Makindo Medical Notes

Related Subjects: | Neutropenic Sepsis | Oncological Emergencies

📘 About

• Agranulocytosis refers to a profound fall in circulating neutrophils (a subtype of white cells crucial for innate immunity).
• It dramatically increases susceptibility to bacterial and fungal infection and underpins many cases of neutropenic sepsis.
• Defined as neutrophil count < 0.5 × 10⁹/L or rapidly falling to that level.

🧬 Aetiology & Pathophysiology

• As neutrophil count drops below 1.0 × 10⁹/L, the risk of overwhelming sepsis rises exponentially.
• Mechanisms include bone marrow suppression, immune destruction, or abnormal marrow infiltration.
• Carbimazole and cytotoxic drugs act via marrow suppression, whereas autoimmune and infectious causes act via peripheral destruction or consumption.

🔍 Causes

• Post-chemotherapy: Classically develops 7–14 days after treatment when bone marrow recovery is lowest (nadir phase).
• Physiological: “Benign ethnic neutropenia” in individuals of African or Middle Eastern ancestry, with normal baseline counts 0.8–1.5 × 10⁹/L.
• Infectious: Brucella, Typhoid, Miliary TB, viral infections (EBV, HIV, Hepatitis), protozoa.
• Autoimmune: SLE, Felty’s syndrome (RA + splenomegaly + neutropenia).
• Endocrine / Genetic: Hypopituitarism, hypothyroidism, congenital or familial neutropenia.

💊 Common Drug Causes of Neutropenia

• Cytotoxic drugs: Cyclophosphamide, Methotrexate, 5-Fluorouracil, Busulfan.
• Antithyroid drugs: Carbimazole, Propylthiouracil — rare but potentially fatal idiosyncratic reaction.
• Other drugs: ACE inhibitors, NSAIDs, antimalarials, anticonvulsants (carbamazepine, phenytoin), antidiabetics (metformin, sulphonylureas), β-lactam antibiotics, co-trimoxazole, clozapine, antidepressants.

📊 Classification of Neutropenia

• Mild: 1.0–1.5 × 10⁹/L
• Moderate: 0.5–1.0 × 10⁹/L
• Severe: < 0.5 × 10⁹/L — high risk of sepsis

🩺 Clinical Approach & Management

• Immediate Actions: Stop potential causative drug; assess for infection; initiate neutropenic sepsis protocol if febrile or unwell.
• Investigations: FBC, CRP, U&E, blood & urine cultures, CXR; inspect oral mucosa, skin, and IV lines.
• Supportive Care: Barrier nursing, oral hygiene (chlorhexidine mouthwash), clean diet, and good hand hygiene.
• Consider: G-CSF (Filgrastim) in prolonged or chemotherapy-induced neutropenia; Palifermin to reduce mucositis risk.

💉 Standard Empiric Therapy for Febrile Neutropenia

• Piperacillin/Tazobactam (Tazocin): 4.5 g IV every 6–8 h. Dose adjust by renal function: eGFR > 40 → QDS | 40–20 → TDS | < 20 → BD.
• Gentamicin: IV once daily — add if severe sepsis or suspected Gram-negative focus.
• If CAP suspected → add oral Doxycycline 200 mg stat, then 100 mg OD, or if unable to take PO, IV Clarithromycin 500 mg BD.
• If MRSA suspected (line-associated / skin source) → add IV Vancomycin (per dosing calculator; watch nephrotoxicity with aminoglycosides).
• If VRE previously isolated → replace Vancomycin with Linezolid 600 mg BD or Daptomycin 6 mg/kg OD.
• If fever persists > 48–72 h despite therapy → evaluate for fungal or resistant infection and escalate appropriately.

🧫 Alternative Empiric Regimens

• Meropenem: 1 g IV TDS — ideal for MDR organisms or severe penicillin allergy.
• Cefepime: 2 g IV BD — alternative broad-spectrum monotherapy.
• Ceftazidime: 2 g IV TDS — good Pseudomonas cover, especially in high-risk units.

🦠 Antifungal Escalation (Persistent Fever ≥72 h)

• Amphotericin B: broadest coverage for severe systemic fungal infection.
• Fluconazole: first-line for Candida (if no resistance or mould infection suspected).
• Posaconazole / Voriconazole: extended spectrum for Aspergillus or refractory cases.

🧠 Teaching Point

Agranulocytosis exemplifies how drug safety depends as much on education as on monitoring. Carbimazole-induced agranulocytosis is unpredictable — not dose-dependent — so every patient must receive a written warning card. Neutropenia from chemotherapy or drugs is a medical emergency once fever develops: antibiotics within 1 hour saves lives.

📚 References

• BNF: Carbimazole
• NICE CG151: Neutropenic Sepsis
• NICE CKS: Hyperthyroidism
• RCP Guideline: Management of Neutropenic Sepsis

🕓 Revisions

• 2025-10 — Reviewed and edited by Dr O’Kane (Makindo edition)