) 3, 4
• Antibiotics (especially trimethoprim-sulfamethoxazole, β-lactams) 2, 5
• Anti-inflammatory drugs (sulfasalazine, dipyrone, diclofenac) 2, 6
• Other medications: ticlopidine, carbamazepine, spironolactone, vancomycin 2, 5

Other Causes

• Hematologic disorders
• Autoimmune conditions
• Severe infections
• Congenital neutropenias

Clinical Presentation

Patients with agranulocytosis may present with:

• Fever (often the only sign in neutropenic patients) 7
• Severe sore throat or odynophagia 2, 6
• Oropharyngeal ulcerations
• Pneumonia
• Sepsis in severe cases 1

It's important to note that due to the lack of neutrophils, the inflammatory response may be muted, making infection difficult to detect clinically 7.

Diagnosis

1. Complete blood count with differential showing:

   • Absolute neutrophil count < 500 cells/mm³
   • Often normal red blood cell and platelet counts

2. Bone marrow examination may show:

   • Maturation arrest of myeloid precursors 6
   • Absence of mature neutrophils

3. Microbiological cultures to identify potential infections

Management

Immediate Actions

1. Discontinue the suspected causative medication immediately 1, 2
2. Obtain blood cultures and site-specific cultures when infection is suspected 2
3. Start empiric broad-spectrum antibiotics promptly in febrile patients 3, 1

Supportive Care

1. Granulocyte colony-stimulating factor (G-CSF) should be considered in:

   • Patients with ANC < 100 cells/mm³
   • Presence of severe infection
   • Underlying comorbidities
   • Prolonged expected duration of neutropenia 3, 2

2. Infection control measures:

   • Isolation precautions if necessary
   • Careful attention to skin and mucosal barriers

Monitoring and Follow-up

• Regular blood count monitoring until neutrophil recovery
• Surveillance for new or worsening infections
• Avoidance of rechallenge with the suspected causative agent

Special Considerations

Clozapine-Induced Agranulocytosis

• Requires mandatory white blood cell monitoring protocol 3
• Risk is highest during the first 18 weeks of treatment 4
• Weekly blood counts required during initial treatment period
• Immediate discontinuation if ANC drops below 1,000/mm³ 3

Antithyroid Drug-Induced Agranulocytosis

• Typically occurs within the first 3 months of therapy
• Patients should be educated about symptoms requiring immediate medical attention 3
• Alternative treatment options should be considered if agranulocytosis develops

Prognosis

With modern management, the case fatality rate for drug-induced agranulocytosis has decreased to approximately 5%, compared to historical rates of up to 76% 2. Factors associated with poorer prognosis include:

• Very low neutrophil counts (<100 cells/mm³)
• Presence of severe infection or sepsis
• Advanced age
• Significant comorbidities
• Delayed recognition and treatment

Prevention

• Medication selection: Consider alternatives to high-risk medications when possible
• Monitoring: Regular blood count monitoring for patients on high-risk medications
• Patient education: Instruct patients to report fever, sore throat, or other signs of infection immediately
• Prompt discontinuation of suspected medications at the first sign of neutropenia

Agranulocytosis remains a serious but manageable condition when recognized promptly. The key to successful outcomes lies in early recognition, immediate discontinuation of the offending agent, and aggressive management of infections.