A 42-year-old woman with acute leukaemia undergoing induction chemotherapy develops fever (38.9°C), cough, and dyspnoea on day 14 of neutropenia (ANC 200/μL). High-resolution CT chest shows multiple nodular infiltrates with a halo sign. Bronchoalveolar lavage culture grows Aspergillus fumigatus. She is started on voriconazole 6 mg/kg IV twice daily on day 1, then 4 mg/kg IV twice daily from day 2 onwards. After 48 hours of therapy, she develops blurred vision and mild confusion. What is the most appropriate management?

Explanation

## Clinical Context This patient has invasive pulmonary aspergillosis (IPA) in a severely immunocompromised host (acute leukaemia + chemotherapy-induced neutropenia). The halo sign on HRCT is pathognomonic for IPA in neutropenic patients. Voriconazole is the first-line agent for IPA per IDSA and ESCMID guidelines, but she has developed characteristic neurological adverse effects within 48 hours of initiation. ## Voriconazole Neurotoxicity: Mechanism and Incidence **Key Point:** Voriconazole causes reversible CNS toxicity in approximately 15–30% of patients, manifesting as visual disturbances (blurred vision, photopsia, colour vision abnormalities), confusion, hallucinations, and rarely seizures. These effects typically occur within 24–72 hours of initiation. Importantly, visual disturbances with voriconazole are **dose-independent** — they occur at standard therapeutic doses and are not reliably reduced by dose reduction alone. The mechanism is thought to involve direct retinal photoreceptor stimulation (transient electroretinographic changes) rather than structural retinal toxicity. **High-Yield:** Visual disturbances are the most common CNS adverse effect and are almost always reversible, typically resolving within 30–60 minutes after each dose or spontaneously within days as the patient acclimates. They do NOT indicate structural retinal toxicity and do NOT require routine ophthalmology referral unless vision loss is severe or persistent beyond 7 days. ## Why Option A is Correct **Clinical Pearl:** Mild visual disturbances (blurred vision) and mild confusion in the first 48–72 hours of voriconazole therapy are expected, well-characterised, and reversible adverse effects. In a patient with life-threatening IPA, the risk of premature discontinuation or dose reduction (which may compromise antifungal efficacy) outweighs the risk of continuing at the current dose. The correct approach is to counsel the patient, continue therapy, and reassess in 3–5 days. Symptoms typically resolve spontaneously. **Regarding TDM:** Therapeutic drug monitoring (target trough 1–5.5 mg/L) is recommended for voriconazole, but in the acute setting of mild, expected early toxicity, TDM does not change the immediate management decision of continuing therapy with reassessment. TDM would be more relevant if toxicity were severe or persistent, or if efficacy were in question. ## Why the Other Options Are Incorrect - **Option B (Reduce dose to 3 mg/kg IV BD):** Since voriconazole visual disturbances are dose-independent, reducing the dose is unlikely to resolve symptoms and risks subtherapeutic antifungal levels in a critically ill patient. This is not recommended for mild, early-onset toxicity. - **Option C (Switch to liposomal amphotericin B 10 mg/kg/day):** Switching is appropriate for severe or persistent toxicity (hallucinations, seizures, vision loss >7 days, hepatotoxicity). Mild, early-onset symptoms do not warrant premature discontinuation of the most efficacious agent for IPA. Additionally, 10 mg/kg/day is a high-dose regimen not routinely used as first-line switch. - **Option D (Urgent ophthalmology + MRI brain):** While CNS aspergillosis must be considered in neutropenic patients, the clinical context here — mild symptoms appearing within 48 hours of voriconazole initiation, consistent with known drug toxicity — makes urgent neuroimaging disproportionate as the *most appropriate* immediate step. MRI brain would be indicated if symptoms were severe, progressive, or atypical for drug toxicity. ## Management Algorithm for Voriconazole CNS Toxicity | Severity | Symptoms | Action | |----------|----------|--------| | Mild | Blurred vision, mild confusion (early onset) | Continue at current dose; counsel patient; reassess in 3–5 days | | Moderate | Persistent visual disturbance >7 days, moderate confusion | Consider dose reduction or TDM-guided adjustment | | Severe | Hallucinations, seizures, vision loss, encephalopathy | Discontinue voriconazole; switch to liposomal amphotericin B | ## Comparison of Antifungal Options for IPA | Agent | Efficacy in IPA | CNS Penetration | Neurotoxicity | Monitoring | |-------|-----------------|-----------------|---------------|------------| | Voriconazole | First-line (~60% response) | Good | Visual disturbance, confusion (15–30%, dose-independent) | TDM (trough 1–5.5 mg/L); LFTs | | Liposomal amphotericin B | Alternative (~40–50%) | Poor | Nephrotoxicity, hypokalaemia | Creatinine, K⁺, Mg²⁺ | | Isavuconazole | Non-inferior alternative | Moderate | Visual disturbance (rare) | TDM; fewer drug interactions | **Key Point (Harrison's Principles, 21st ed.; KD Tripathi Essentials of Medical Pharmacology, 8th ed.):** Voriconazole CNS toxicity is reversible and does not indicate treatment failure. Switching agents prematurely may compromise IPA control in a neutropenic patient where mortality from untreated IPA exceeds 50%.