What are the current clinical guidelines for diagnosing and managing pulmonary aspergillosis, including invasive pulmonary aspergillosis, chronic pulmonary aspergillosis, and allergic bronchopulmonary aspergillosis?

Guidelines for Pulmonary Aspergillosis

Classification and Diagnostic Criteria

Pulmonary aspergillosis encompasses distinct clinical entities that require different management approaches, with diagnosis hinging on a combination of imaging findings, immunological evidence, and a minimum 3-month duration to distinguish chronic from invasive disease. 1, 2

Chronic Pulmonary Aspergillosis (CPA)

The diagnosis of CPA requires all of the following present for at least 3 months: 1, 2

• One or more pulmonary cavities (with or without fungal ball) or nodules on thoracic imaging 1
• Direct evidence of Aspergillus infection (microscopy/culture from biopsy) OR immunological response to Aspergillus species 1
• Exclusion of alternative diagnoses 1
• Aspergillus IgG antibody (precipitins) is elevated in >90% of patients and is the most sensitive microbiological test 1, 3, 4

The 3-month duration criterion is critical—symptoms present for less than 3 months suggest subacute invasive aspergillosis (SAIA) or invasive disease requiring more aggressive management. 2

CPA Subtypes:

Simple (Single) Aspergilloma: 1, 2

• Single fungal ball in a single pulmonary cavity 1
• Minimal or no symptoms 1, 2
• No radiological progression over at least 3 months 1
• Positive Aspergillus serology confirms diagnosis when fungal ball is visible 1, 4

Chronic Cavitary Pulmonary Aspergillosis (CCPA)—the most common form: 1, 2

• One or more pulmonary cavities with thin or thick walls 1
• May contain aspergillomas or irregular intraluminal material 1
• Significant pulmonary/systemic symptoms (chronic cough, dyspnea, hemoptysis, weight loss, fatigue) 1, 4
• Overt radiological progression: new cavities, increasing pericavitary infiltrates, or increasing fibrosis 1, 2

Chronic Fibrosing Pulmonary Aspergillosis (CFPA): 1, 2

• Severe fibrotic destruction of at least two lobes 1
• Major loss of lung function 1
• Represents end-stage progression of CCPA 1

Aspergillus Nodule: 1, 2

• One or more nodules that may or may not cavitate 1
• Mimics tuberculoma, lung carcinoma, or other endemic fungal infections 1
• Definitive diagnosis requires histology showing no tissue invasion 1

Subacute Invasive Aspergillosis (SAIA)

SAIA develops over 1-3 months in moderately immunocompromised patients (chronic corticosteroid use >10 mg prednisolone daily, diabetes, liver disease, malnutrition, COPD). 1, 2, 4

Key distinguishing features: 1, 2

• More rapid progression than CPA (1-3 months vs. >3 months) 1, 2
• Variable radiological features: cavitation, nodules, progressive consolidation 1, 2
• Both Aspergillus-specific IgG antibodies AND circulating galactomannan antigen are usually detectable in serum 2
• Histopathology reveals hyphal invasion of lung parenchyma 1, 2
• Should be managed as invasive aspergillosis, not CPA 1

Invasive Pulmonary Aspergillosis (IPA)

IPA occurs in severely immunocompromised patients (neutropenia, hematologic malignancy, solid organ transplant) and presents as necrotizing pneumonia. 5, 6

Clinical features: 5

• Fever, cough, dyspnea, chest pain, hemoptysis, hypoxemia 5
• CT findings: "halo sign" (early) and "air crescent sign" (late, with cavitation) 5
• Aspergillus serology typically negative in invasive disease 2

Diagnostic Workup

Imaging

High-resolution CT is essential and demonstrates: 2, 4

• Irregular-walled cavities in CCPA, often with progressive enlargement 2
• Fungal balls (aspergillomas) appearing as mobile intracavitary masses 1
• Pericavitary infiltrates and pleural thickening 3

Microbiological Testing

Respiratory cultures are positive for Aspergillus in 56-81% of CPA cases, but isolation from sputum alone does not confirm infection because Aspergillus is ubiquitous. 2, 4

Bronchoscopic specimens are far more indicative of true disease than sputum samples. 2

For cavitary lesions consistent with CPA, diagnosis can be confirmed by any of the following (after excluding alternatives): 1

