Fungal Infections — Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Mr William Chen is a 60-year-old retired schoolteacher with newly diagnosed acute myeloid leukaemia, admitted on day 16 of 7+3 induction chemotherapy (cytarabine and daunorubicin). He has been neutropenic for 12 days (neutrophils 0.08 x 10^9 per litre) and developed persistent fever on day 12 despite intravenous piperacillin-tazobactam for febrile neutropenia. On day 16 he reported a dry cough and right-sided pleuritic chest pain. His chest X-ray was unremarkable, but a high-resolution chest CT showed a 2.5 cm right upper lobe nodule with a surrounding ground-glass halo, and his serum galactomannan index was 2.1, with a positive bronchoalveolar lavage galactomannan. The diagnosis is probable invasive pulmonary aspergillosis. [1] />

His main problems are:

1. Invasive pulmonary aspergillosis complicating AML induction — the central issue, with a mortality of 50 to 60 per cent despite treatment.
2. Profound and prolonged neutropenia post-chemotherapy — the key risk factor and the rate-limiting step in his recovery.
3. Acute myeloid leukaemia requiring further therapy, the timing of which is now complicated by the fungal infection.
4. The psychological impact of a serious infection superimposed on a new cancer diagnosis. [1] />

His management to date has been the febrile neutropenia protocol on day 12 with piperacillin-tazobactam, the diagnostic workup on day 16 with chest CT and serum and BAL galactomannan, and the commencement of intravenous voriconazole loaded at 6 mg/kg every 12 hours for two doses then 4 mg/kg every 12 hours, with a plan to monitor the trough level, serial galactomannan, and chest CT, to reduce immunosuppression where the haematology team permits, and to continue mould-active secondary prophylaxis through his subsequent chemotherapy cycles and any allogeneic stem cell transplant." [1] />

Examiner probing questions and model answers

Q1: "Walk me through why voriconazole is the first-line treatment for invasive aspergillosis, and what evidence underpins that choice." [1] />

"Voriconazole is first-line because of the Herbrecht randomised trial, published in the New England Journal of Medicine in 2002, which compared voriconazole with amphotericin B deoxycholate for the primary therapy of invasive aspergillosis in 277 patients [2]. At 12 weeks, the response rate was 52.8 per cent in the voriconazole group versus 31.6 per cent in the amphotericin group, and the survival rate was 70.8 per cent versus 57.9 per cent — a survival benefit that established voriconazole as the new standard of care and consigned amphotericin B deoxycholate to second-line or alternative therapy. The IDSA 2016 aspergillosis guideline reaffirmed voriconazole as the primary recommendation [1]. Voriconazole is a triazole that inhibits lanosterol 14-alpha-demethylase in the ergosterol synthesis pathway; it has excellent oral bioavailability (above 90 per cent) and good CSF penetration, which matters for cerebral involvement. Its limitations are the nonlinear pharmacokinetics and the CYP2C19 polymorphism that produce wide inter-patient variability, which is why I monitor the trough level (target 1 to 5.5 mg/L). The transient visual disturbance — bright lights, altered colour perception — is common (above 20 per cent) and usually reversible, and I will counsel Mr Chen about it."

Q2: "When would you use isavuconazole instead of voriconazole, and what trial supports it?" [1] />

"Isavuconazole is a non-inferior alternative to voriconazole, established by the SECURE randomised non-inferiority trial of isavuconazole versus voriconazole for the primary treatment of invasive mould disease, published in the Lancet in 2016 [3]. It enrolled 527 patients and demonstrated non-inferiority for all-cause mortality at day 42. Isavuconazole has several advantages over voriconazole: predictable linear pharmacokinetics that do not require routine therapeutic drug monitoring, a loading dose built into the first 48 hours (200 mg every 8 hours for six doses, then 200 mg daily), fewer visual and hepatotoxic adverse events, fewer drug interactions (it is a weaker CYP inhibitor), and — uniquely among the triazoles — it shortens the QT interval rather than prolonging it, which is a potential advantage in patients on QT-prolonging polypharmacy. I would choose isavuconazole for a patient with significant drug interactions (such as a transplant recipient on tacrolimus or sirolimus where the voriconazole interaction is problematic), for a patient who develops voriconazole intolerance or visual adverse events, and potentially for a patient on QT-prolonging therapy where the QT-shortening effect of isavuconazole is a benefit. For Mr Chen, who is not on interacting therapy and has no baseline QT issue, voriconazole remains the standard first-line choice, but isavuconazole is my immediate alternative."

