Pulmonary Aspergillosis

📋 Key Information Summary

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Pulmonary aspergillosis encompasses a spectrum from invasive disease in immunocompromised hosts to chronic colonisation in structurally abnormal lungs.
Invasive pulmonary aspergillosis (IPA) carries mortality of 30–90% depending on host factors; early diagnosis and prompt antifungal therapy are critical.
Key risk factors for IPA include prolonged neutropenia (>10 days), haematological malignancy on intensive chemotherapy, haematopoietic stem cell transplant (HSCT), solid organ transplant (SOT), high-dose corticosteroids, and advanced HIV (CD4 <50).
CT chest showing the halo sign (ground-glass opacity surrounding a nodule) in an immunocompromised patient is highly suggestive of IPA and should prompt urgent workup.
Serum galactomannan (GM) and (1→3)-β-D-glucan (BDG) are essential non-invasive biomarkers; bronchoalveolar lavage (BAL) GM has higher sensitivity for pulmonary disease.
Voriconazole (Vfend®) is the first-line antifungal for IPA; therapeutic drug monitoring (TDM) of trough levels (1–5.5 mg/L) is mandatory to optimise efficacy and reduce toxicity.
Chronic pulmonary aspergillosis (CPA) affects patients with pre-existing structural lung disease (tuberculosis, COPD, bronchiectasis); Aspergillus IgG serology is the principal diagnostic marker.
Aspergilloma may present with life-threatening haemoptysis; bronchial artery embolisation is the first-line intervention for massive haemoptysis, with surgical resection reserved for localised disease.
Itraconazole is the first-line oral antifungal for CPA; voriconazole is an alternative for refractory or azole-resistant disease.
Azole-resistant Aspergillus fumigatus is emerging in Australia; susceptibility testing should be performed on culture isolates from patients failing first-line therapy.
Antifungal toxicity monitoring includes LFTs, FBC, electrolytes (voriconazole: hepatotoxicity, visual disturbance, photosensitivity; amphotericin B: nephrotoxicity, electrolyte wasting).
Aboriginal and Torres Strait Islander Australians may have higher rates of underlying structural lung disease and reduced access to specialist antifungal care in remote settings.

Introduction & Australian Epidemiology

Pulmonary aspergillosis is a spectrum of lung diseases caused by Aspergillus species, most commonly A. fumigatus, A. niger, and A. flavus. The clinical manifestations range from life-threatening invasive disease in severely immunocompromised patients to chronic localised infection and simple colonisation in those with structural lung abnormalities.

In Australia, invasive aspergillosis (IA) is an increasingly recognised complication of intensive immunosuppressive therapies. The Australian Mycoses Registry reports an annual incidence of approximately 3–5 cases per 100,000 hospital admissions, with peaks during winter months correlating with construction activity and environmental spore counts. Chronic pulmonary aspergillosis is estimated to affect 1,500–2,500 Australians, many undiagnosed, particularly among those with prior tuberculosis, chronic obstructive pulmonary disease (COPD), or bronchiectasis.

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Key public health point: Environmental Aspergillus conidia are ubiquitous in soil, decaying vegetation, and construction dust. Hospital HEPA filtration with >99.97% efficiency at 0.3 µm and positive-pressure isolation are recommended for high-risk immunosuppressed patients during hospital renovation works.

The incidence of azole-resistant A. fumigatus has risen globally and has been detected in Australian agricultural regions, with resistance rates of 3–8% reported in surveillance studies. This has implications for empirical antifungal selection and mandates susceptibility testing where culture is available.

