A patient on methimazole develops high fever and sore throat with an absolute neutrophil count of 400 per microliter; what is the most appropriate next step?

Stop Methimazole Immediately

The antithyroid drug must be discontinued immediately in this patient presenting with fever, sore throat, and severe neutropenia (ANC 400/µL). This clinical triad represents methimazole-induced agranulocytosis, a potentially life-threatening emergency that requires immediate drug cessation and urgent medical intervention.

Immediate Management Algorithm

1. Drug Discontinuation (Within Minutes)

• Stop methimazole immediately upon recognition of agranulocytosis (ANC < 500/µL with fever and sore throat), as continued exposure increases mortality risk. 1, 2
• Do not switch to propylthiouracil or any other antithyroid agent, as cross-reactivity can occur and agranulocytosis may persist despite the medication change. 3
• The FDA explicitly warns that methimazole should be discontinued in the presence of agranulocytosis, with bone marrow indices monitored until recovery. 1

2. Emergency Infectious Disease Workup (Within 2 Hours)

• Obtain two sets of blood cultures from separate sites before initiating antibiotics. 2, 4
• Collect throat swab culture given the presenting symptom of sore throat. 3
• Perform chest radiograph if any respiratory symptoms are present. 2
• Check complete blood count with differential, comprehensive metabolic panel, and inflammatory markers (CRP). 2, 4

3. Empiric Broad-Spectrum Antibiotics (Within 2 Hours)

• Initiate IV antipseudomonal β-lactam therapy immediately (cefepime 2g every 8 hours is preferred) for this high-risk febrile neutropenic patient. 2, 4, 5
• This patient meets criteria for febrile neutropenia: fever (implied by "high fever") plus ANC < 500/µL, which constitutes a medical emergency requiring antibiotics within 2 hours. 2
• Add vancomycin only if specific high-risk features develop (hemodynamic instability, suspected catheter infection, or known MRSA colonization). 2

4. Granulocyte Colony-Stimulating Factor (G-CSF)

• Administer filgrastim 5 µg/kg/day subcutaneously given the severe neutropenia (ANC 400/µL) and symptomatic infection. 2, 3, 6
• G-CSF is specifically indicated in antithyroid drug-induced agranulocytosis when neutrophil count is < 500/µL with clinical infection, as it decreases recovery duration from 7-13 days to 3-6 days. 3, 6
• Continue G-CSF until ANC exceeds 500/µL for two consecutive days. 3, 6

5. Supportive Care & Monitoring

• Implement reverse isolation or neutropenic precautions. 6
• Monitor temperature every 4-6 hours and obtain daily CBC with differential until ANC > 500/µL. 4
• Continue IV antibiotics until the patient is afebrile for ≥48 hours and ANC > 500/µL for at least two consecutive days. 2, 5

Why Other Options Are Incorrect

Dose Reduction (Option A) Is Dangerous

• Agranulocytosis from methimazole is dose-independent and immune-mediated, not dose-related. 4
• Any continued exposure to methimazole perpetuates the immune destruction of neutrophils and increases mortality risk. 1, 2
• The FDA label explicitly states the drug must be discontinued, not reduced, in the presence of agranulocytosis. 1

Switching to PTU (Option B) Is Contraindicated

• Cross-reactivity between antithyroid drugs occurs, with documented cases showing persistent agranulocytosis despite switching from propylthiouracil to methimazole or vice versa. 3
• Re-exposure to any thionamide antithyroid agent can trigger rapid-onset severe agranulocytosis in sensitized patients. 4

Continuing Medication (Option C) Is Life-Threatening

• Current mortality from antithyroid drug-induced agranulocytosis is approximately 2-5% with optimal management, but rises dramatically if the offending drug is continued. 2, 5
• The clinical presentation of fever, sore throat, and ANC 400/µL represents established agranulocytosis requiring immediate cessation, not monitoring. 1, 2

Critical Pitfalls to Avoid

• Do not delay antibiotic initiation beyond 2 hours while awaiting culture results; febrile neutropenia is a medical emergency. 2, 4
• Do not attempt to "ride out" the neutropenia with continued methimazole at any dose; immune-mediated destruction will persist until drug elimination. 1, 4
• Do not switch to another antithyroid drug during the acute phase; all thionamides carry cross-reactivity risk. 3
• Do not withhold G-CSF in patients with ANC < 500/µL and active infection; early administration improves outcomes. 3, 6
• Do not discharge the patient for outpatient management; this high-risk scenario (hematologic indication for antithyroid drug, ANC 400/µL, symptomatic infection) mandates inpatient care. 2, 5

Expected Clinical Course

• With immediate drug discontinuation, broad-spectrum antibiotics, and G-CSF therapy, neutrophil recovery typically begins within 3-6 days and normalizes within 7-13 days. 3, 6
• The patient must avoid all thionamide antithyroid drugs permanently; alternative hyperthyroidism management (radioactive iodine or thyroidectomy) should be arranged after recovery. 5

Answer: D. Stop the antithyroid drug immediately