Q3: "He is on day 4 of voriconazole. How will you monitor his therapy and his response?" [1] />

"I will monitor four domains. First, the voriconazole trough level after 4 to 7 days of therapy — target 1 to 5.5 mg/L — because the pharmacokinetics are nonlinear and the CYP2C19 polymorphism produces wide inter-patient variability; I will dose-adjust to keep the level in range. Second, the serial galactomannan every 1 to 2 weeks — a falling titre supports response, a rising titre suggests progressive disease or resistance and prompts a review of the diagnosis (could this be mucormycosis, which is galactomannan-negative?), the level, and the drug. Third, the chest CT at 4 to 6 weeks to assess the radiological response — I expect the halo sign to evolve into cavitation and eventually the air-crescent sign as the necrotic lung sequesters with neutrophil recovery, and then gradual contraction of the lesion; radiological worsening in the first 1 to 2 weeks can reflect the inflammatory response of neutrophil recovery rather than failure. Fourth, the clinical picture — resolution of fever, cough, and pleuritic pain, and the return of the neutrophil count, which is the single strongest predictor of survival from invasive aspergillosis. I will also monitor his liver function (voriconazole hepatotoxicity) and his renal function and electrolytes." [1] />

Q4: "He recovers. What is his secondary prophylaxis plan, and how does the aspergillosis change his leukaemia treatment?" [1] />

"This is a multidisciplinary decision with the haematology team. Because a prior episode of invasive aspergillosis confers a very high risk of recurrence with the next neutropenic phase, he will need mould-active secondary prophylaxis — posaconazole or voriconazole — through every subsequent chemotherapy cycle and through any allogeneic stem cell transplant. The aspergillosis is a relative contraindication to immediate further intensive chemotherapy, because the next cycle will prolong the neutropenia and worsen the fungal infection. The principles are: complete the antifungal induction and achieve a clinical and mycological response first; consider whether a less myelosuppressive regimen, a delayed consolidation, or a bridging strategy is appropriate; and continue the secondary prophylaxis throughout. If he is a candidate for allogeneic transplant, the aspergillosis must be controlled before conditioning begins. I will communicate the plan clearly to Mr Chen, his family, the haematology and infectious diseases teams, and the general practitioner." [1] />

Q5: "What is the role of combination antifungal therapy in invasive aspergillosis, and would you use it here?" [1] />

"Combination therapy — typically a triazole plus an echinocandin — is sometimes considered for refractory invasive aspergillosis, on the rationale that the echinocandin targets the fungal cell wall (beta-glucan) while the triazole targets the cell membrane (ergosterol), providing a dual mechanistic attack. A small randomised trial suggested a mortality benefit for the combination in selected patients, particularly those with galactomannan-positive disease, but the evidence is not robust enough to recommend combination therapy as routine first-line, and the IDSA 2016 guideline recommends voriconazole monotherapy as first-line [1]. I would not use combination therapy for Mr Chen at present, because he is responding to voriconazole monotherapy and the addition of an echinocandin would add cost and potential toxicity without clear benefit. I would consider switching to or adding liposomal amphotericin B, or combination therapy, only if he deteriorates or his galactomannan rises despite an adequate voriconazole level — in which case I would also re-evaluate the diagnosis (mucormycosis, in particular, is galactomannan-negative and intrinsically resistant to voriconazole)."

Q6: "How will you counsel him and his family about this turn in his illness?" [1] />

"I will be honest and clear. I will explain that the chemotherapy has lowered his white cells to a point where his body cannot fight certain moulds that we all breathe in, that a mould has taken hold in his lung, and that we have a specific antifungal — voriconazole — that has been shown in trials to improve survival. I will be honest that this is a serious complication, that the treatment will continue for several months, and that it changes the timing of his leukaemia therapy. I will explain the visual effects of voriconazole (the bright lights and altered colours are common and reversible) so that he is not alarmed when they occur. I will ask about his values and goals — what matters most to him, what his understanding of prognosis is, whether he wishes to continue intensive treatment — and I will involve the palliative care team early for symptom support alongside disease-directed therapy if he wishes. I will arrange a family meeting with haematology, infectious diseases, and nursing, and I will give written information and a clear point of contact. The communication is part of the treatment." [1] />

Short Case Discussion

Bedside assessment of the diabetic patient with suspected rhinocerebral mucormycosis

Examiner instruction: "You are called to the emergency department to assess a 58-year-old man with type 2 diabetes who presented in diabetic ketoacidosis and now has left facial pain, black nasal discharge, and a left sixth cranial nerve palsy. Describe your systematic bedside assessment, the immediate investigations you would arrange, and the principles of management." [1] />