Pathophysiology

Aspergillus conidia (2–3 µm) are inhaled and deposited in the terminal airways. In immunocompetent hosts, alveolar macrophages and neutrophilic oxidative killing clear conidia effectively. Disease occurs when host defences are impaired:

Invasive pulmonary aspergillosis (IPA): Conidia germinate into hyphae that invade pulmonary vasculature, causing thrombosis, haemorrhagic infarction, and tissue necrosis. Angioinvasion leads to dissemination to brain, liver, kidneys, and skin.
Chronic pulmonary aspergillosis (CPA): In the setting of pre-existing cavitary or fibrotic lung disease, Aspergillus colonises cavities, forming fungal balls (aspergilloma) or driving progressive cavitary or fibrosing disease. Host immune response is partially intact, resulting in chronic granulomatous inflammation rather than angioinvasion.
Allergic bronchopulmonary aspergillosis (ABPA): Hypersensitivity reaction in atopic individuals (especially asthma and cystic fibrosis) — characterised by eosinophilic airway inflammation, mucoid impaction, and proximal bronchiectasis. Distinct from IPA and CPA but part of the broader Aspergillus disease spectrum.

Virulence factors of A. fumigatus include thermotolerance (growth at 37–50°C), melanin production (protects against reactive oxygen species), gliotoxin secretion (immunosuppressive mycotoxin), and protease enzymes facilitating tissue invasion.

Invasive Aspergillosis

Invasive pulmonary aspergillosis (IPA) is the most severe manifestation of Aspergillus disease, occurring almost exclusively in immunocompromised hosts. It requires rapid diagnosis and immediate initiation of antifungal therapy.

Risk Factors

Host risk factors are categorised by degree of immunosuppression:

Highest Risk

Profound Immunosuppression

Prolonged neutropenia (>10 days, ANC <0.5 × 10⁹/L), allogeneic HSCT, induction chemotherapy for acute leukaemia, graft-versus-host disease (GvHD) on high-dose corticosteroids.

Incidence: 5–15% in acute leukaemia; 3–10% post-allo-HSCT

High Risk

Significant Immunosuppression

SOT recipients (especially lung transplant), autologous HSCT, corticosteroids ≥20 mg prednisolone/day for ≥3 weeks, T-cell–depleting agents (alemtuzumab, ATG), advanced HIV (CD4 <50 cells/µL).

Incidence: 1–5% post-SOT

Moderate Risk

Moderate Immunosuppression

Intensive care patients (especially post-influenza, COVID-19 ARDS), chronic granulomatous disease, liver cirrhosis, prolonged ICU stay with broad-spectrum antibiotics.

Incidence: 0.5–2% in ICU; higher post-viral

Diagnosis of Invasive Aspergillosis

Diagnosis follows the revised EORTC/MSG criteria, integrating host factors, clinical features, mycological evidence, and radiology. A classification of proven, probable, or possible IA guides management urgency.

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Clinical emergency: In a febrile, neutropenic patient who fails to respond to broad-spectrum antibiotics by day 4–7, IPA must be actively sought. Empirical antifungal therapy should not be delayed pending confirmatory results if clinical suspicion is high.

CT Halo Sign

The CT halo sign — a zone of ground-glass attenuation surrounding a pulmonary nodule or mass — represents haemorrhage around angioinvasive hyphae. It is seen in 30–60% of early IPA cases in neutropenic patients and is highly suggestive in the appropriate host context. The air crescent sign (crescent of air separating necrotic centre from surrounding lung) appears later during neutrophil recovery and indicates cavity formation.

Galactomannan and Biomarkers

Biomarker	Specimen	Sensitivity	Specificity	Notes
Serum galactomannan (GM)	Blood	60–70%	85–95%	Index ≥0.5 positive; reduced by mould-active azole prophylaxis; twice-weekly monitoring recommended in neutropenic patients
BAL galactomannan	Bronchoalveolar lavage	80–90%	85–95%	Higher sensitivity than serum for pulmonary IPA; index ≥0.8 recommended cutoff; perform BAL early when IPA suspected
(1→3)-β-D-glucan (BDG)	Blood	55–75%	70–85%	Non-specific (also elevated in Candida, Pneumocystis); cutoff ≥80 pg/mL; useful combined with GM
Aspergillus PCR (blood/BAL)	Blood or BAL	70–85%	80–95%	Not yet standardised; increasingly available at reference laboratories; positive predictive value increases in high-risk hosts
Histopathology / culture	Tissue biopsy	30–50%	>99%	Required for proven IA; shows septate hyphae with acute-angle branching; culture identifies species and allows susceptibility testing

Voriconazole Therapy for IPA

Voriconazole remains the first-line treatment for IPA as established by the landmark Herbrecht et al. (2002) trial demonstrating superior efficacy and survival compared with conventional amphotericin B.

