What are the different forms of pulmonary aspergillosis, their diagnostic work‑up, and first‑line treatment options?

Pulmonary Aspergillosis: Forms, Diagnosis, and Treatment

Overview of Disease Spectrum

Pulmonary aspergillosis encompasses distinct clinical entities that differ fundamentally in pathophysiology, patient populations, and management—ranging from invasive disease in immunocompromised hosts to chronic infection in structurally damaged lungs to allergic reactions in hyperreactive airways. 1

The major forms include:

• Invasive pulmonary aspergillosis (IPA) - occurs in immunocompromised patients 1
• Chronic pulmonary aspergillosis (CPA) - affects non-immunocompromised patients with underlying lung disease 1
• Allergic bronchopulmonary aspergillosis (ABPA) - hypersensitivity reaction in asthma/cystic fibrosis patients 2
• Aspergilloma - fungal ball in pre-existing cavity 1

---

Invasive Pulmonary Aspergillosis (IPA)

Patient Population

• Prolonged neutropenia, allogeneic HSCT recipients, solid organ transplant recipients, inherited/acquired immunodeficiencies, high-dose corticosteroid use 1
• Emerging risk groups: critically ill ICU patients, severe influenza/COVID-19, advanced COPD, cirrhosis 3, 4

Diagnostic Approach

• Tissue and fluid specimens should be submitted for simultaneous histopathologic examination and culture 1
• Bronchoscopy with bronchoalveolar lavage (BAL) is strongly recommended, with samples sent for culture, cytology, and galactomannan testing 5
• Serum galactomannan antigen testing has high sensitivity in neutropenic patients 1
• CT imaging typically shows nodules, cavitation, or the "halo sign" (ground-glass opacity surrounding nodules) 3

First-Line Treatment

Voriconazole remains the primary first-line agent for invasive aspergillosis 1, but isavuconazole is equally recommended as first-line therapy with superior tolerability and fewer adverse effects 6.

• Voriconazole or isavuconazole (both AI-level recommendations) 1, 6
• Liposomal amphotericin B is an alternative for patients intolerant of azoles 1
• Treatment duration: minimum 6-12 weeks, continuing throughout immunosuppression until complete clinical and radiographic resolution 6
• Therapeutic drug monitoring is strongly recommended for voriconazole to optimize efficacy and minimize toxicity 5, 6

Key Advantages of Isavuconazole

• Non-inferior efficacy to voriconazole demonstrated in the SECURE trial 6
• Less hepatotoxicity, no neuro-visual toxicity, no QTc prolongation 6
• Fewer drug-drug interactions compared to voriconazole 6

---

Chronic Pulmonary Aspergillosis (CPA)

Clinical Forms and Definitions

CPA requires ≥3 months of symptoms/radiographic findings to distinguish from acute invasive disease 1, 2:

• Chronic cavitary pulmonary aspergillosis (CCPA): One or more pulmonary cavities with progressive symptoms and radiological progression over ≥3 months 1
• Chronic fibrosing pulmonary aspergillosis (CFPA): Severe fibrotic destruction of ≥2 lobes complicating CCPA with major loss of lung function 1
• Simple aspergilloma: Single fungal ball in single cavity with minimal symptoms and no progression 1
• Aspergillus nodule: One or more nodules that may cavitate, mimicking tuberculoma or malignancy 1

Patient Population

• Non-immunocompromised patients with prior/current lung disease (tuberculosis, COPD, sarcoidosis, prior pneumothorax) 1, 2
• Critical distinction: CPA occurs in non-immunocompromised hosts, unlike IPA 2

Diagnostic Criteria

Diagnosis requires all of the following present for ≥3 months 1:

• One or more cavities with/without fungal ball or nodules on thoracic imaging 1
• Direct evidence of Aspergillus infection (microscopy/culture from biopsy) OR immunological response to Aspergillus 1
• Exclusion of alternative diagnoses 1

Key Diagnostic Tests

• Aspergillus-specific IgG antibodies (precipitins): elevated in >90% of CPA cases 1, 2
• Peripheral eosinophilia is NOT a feature of CPA (helps distinguish from ABPA) 2
• Chest CT (preferably high-resolution) is the primary imaging modality 5
• CT angiography required at baseline if hemoptysis present 5

First-Line Treatment

Long-term oral antifungal therapy is recommended for CCPA to improve health status, arrest hemoptysis, and prevent progression 1:

