What is the treatment for pulmonary aspergillosis?

Pulmonary Aspergillosis: Manifestations, Diagnosis, and Treatment

Clinical Manifestations

Pulmonary aspergillosis presents in several distinct forms depending on the host immune status:

Invasive pulmonary aspergillosis (IPA) occurs primarily in severely immunocompromised patients, including those with hematologic malignancies, bone marrow transplantation, solid organ transplantation, and prolonged neutropenia 1, 2. The infection typically manifests as pulmonary infiltrates with potential for dissemination to other organs including the CNS, sinuses, and bone 1, 3.

Chronic cavitary pulmonary aspergillosis develops in patients with underlying lung disease and innate immune defects, presenting with progressive cavitary lesions over months 1, 2.

Aspergilloma represents fungal colonization within pre-existing lung cavities without tissue invasion 1, 2.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction occurring in asthmatic patients and those with cystic fibrosis 1, 2.

Diagnosis

Diagnosis of definite or probable invasive aspergillosis requires modified NIAID MSG/EORTC criteria, including host factors, clinical/radiographic findings, and mycological evidence 4. Key diagnostic elements include:

• Radiographic findings: CT imaging showing nodules, cavitation, or the "halo sign" in early disease 4
• Galactomannan assay: Serum or bronchoalveolar lavage testing for fungal antigen 1, 2
• Culture and histopathology: Tissue biopsy showing septate hyphae with acute-angle branching 4
• Bronchoscopy: For obtaining respiratory specimens when feasible 4

Treatment by Disease Type

Invasive Pulmonary Aspergillosis

Voriconazole is the definitive first-line treatment for invasive pulmonary aspergillosis, demonstrating superior efficacy and survival compared to amphotericin B formulations 2, 5, 4, 6. The landmark randomized trial showed 53% successful outcomes with voriconazole versus 32% with amphotericin B, with 71% survival at 12 weeks versus 58% (p<0.0001) 4, 6.

Dosing regimen for voriconazole:

• Loading dose: 6 mg/kg IV every 12 hours for the first 24 hours 2, 5, 4
• Maintenance dose: 4 mg/kg IV every 12 hours for minimum 7 days 2, 5, 4
• Oral transition: 200 mg PO every 12 hours once clinically improved 2, 5
• Pediatric dosing (≥2 years): 5-7 mg/kg IV every 12 hours 2, 5

Therapeutic drug monitoring is mandatory for voriconazole due to variable pharmacokinetics, genetic polymorphism in CYP2C19 metabolism (15-20% of Asians and 3-5% of Caucasians/Blacks are poor metabolizers with 4-fold higher drug exposure), and narrow therapeutic window 2, 5, 4. Target trough levels must be monitored, particularly in patients on ECMO where standard dosing is inadequate and doses up to 6.5 mg/kg three times daily may be necessary 7.

Alternative primary therapy:

• Liposomal amphotericin B (L-AMB): 3-5 mg/kg/day IV for patients with voriconazole contraindications or intolerance 1, 2, 5
• Posaconazole: Recent non-inferiority trial demonstrated comparable efficacy to voriconazole (15% vs 21% mortality at day 42) with fewer treatment-related adverse events (30% vs 40%) 8. Dosing is 300 mg twice on day 1, then 300 mg once daily 8
• Isavuconazole: Network meta-analysis shows comparable efficacy to voriconazole with potentially better safety profile 9

Treatment duration: 6-12 weeks minimum, continued throughout immunosuppression period and until complete resolution or stabilization of clinical and radiographic findings 2, 5. Median duration in clinical trials was 10 days IV followed by 76 days oral therapy 5, 4.

Salvage therapy options:

• Liposomal amphotericin B 3-5 mg/kg/day IV 1, 5
• Caspofungin: 70 mg loading dose day 1, then 50 mg/day IV 1, 5
• Posaconazole (approved in European Union for salvage) 1

Combination therapy with voriconazole plus anidulafungin has been studied but does not significantly improve outcomes in advanced disease compared to voriconazole monotherapy 10. However, it may serve as an alternative for patients with limited drug tolerance 9.

Reversal of immunosuppression is critical for favorable outcomes and should be pursued whenever feasible 1, 2.

Surgical resection should be considered for localized disease refractory to medical therapy 2, 5.

CNS Aspergillosis

Voriconazole with surgical resection is the treatment of choice for CNS aspergillosis, as this carries the highest mortality among all invasive aspergillosis patterns 3. Neurosurgical resection is strongly recommended as an adjunct and significantly improves survival (p=0.02) 3.

Voriconazole dosing for CNS disease:

• Same loading and maintenance regimen as pulmonary disease 3
• Voriconazole penetrates well into the CNS, unlike other antifungal agents 3
• Monitor for drug interactions with anticonvulsants (phenytoin, carbamazepine) commonly used in CNS infections 3

Long-term therapy measured in months is required, with treatment continued throughout immunosuppression 3.

Chronic Cavitary Pulmonary Aspergillosis

Itraconazole or voriconazole are the preferred treatments, allowing for protracted oral therapy 1, 2.

Itraconazole is the preferred option for long-term therapy: 200 mg PO every 12 hours 1, 2. Dosing for invasive disease with tablets is 600 mg/day for 3 days, then 400 mg/day 1.

Long-term therapy measured in months is required due to innate immune defects demonstrated in most patients 1, 2. Surgical resection may lead to significant complications and should be approached cautiously 1.

Aspergilloma

Management prioritizes observation or surgical resection, as the role of medical therapy remains uncertain 1, 2. Penetration of amphotericin B into pre-existing cavities is minimal, but itraconazole demonstrates excellent cavity penetration 1, 2.

Medical therapy with itraconazole or voriconazole can be attempted when surgery is not feasible 1, 2.

Allergic Bronchopulmonary Aspergillosis (ABPA)

Itraconazole combined with corticosteroids is the treatment of choice, providing a demonstrable corticosteroid-sparing effect 1, 2. Corticosteroids remain the cornerstone of therapy, with itraconazole reducing steroid requirements and minimizing steroid-related side effects 1, 2.

Alternative antifungals: Voriconazole 200 mg PO every 12 hours or posaconazole 400 mg PO twice daily 1.

Allergic Aspergillus Sinusitis

Management can be observation alone or itraconazole, as limited data support aggressive antifungal therapy 1, 2.

Critical Pitfalls to Avoid

Never use amphotericin B deoxycholate when other options are available due to substantial nephrotoxicity 2. The randomized trial showed significantly more severe drug-related adverse events with amphotericin B compared to voriconazole 4, 6.

Always perform therapeutic drug monitoring for voriconazole due to variable pharmacokinetics and genetic polymorphism 2, 5, 4. Poor metabolizers have 4-fold higher exposure, while heterozygous extensive metabolizers have 2-fold higher exposure 4.

In patients on ECMO, standard voriconazole dosing is inadequate due to drug sequestration in circuits; much higher doses and frequent monitoring are mandatory 7.

Consider surgical intervention for invasive disease involving CNS, bone, cartilage, or when medical therapy fails 2, 3.

Assess for drug interactions, particularly with voriconazole and anticonvulsants in CNS aspergillosis, as voriconazole has significant interactions with phenytoin and other anticonvulsants 3.

Transient visual disturbances occur in 44.8% of patients on voriconazole but are generally not severe enough to warrant discontinuation 4, 6.