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Voriconazole

Vfend® · Pfizer · Triazole antifungal

Adult dose (IV) 6 mg/kg IV q12h for 24 hours (day 1), then 4 mg/kg IV q12h

Adult dose (PO, ≥40 kg) 400 mg PO q12h for 24 hours (day 1), then 200 mg PO q12h

Paediatric dose 7 mg/kg IV q12h (loading), then 7 mg/kg IV q12h (maintenance); 200 mg PO q12h if >30 kg

Route IV (SBECD formulation) then switch to PO when stable

Duration Minimum 6–12 weeks; continue until radiographic resolution and immune reconstitution; lifelong suppressive therapy may be required if immunosuppression persists

Renal adjustment No dose adjustment required for IV or PO; avoid IV voriconazole if eGFR <50 mL/min (SBECD accumulation) — use PO formulation

Hepatic adjustment Child-Pugh A/B: reduce maintenance dose by 50%; Child-Pugh C: avoid

TDM Trough 1–5.5 mg/L (measured before 4th dose); adjust dose in 50 mg increments

PBS status ✔ PBS Authority Required

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Major drug interactions: Voriconazole is a potent inhibitor of CYP2C19, CYP2C9, and CYP3A4. Contraindicated with sirolimus, ergot alkaloids, and long-acting barbiturates. Use with extreme caution with cyclosporin, tacrolimus, warfarin, and statins — dose reduction and TDM of interacting drugs are essential. Avoid in CYP2C19 ultra-rapid metabolisers (high prevalence in some populations) due to subtherapeutic levels.

Chronic Pulmonary Aspergillosis

Chronic pulmonary aspergillosis (CPA) is a slowly progressive Aspergillus infection of the lung occurring in patients with pre-existing structural lung disease and mildly impaired immunity (e.g., malnutrition, diabetes, COPD, prior TB). Unlike IPA, CPA is not immediately life-threatening but causes significant morbidity and progressive lung destruction if untreated.

Clinical Subtypes

Subtype	Description	Key Features	Imaging
Simple aspergilloma	Fungal ball within a pre-existing pulmonary cavity	Often asymptomatic or mild haemoptysis; stable over years	Mobile intracavitary mass with air crescent sign; upper lobe predilection
Chronic cavitary pulmonary aspergillosis (CCPA)	One or more expanding pulmonary cavities with progressive fibrosis	Chronic cough, weight loss, haemoptysis, fatigue; progressive over months–years	Increasing cavity size, new cavities, pericavitary infiltrates, pleural thickening
Chronic fibrosing pulmonary aspergillosis (CFPA)	End-stage CCPA with extensive fibrosis	Severe breathlessness, respiratory failure; often treatment-refractory	Dense upper lobe fibrosis with volume loss; may mimic fibrotic TB
Aspergillus nodule	Single or multiple parenchymal nodules	Usually incidental; may mimic malignancy	Solitary or multiple nodules; central necrosis possible

Diagnosis of CPA

Diagnostic criteria for CPA (modified from Denning et al., 2016):

Chronic (>3 months) pulmonary or systemic symptoms (cough, sputum, haemoptysis, weight loss, fatigue)
Radiological evidence of progressive pulmonary cavity, infiltrate, or fibrosis on CT chest
Aspergillus IgG antibody positive (or other serological/mycological evidence)
Exclusion of alternative diagnoses (TB, malignancy, other fungal infection)
Mild or no immunocompromise (i.e., not meeting criteria for IPA)

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Aspergillus IgG serology (by ELISA or precipitin testing) is the single most useful diagnostic test for CPA. Sensitivity is 70–90% and specificity >80%. Titres correlate with disease burden and can be used to monitor treatment response. Available through major Australian pathology services (e.g., PathWest, Sullivan Nicolaides, Dorevitch).

