Agranulocytosis: Signs and Symptoms
Cardinal Warning Signs
Fever and sore throat are the hallmark early warning signs of agranulocytosis that demand immediate medical attention and complete blood count evaluation. 1 These symptoms typically appear acutely and represent the body's inability to mount an adequate inflammatory response due to profound neutropenia.
Primary Clinical Manifestations
- Fever: Present in the vast majority of patients, often high-grade and representing the most consistent early sign despite absent neutrophils 1, 2
- Severe sore throat: A prominent symptom that should trigger immediate evaluation, particularly in patients on high-risk medications 1, 2, 3
- Flu-like symptoms: Including generalized weakness, malaise, and chills are common initial manifestations 1
Infectious Complications
Patients with agranulocytosis frequently present with severe sepsis, pneumonia, or septicemia due to their inability to fight infection. 2, 4 The severity of neutropenia directly correlates with infection risk:
- Severe infections: Occur in approximately two-thirds of patients, including deep tissue infections, pneumonia, and septic shock 4
- Isolated fever: May be the only presenting sign without localizing symptoms 2
- Septicemia: Can develop rapidly and represents a poor prognostic factor 4
Laboratory Findings
Defining Hematologic Abnormalities
Agranulocytosis is definitively characterized by an absolute neutrophil count (ANC) below 0.5 × 10⁹/L. 5, 6, 7, 2 More specific laboratory features include:
- Profound neutropenia: ANC <0.5 × 10⁹/L, with severe cases showing ANC <0.1 × 10⁹/L 7, 4
- Severe leukopenia: White blood cell counts frequently drop to 0.5-2.0 × 10³ cells/μL 7
- Relative lymphocytosis: May appear proportionally increased on differential count, though absolute lymphocyte count may be normal or decreased 7
- Monocytopenia: Often accompanies the neutropenia 7
- Thrombocytopenia: Can occur but is not a defining feature; may be present in some patients 5, 1, 7
Bone Marrow Characteristics
- Normocellular or hypercellular marrow: Typical finding that distinguishes drug-induced agranulocytosis from aplastic anemia 7
- Marked reduction of mature granulocytes: With preservation of early myeloid precursors in some cases 7
- Absence of blasts: On peripheral smear, distinguishing agranulocytosis from acute leukemia 7
Clinical Course and Severity
Onset Pattern
The onset of agranulocytosis is typically acute and symptomatic, with peak incidence occurring within the first 3 months of exposure to causative drugs. 6, 7 Patients may initially be asymptomatic when neutropenia is discovered, but rapidly progress to severe complications 8, 9.
Poor Prognostic Factors
- Advanced age: Patients >65 years have worse outcomes 4
- Severe neutropenia: ANC <0.1 × 10⁹/L carries highest risk 6, 4
- Septicemia or septic shock: Present at diagnosis 4
- Metabolic disorders: Including renal failure 4
- Severe underlying disease or comorbidity: Increases mortality risk 2
Critical Clinical Pitfalls
Do not confuse agranulocytosis with acute leukemia (which shows ≥20% blasts) or aplastic anemia (which shows pancytopenia with hypocellular marrow <25% cellularity). 7 Key distinguishing features:
- Agranulocytosis: Isolated severe neutropenia with normal or hypercellular marrow, no blasts 7
- Acute leukemia: Presence of blasts on peripheral smear 7
- Myelodysplastic syndrome: Dysplastic changes in multiple cell lines with cytogenetic abnormalities 7
High-Risk Medications
Patients taking these drugs require heightened vigilance for symptoms 2, 8:
- Antithyroid drugs (methimazole, propylthiouracil)
- Clozapine
- Trimethoprim-sulfamethoxazole
- Ticlopidine
- Sulfasalazine
- Carbamazepine
- Dipyrone
Patient education about fever, sore throat, and flu-like symptoms is more cost-effective than routine monitoring, as agranulocytosis onset is typically acute and symptomatic. 6 Patients should seek immediate medical attention if these symptoms develop, especially within the first 3 months of treatment with high-risk medications.