Candidate's model answer: [1]

"My first principle is that any diabetic patient in ketoacidosis with facial or sinus pain, black nasal discharge, or a cranial nerve palsy has rhinocerebral mucormycosis until proven otherwise. This is a surgical and medical emergency, and delay is the single greatest predictor of death. I assess and act in parallel. [1] />

The structured assessment: [1]

1. Recognise the risk and the tempo. Confirm the diabetic ketoacidosis (the glucose, the ketones, the pH, the bicarbonate) and the duration; the combination of acidosis, ketosis, and free iron from disabled transferrin is the substrate for Mucorales. The tempo is days, not weeks — the fungus progresses by angioinvasion and tissue infarction, and every hour matters. [1] />

2. The focused bedside examination. I inspect the face and periorbital region for swelling, erythema, and discolouration. I inspect the nasal cavity and the oral cavity — I am looking for the black necrotic eschar on the turbinate, septum, or palate, which is tissue infarction made visible at the mucosal surface and is the pathognomonic sign. I examine the cranial nerves — the abducens (sixth) and oculomotor (third) nerves are commonly affected by cavernous sinus involvement, and visual loss from orbital or optic nerve involvement is a grave sign. I assess the mental state — reduced consciousness indicates intracranial extension. I look for cutaneous lesions (a necrotic plaque at a site of inoculation) and I examine the chest and abdomen for disseminated disease. [1] />

3. The immediate investigations. I arrange urgent CT of the sinuses, orbits, and brain with contrast — looking for sinus opacification, bony destruction, orbital cellulitis, cavernous sinus thrombosis, and cerebral infarction or abscess. I arrange urgent tissue biopsy of the necrotic area by ear-nose-throat surgery, sent for histopathology (looking for the broad, non-septate, ribbon-like hyphae branching at right angles that distinguish Mucorales from the septate acute-angle-branching Aspergillus) and for culture (which confirms the genus and species). I send bloods including glucose, ketones, venous gas, full blood count, electrolytes, and renal and liver function. [1] />

The principles of management: [1]

The ECMM 2019 global guideline for mucormycosis frames the management on three simultaneous pillars [4]. First, high-dose liposomal amphotericin B — 5 to 10 mg/kg/day intravenously, with the higher dose for cerebral or extensive disease, continued for several weeks until clinical and radiological stability, then step-down to isavuconazole or posaconazole. Liposomal is preferred over amphotericin B deoxycholate because of the better toxicity profile at these high doses. Second, aggressive, repeated surgical debridement by ENT — the cornerstone; antifungals alone cannot clear infarcted, organism-laden tissue because the angioinvasion has cut off its blood supply, and only surgery can remove it. The surgery is often disfiguring (palate, orbit, sinuses) and must be repeated until clear margins are achieved. Third, rapid reversal of the underlying metabolic and immune derangement — aggressive treatment of the diabetic ketoacidosis, reduction or cessation of corticosteroids where possible, and reduction of transplant immunosuppression in consultation with the transplant team. I will involve the infectious diseases, ENT, ophthalmology, and intensive care teams from the outset. I will be honest with the patient and family that this is a rapidly destructive infection with a mortality above 50 per cent despite optimal therapy, and that the surgery is as important as the medication."*

Examiner follow-up: "Why is voriconazole the wrong drug here, and why is the distinction between mucormycosis and aspergillosis so critical?" [1] />

"Voriconazole has no activity against the Mucorales — the organism has an intrinsic resistance to voriconazole, which is why breakthrough mucormycosis occurs in patients on voriconazole prophylaxis. The distinction is critical because the two infections share a risk profile (prolonged neutropenia, transplant, immunosuppression) and a clinical presentation (pulmonary nodules, sinus disease, fever), but the antifungal differs entirely: voriconazole for Aspergillus, liposomal amphotericin B for the Mucorales. The histopathology is the discriminator at the bedside — Aspergillus shows septate hyphae branching at acute angles, while the Mucorales show broad non-septate ribbon-like hyphae branching at right angles. The CT can also help — the halo sign (nodule with surrounding ground-glass haemorrhage) favours Aspergillus, while the reverse halo or atoll sign (a rounded area of ground-glass surrounded by a ring of consolidation), especially with multiple lesions and rapid progression and sinus involvement, favours Mucorales. Getting the distinction right at the first hour determines whether the patient receives the drug that will save them or the drug that will not." [1] />