Antifungal Indications in CPA

Aspergilloma: Treat only if symptomatic (haemoptysis, cough) or enlarging on imaging. Many simple aspergillomata are stable and require surveillance only.
CCPA / CFPA: Antifungal therapy is indicated for all symptomatic patients and those with radiological progression. Early treatment may prevent progression to fibrosing disease.
Aspergillus nodule: Resection may be diagnostic (to exclude malignancy) and curative; antifungal therapy is considered if resection is incomplete or the patient is unfit for surgery.

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Itraconazole

Sporanox® · Janssen · Triazole antifungal

Adult dose 200 mg PO TDS for 3 days (loading), then 200 mg PO BD (capsules with food) or 200 mg PO OD (solution, empty stomach)

Duration Minimum 6 months; often 12–24 months or lifelong if ongoing immunosuppression/structural disease

TDM Trough ≥1 mg/L (hydroxy-itraconazole) measured after 2 weeks; adjust dose in 100 mg increments

Renal adjustment No adjustment required; avoid IV formulation (cyclodextrin vehicle) if eGFR <30 mL/min

PBS status ✔ PBS General Benefit

Clinical Presentation & Diagnostic Criteria

Invasive Pulmonary Aspergillosis

Persistent fever unresponsive to broad-spectrum antibiotics in neutropenic patients (classic presentation)
Cough, pleuritic chest pain, dyspnoea, haemoptysis (may be absent early)
Tachypnoea, hypoxia, pleural rub on auscultation
Disseminated disease: cutaneous lesions (necrotic papules), mental status changes (cerebral aspergillosis), hepatosplenic lesions

Chronic Pulmonary Aspergillosis

Insidious onset over months to years
Chronic productive cough, haemoptysis (minor to massive), weight loss, fatigue, exertional dyspnoea
May be initially misattributed to underlying COPD, bronchiectasis, or TB
Physical signs: clubbing (late), crackles, upper lobe signs of fibrosis/cavitation

EORTC/MSG Criteria for Invasive Aspergillosis (2020 Revision)

Classification	Host Criteria	Clinical Criteria	Mycological Criteria
Proven	Not required	Not required	Histological evidence of septate, acutely branching hyphae with tissue invasion; or positive sterile-site culture for Aspergillus
Probable	≥1 host factor (immunosuppression as above)	≥1 clinical feature (CT halo sign, air crescent, cavity, new infiltrate not responding to antibiotics)	≥1 mycological criterion (positive GM, positive culture from BAL, positive Aspergillus PCR from BAL, positive BDG)
Possible	≥1 host factor	≥1 clinical feature	No mycological evidence

Investigations

Essential High-resolution CT chest (HRCT) First-line imaging for suspected IPA or CPA. Look for halo sign, ground-glass opacities, cavitation, air crescent sign, tree-in-bud nodules. Contrast-enhanced CT may demonstrate vascular invasion. Available at all major Australian hospitals. MBS item 56300/56301.

Essential Serum galactomannan (GM) ELISA Twice-weekly screening in high-risk neutropenic patients. Index ≥0.5 considered positive. Available through all major Australian pathology laboratories. MBS item 69408.

Essential Aspergillus IgG serology Principal diagnostic marker for CPA. ELISA-based; titres correlate with disease activity. Available through major reference labs (Sullivan Nicolaides, PathWest, Melbourne Pathology). MBS item 69406.

Available Bronchoscopy with BAL Essential for suspected IPA when serum GM is negative. BAL for GM, fungal culture, PCR, cytology. Transbronchial biopsy if safe (check platelets, INR). Available at all major centres; specialist referral for remote areas.

Available (1→3)-β-D-glucan (BDG) Supportive test; non-specific (positive in candidiasis, PJP). Cutoff ≥80 pg/mL. Available at reference laboratories. MBS item 69408.

Available Aspergillus PCR (blood / BAL) Increasingly available at Australian reference laboratories (e.g., SA Pathology, Westmead). May be used in combination with GM for improved sensitivity. Not yet MBS-listed.