• Oral triazoles (voriconazole preferred) for ≥6 months 2, 5
• Careful monitoring of azole serum concentrations, drug interactions, and toxicities is mandatory 1, 5
• Corticosteroids are contraindicated in CPA—they worsen infection and can precipitate invasive aspergillosis 2

Surgical Management

For simple aspergilloma: surgical excision is recommended if technically feasible, preferably via video-assisted thoracic surgery (VATS) 1, 5:

• Surgery is strongly recommended for symptomatic patients, especially with significant hemoptysis 5
• Medical therapy alone for patients who cannot tolerate surgery 5

Management of Hemoptysis

• Oral tranexamic acid for hemoptysis control 1, 5
• Bronchial artery embolization for severe hemoptysis 1, 5
• Hemoptysis may indicate therapeutic failure or antifungal resistance 1

---

Allergic Bronchopulmonary Aspergillosis (ABPA)

Patient Population

ABPA occurs almost exclusively in patients with asthma or cystic fibrosis 2:

• Approximately 25% of asthmatic patients and 10% of cystic fibrosis patients may develop ABPA 7

Pathophysiology

ABPA results from immune-mediated inflammation in response to inhaled Aspergillus fumigatus antigen, causing pulmonary infiltrates, mucus plugging, and marked eosinophilia 2

Diagnostic Criteria

Essential criteria include 2:

• Asthma or cystic fibrosis 2
• Peripheral blood eosinophilia (core diagnostic criterion) 2
• Immediate cutaneous reactivity to Aspergillus 2
• Elevated total serum IgE (>417 IU/L) 2
• Elevated Aspergillus-specific IgG and IgE 2

Key Distinguishing Features from CPA

• Peripheral eosinophilia present in ABPA, absent in CPA 2
• Total IgE >417 IU/L supports ABPA; CPA does not cause IgE elevation 2
• Imaging: central bronchiectasis, mucus plugging, infiltrates in ABPA vs. cavities with fungal balls in CPA 2

First-Line Treatment

Systemic corticosteroids are first-line therapy for ABPA, with antifungals as adjunctive treatment 2:

• This contrasts sharply with CPA, where corticosteroids are contraindicated 2
• Itraconazole is the preferred antifungal adjunct 4

---

Subacute Invasive Aspergillosis (SAIA)

Formerly called chronic necrotizing pulmonary aspergillosis, SAIA is a more rapidly progressive infection (<3 months) in moderately immunocompromised patients 1:

• Should be managed as invasive aspergillosis, not as CPA 1
• Biopsy shows hyphae invading lung tissue 1
• Positive Aspergillus galactomannan antigen in blood or respiratory fluids 1

---

Critical Diagnostic Algorithm

When encountering suspected pulmonary aspergillosis:

Step 1: Assess immune status

• Severely immunocompromised (neutropenia, transplant, high-dose steroids) → suspect IPA 1
• Non-immunocompromised with structural lung disease → suspect CPA 1, 2
• Asthma or cystic fibrosis → suspect ABPA 2

Step 2: Check for peripheral eosinophilia

• Present → strongly suggests ABPA 2
• Absent → favors CPA or IPA 2

Step 3: Measure total serum IgE

• 417 IU/L → supports ABPA 2

• Normal → favors CPA or IPA 2

Step 4: Obtain Aspergillus-specific antibodies

• Elevated IgG (precipitins) in >90% of CPA cases 1, 2
• Elevated IgE and IgG → ABPA 2

Step 5: Review imaging pattern

• Cavities with fungal balls, pleural thickening → CPA 2, 5
• Central bronchiectasis, mucus plugging, infiltrates → ABPA 2
• Nodules with halo sign, cavitation → IPA 3

Step 6: Assess duration

• <3 months → IPA or SAIA 1
• ≥3 months → CPA 1

---

Common Pitfalls and Caveats

• Never use corticosteroids in CPA patients—this can convert chronic infection to invasive disease 2
• Do not assume azole cross-susceptibility: isavuconazole MICs must be tested separately if using this agent 6
• Hemoptysis in CPA may indicate treatment failure or emerging azole resistance—requires urgent reassessment 1
• ABPA diagnosis requires asthma or cystic fibrosis; do not diagnose ABPA in patients without these conditions 2
• Therapeutic drug monitoring is essential for voriconazole due to variable pharmacokinetics and narrow therapeutic window 5, 6
• Treatment duration for IPA must continue throughout immunosuppression period, not just a fixed duration 6
• Simple aspergilloma patients with single nodules only need antifungal therapy if not fully resected; multiple nodules may benefit from treatment 1