Available Fungal culture and susceptibility testing Identifies Aspergillus species; essential for azole susceptibility testing (EUCAST methodology). Culture takes 2–5 days. Refer isolates to mycology reference lab if azole resistance suspected.

Referral CT-guided percutaneous lung biopsy / VATS biopsy For proven diagnosis when less invasive methods are non-diagnostic and diagnosis is uncertain (e.g., suspected malignancy vs CPA nodule). Requires respiratory medicine or thoracic surgery referral.

Available Voriconazole therapeutic drug monitoring (TDM) Trough level measured just before 4th dose (day 3–5). Target: 1–5.5 mg/L. Available at major hospital laboratories. MBS item 63756 (chromatographic assay). Essential to guide dosing.

Risk Stratification

Risk stratification guides intensity of surveillance and urgency of empirical therapy:

High Risk

Prophylaxis + Active Surveillance

Allogeneic HSCT recipients, acute leukaemia on induction, GvHD on ≥1 mg/kg prednisolone. Prophylaxis with posaconazole or voriconazole recommended. Twice-weekly serum GM during neutropenia.

Setting: Tertiary haematology/HSCT centre

Intermediate Risk

Consider Prophylaxis

SOT recipients, autologous HSCT, prolonged corticosteroids, prolonged ICU stay. Consider mould-active azole prophylaxis. GM monitoring at clinician discretion.

Setting: Specialist transplant/ICU service

Lower Risk

Clinical Vigilance

COPD on intermittent corticosteroids, diabetes, well-controlled HIV, non-intensive immunosuppression. No routine prophylaxis. Clinician awareness and low threshold for investigation if symptoms develop.

Setting: General hospital / GP

Prophylaxis Agents

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Posaconazole

Noxafil® · MSD · Triazole antifungal

Prophylaxis dose (tablet) 300 mg PO OD (after 2 × 300 mg on day 1)

Prophylaxis dose (oral suspension) 200 mg PO TDS (with food or acidic beverage)

Indication Primary antifungal prophylaxis in prolonged neutropenia, allogeneic HSCT, GvHD

PBS status ✔ PBS Authority Required

Treatment Strategies

First-Line Therapy for IPA

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Standard of care: Voriconazole is the recommended first-line treatment for invasive pulmonary aspergillosis (ESCMID/ECMM/ERS guideline, 2017). Initiate IV therapy in critically ill patients and switch to oral step-down when clinically stable with adequate absorption.

Antifungal Selection

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Isavuconazole

Cresemba® · Basilea · Triazole antifungal

Adult dose (IV/PO) 200 mg IV or PO TDS for 6 doses (48 hours), then 200 mg OD

Indication First-line alternative to voriconazole for IPA; preferred in patients with QTc prolongation risk or those intolerant of voriconazole (less CYP-mediated interactions, no visual disturbance)

TDM Not routinely required; consider if treatment failure suspected or drug interactions (target trough ≥2 mg/L)

Renal adjustment No dose adjustment; avoid IV if eGFR <50 mL/min (cyclodextrin vehicle)

PBS status ✘ Not PBS-listed (available via Special Access Scheme — SAS Category A)

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Liposomal Amphotericin B

AmBisome® · Gilead · Polyene antifungal

Adult dose 3–5 mg/kg IV OD

Indication First-line if azole contraindicated (allergy, drug interaction, azole-resistant A. fumigatus); salvage therapy for refractory IPA

Duration Minimum 6–12 weeks; until clinical and radiological improvement; can be combined with azole or echinocandin in salvage

Renal adjustment Monitor creatinine and electrolytes closely; reduce dose or switch if nephrotoxicity develops (creatinine doubling)

Key toxicity Nephrotoxicity (less than conventional amphotericin), infusion reactions, hypokalaemia, hypomagnesaemia — pre-medicate with paracetamol ± hydrocortisone

PBS status ✔ PBS Authority Required

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Caspofungin

Cancidas® · MSD · Echinocandin

Adult dose 70 mg IV day 1, then 50 mg IV OD

Indication Salvage therapy for refractory IPA; combination with voriconazole or amphotericin B in select cases

Renal adjustment No dose adjustment required

PBS status ✔ PBS Authority Required

Treatment Algorithm

1

Clinical suspicion of IPA

Febrile neutropenia failing antibiotics ≥96h; CT halo sign or new infiltrate; positive serum GM.

2

Start IV voriconazole

Loading dose 6 mg/kg IV q12h × 2, then 4 mg/kg IV q12h. Arrange BAL if not yet done.

3

TDM at day 3–5

Measure voriconazole trough before 4th dose. Target 1–5.5 mg/L. Adjust dose accordingly.

4

Reassess at 72 hours

If clinical/imaging improvement: continue therapy. If no improvement: consider switch to isavuconazole, liposomal amphotericin B, or combination salvage.

5

Oral step-down

When clinically stable, switch to oral voriconazole 200–300 mg BD. Continue ≥6–12 weeks and until immune reconstitution.

Surgical Resection

Surgical resection is considered in the following scenarios:

Aspergilloma with life-threatening haemoptysis not controlled by bronchial artery embolisation — lobectomy or segmentectomy if disease is localised and patient is fit for surgery.
Localised IPA failing medical therapy (e.g., pulmonary lesion invading great vessels or chest wall).
Aspergillus nodule where malignancy cannot be excluded — diagnostic and potentially curative wedge resection.

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Surgical risk: Peri-operative antifungal therapy must be continued, and surgery should ideally be performed after immune recovery (e.g., recovery from neutropenia). Mortality for pulmonary resection in immunocompromised hosts is 10–20% — multidisciplinary team (MDT) discussion is essential.

Duration of Therapy

Condition	Minimum Duration	End-of-Treatment Criteria
IPA (haematological)	6–12 weeks	Radiological resolution/stabilisation; clinical improvement; immune reconstitution (ANC recovery, reduction of immunosuppression); GM normalisation
IPA (SOT recipient)	12+ weeks; often lifelong	May require lifelong suppression if ongoing immunosuppression; specialist transplant ID guidance essential
CPA (CCPA)	6 months minimum	Symptom improvement; stable/improving imaging; declining Aspergillus IgG; many patients require lifelong therapy
Simple aspergilloma	3–6 months if symptomatic	Resolution of haemoptysis; stable size on imaging

Monitoring & Complications

Antifungal Therapy Monitoring

Parameter	Frequency	Purpose / Target
Voriconazole trough level	Day 3–5, then weekly for first month; monthly thereafter	Target 1–5.5 mg/L; levels <1 associated with treatment failure; >5.5 with neurotoxicity and hepatotoxicity
LFTs (ALT, AST, ALP, bilirubin)	Baseline, twice weekly for 2 weeks, then weekly, then monthly	Voriconazole and itraconazole: hepatotoxicity; stop if ALT/AST >5× ULN or symptomatic hepatitis
FBC	Baseline, then weekly	Azole-related: rarely agranulocytosis; monitor for cytopaenias in combination with chemotherapy
Electrolytes (K⁺, Mg²⁺, Ca²⁺)	Daily during IV amphotericin B; weekly with azoles	Amphotericin B: hypokalaemia, hypomagnesaemia; aggressive supplementation often required
Creatinine / eGFR	Baseline, twice weekly during amphotericin B; weekly with azoles	Amphotericin B nephrotoxicity: reduce dose or switch if creatinine doubles from baseline
Serum galactomannan	Twice weekly during neutropenia for IPA; every 1–2 weeks during treatment	Declining GM correlates with response; rising GM suggests treatment failure or relapse
Aspergillus IgG (CPA)	Every 1–3 months during treatment	Declining titres indicate response; rising titres suggest progression or relapse
CT chest	6–8 weeks post-treatment initiation; then 3–6 monthly for CPA	Assess cavity size, resolution of infiltrates, new lesions

Voriconazole-Specific Adverse Effects

Visual disturbance (30% of patients): blurred vision, photopsia, altered colour perception — typically transient and dose-dependent; usually resolves with continued therapy
Photosensitivity and skin cancer risk: chronic use associated with squamous cell carcinoma and melanoma; mandatory sun protection (SPF 50+, protective clothing); regular dermatological review in long-term users
Hepatotoxicity: jaundice, transaminitis; usually reversible on cessation
Periosteal bone pain: rare but characteristically associated with prolonged voriconazole use (periostitis); consider switching antifungal
Skin reactions: cheilosis, alopecia, erythema multiforme (rare)

Haemoptysis Management

1

Minor haemoptysis (<100 mL/24h)

Investigate source, continue/initiate antifungal therapy, correct coagulopathy, respiratory medicine review.

2

Major haemoptysis (≥100 mL/24h)

Emergency: secure airway (affected side down), IV access, cross-match blood, coagulation correction. Urgent interventional radiology for bronchial artery embolisation (BAE).

3

Recurrent or life-threatening haemoptysis

MDT discussion (respiratory, IR, thoracic surgery). Consider surgical resection for localised disease (e.g., aspergilloma in single lobe).

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Massive haemoptysis is a medical emergency. Bronchial artery embolisation is the first-line intervention and is available at all major Australian tertiary centres. Mortality for untreated massive haemoptysis exceeds 50%. Do not delay transfer for definitive intervention.

Special Populations

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Pregnancy

Voriconazole: Teratogenic in animal studies (Category D). Contraindicated in pregnancy.

Isavuconazole: Contraindicated (embryotoxic in animal models).

Liposomal amphotericin B: Preferred agent for IPA in pregnancy (Category B3). No dose adjustment.

Itraconazole: Category B3 — use with caution; generally avoided in first trimester.

Infectious diseases and obstetric MDT input essential. Amphotericin B is the safest option for life-threatening aspergillosis in pregnancy.

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Paediatrics

Voriconazole: 7 mg/kg IV q12h (loading and maintenance); 200 mg PO q12h for children >30 kg. TDM essential (children may require higher mg/kg doses).

Liposomal amphotericin B: 3–5 mg/kg IV OD. Safe in children >1 month.

Caspofungin: 70 mg/m² IV day 1, then 50 mg/m² IV OD (max 70 mg/day).

IPA in paediatric oncology patients has comparable mortality to adults. Paediatric haematology/ID specialist involvement mandatory. Weight-based dosing and TDM are critical.

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Elderly

CPA is more common in older adults due to accumulated structural lung disease and comorbidities (COPD, diabetes).

Voriconazole: Increased risk of hepatotoxicity; more frequent TDM and LFT monitoring recommended. Consider lower starting doses if weight <60 kg.

Amphotericin B: Higher nephrotoxicity risk due to age-related decline in renal function; use liposomal formulation exclusively.

Polypharmacy risk is high — review all concurrent medications for azole drug interactions (particularly anticoagulants, statins, antihypertensives, benzodiazepines).

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Renal Impairment

IV Voriconazole: Avoid IV formulation if eGFR <50 mL/min (SBECD accumulation causes nephrotoxicity). Use oral formulation.

Amphotericin B: Liposomal formulation preferred; avoid conventional amphotericin B deoxycholate entirely. Monitor creatinine daily during therapy.

Echinocandins (caspofungin): No renal dose adjustment required — useful alternative in severe renal impairment.

Avoid concomitant nephrotoxins (aminoglycosides, vancomycin, NSAIDs) where possible. Nephrology co-management for patients on dialysis.

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Hepatic Impairment

Voriconazole: Child-Pugh A/B: reduce maintenance dose by 50%; Child-Pugh C: avoid. Hepatotoxicity risk increased.

Isavuconazole: No dose adjustment in mild-to-moderate hepatic impairment; avoid in severe impairment.

Liposomal amphotericin B: No specific hepatic dose adjustment; generally well tolerated from hepatic perspective.

Baseline LFTs and close monitoring essential. Hepatic impairment increases azole toxicity risk due to reduced metabolism.

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Immunocompromised

IPA risk is directly proportional to degree and duration of immunosuppression. Reduction of immunosuppression (if safe) is a critical adjunct to antifungal therapy.

HSCT patients: G-CSF may be considered to shorten neutropenia duration and improve neutrophil antifungal function.

SOT recipients: reduce tacrolimus/mycophenolate doses if possible (in consultation with transplant team); beware of azole-calcineurin inhibitor interactions (voriconazole increases tacrolimus levels 3–10-fold).

HIV patients: initiate or optimise antiretroviral therapy; IPA may occur as immune reconstitution is pending.

Duration of antifungal therapy is generally longer in immunocompromised patients (≥12 weeks or until immune reconstitution). Lifelong secondary prophylaxis may be required if immunosuppression cannot be reversed.

Aboriginal and Torres Strait Islander Health Considerations

Aboriginal and Torres Strait Islander Health

Aboriginal and Torres Strait Islander Australians bear a disproportionate burden of structural lung disease, which increases the risk of chronic pulmonary aspergillosis. Historically high rates of tuberculosis (now largely controlled), chronic suppurative lung disease, bronchiectasis, and rheumatic heart disease contribute to a higher prevalence of underlying cavitation and fibrosis. Access to specialist antifungal care, advanced imaging, and mycology services is limited in many remote and regional communities.

Structural lung disease burden

Bronchiectasis prevalence in Aboriginal and Torres Strait Islander children is 5–15 times higher than non-Indigenous children (Chang et al., 2008). Adult COPD rates are 2.5 times higher. These conditions create susceptibility to CPA and aspergilloma that may go unrecognised.

Diagnostic access

HRCT, bronchoscopy, and GM testing require transfer to regional or tertiary centres. Aspergillus IgG serology is available by post from some reference laboratories but results may take 1–2 weeks. Point-of-care tests are not yet available.

Medication supply and TDM

Itraconazole and voriconazole are available through Remote Area Aboriginal Health Services (RAAHS) and Section 100 (S100) highly specialised drugs program. However, TDM for voriconazole requires blood draw and laboratory assay at a distant facility, creating logistical barriers to dose optimisation.

Treatment adherence

Long treatment durations (6–24 months) for CPA present adherence challenges. Community-controlled health services and Aboriginal Health Practitioners can support medication adherence through regular follow-up, blister packing, and culturally safe health education. Ringhousing and "sorry business" may interrupt treatment — flexible, non-judgemental re-engagement strategies are essential.

Haemoptysis management

Massive haemoptysis from aspergilloma or CPA may present initially to remote clinics without interventional radiology capability. Emergency transfer protocols to the nearest tertiary centre (e.g., Royal Darwin Hospital, Alice Springs Hospital, Cairns Hospital) should be pre-established. Clinician education on haemoptysis first aid and safe airway management in resource-limited settings is critical.

Surgical access

Pulmonary resection for localised aspergilloma or CPA requires thoracic surgical expertise available only at major tertiary centres (Royal Melbourne, Royal Prince Alfred, Princess Alexandra). Pre-operative optimisation and post-operative recovery may necessitate prolonged urban stays, impacting cultural and family connections. Patient navigator programs and accommodation support (e.g., Ronald McDonald House, state lodging services) should be arranged early.

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Clinical practice point: In remote Aboriginal and Torres Strait Islander communities, a high index of suspicion for CPA should be maintained in any patient with chronic respiratory symptoms and a history of prior TB, bronchiectasis, or lung cavitation. Aspergillus IgG serology (collected at the local clinic and sent to a reference laboratory) is a practical first-line investigation. Empirical itraconazole therapy can be considered while awaiting results in patients with classic clinical and radiological features, under specialist advice.

📚 References

1. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408–415.
2. Ullmann AJ, Aguado JM, Arikan-Akdagli S, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24(Suppl 1):e1–e38.
3. Denning DW, Cadranel J, Beigelman-Aubry C, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016;47(1):45–68.
4. Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10017):760–769.
5. Donnelly JP, Chen SC, Kauffman CA, et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSG). Clin Infect Dis. 2020;71(6):1367–1376.
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