• Positive Aspergillus IgG or precipitins (>90% sensitive) 1
• Strongly positive Aspergillus antigen or DNA in respiratory fluids 1
• Percutaneous or excision biopsy showing fungal hyphae on microscopy or growing Aspergillus species from a cavity 1

Critical Differential Diagnoses

Mycobacterial infection (tuberculosis or non-tuberculous mycobacteria) is the principal alternative diagnosis and may coexist with CPA—dual infections are frequent and associated with poorer outcomes. 1, 2, 4

Mandatory testing includes: 1, 4

• Sputum smear for acid-fast bacilli 1, 4
• Mycobacterial nucleic acid amplification 1, 4
• Mycobacterial culture 1, 4

Endemic fungal infections to exclude (based on geography/travel): 1, 2

• Chronic cavitary histoplasmosis 1, 2
• Coccidioidomycosis 1, 2
• Paracoccidioidomycosis 1, 2
• Distinguish by specific antibody/antigen testing and culture 2

Other differential diagnoses: 1, 4

• Necrotizing lung cancer 1, 4
• Pulmonary infarction 1, 4
• Vasculitides 1, 4
• Rheumatoid nodule 1, 4

Concurrent bacterial superinfection of persistent cavities (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa) is common and warrants appropriate antibacterial therapy. 2

Management

Chronic Pulmonary Aspergillosis

Simple Aspergilloma:

Surgical excision is recommended if technically possible, preferably via video-assisted thoracic surgery (VATS). 1, 2

Antifungal therapy is only needed if not fully resected; multiple nodules may benefit from antifungal treatment and require careful follow-up. 1

Chronic Cavitary Pulmonary Aspergillosis:

Long-term oral antifungal therapy is recommended to improve overall health status and respiratory symptoms, arrest hemoptysis, and prevent progression. 1

First-line antifungal agents: 2, 3

• Voriconazole: Loading dose 6 mg/kg IV every 12 hours for two doses, then maintenance 4 mg/kg IV every 12 hours or 200 mg orally twice daily 2
• Itraconazole: Accepted alternative requiring long-term therapy 1, 2

Duration of therapy: 3

• Minimum 4-6 months initially 3
• Extend to 9 months if minimal response 3
• Long-term or indefinite suppressive therapy may be required for CCPA 3

Critical monitoring requirements: 1, 3

• Therapeutic drug monitoring of azole serum concentrations 1, 3
• Monitor for drug interactions (especially with rifampicin in concurrent TB—requires dose adjustments) 1, 3
• Monitor for azole toxicities 1
• Liver function tests 3
• Visual acuity and color discrimination testing for patients on voriconazole 3

Hemoptysis Management

Hemoptysis may signal therapeutic failure and/or antifungal resistance. 1

Treatment approach: 1, 3

• Oral tranexamic acid for mild-moderate hemoptysis 3
• Bronchial artery embolization for severe hemoptysis 1, 3
• Surgical resection rarely, for localized disease with persistent hemoptysis despite other measures 1, 3

Subacute Invasive Aspergillosis and Invasive Pulmonary Aspergillosis

SAIA and IPA in severely immunocompromised patients should be treated aggressively with voriconazole or other mold-active agents according to established invasive aspergillosis protocols. 2

Intravenous voriconazole is the recommended primary treatment for IPA. 7

Liposomal amphotericin B also has clinical utility. 7

Caspofungin or antifungal combinations are recommended as salvage therapy. 7

Concurrent Tuberculosis and CPA

For patients with concurrent pulmonary tuberculosis and CPA, standard anti-tuberculosis therapy PLUS oral triazole antifungal therapy (voriconazole or itraconazole) is strongly recommended. 3

Drug interactions between rifampicin and triazole antifungals require dose adjustments and therapeutic drug monitoring is essential. 3

Common Pitfalls

Do not diagnose CPA based on positive sputum culture alone—Aspergillus is ubiquitous and colonization is common. 2

Do not miss concurrent mycobacterial infection—always send mycobacterial studies in cavitary lung disease. 1, 2

Do not use the 3-month duration criterion loosely—progression over 1-3 months suggests SAIA requiring invasive aspergillosis treatment protocols, not CPA management. 1, 2

Do not forget therapeutic drug monitoring for azoles—bioavailability varies significantly and toxicity is common. 1, 3, 7

Do not overlook bacterial superinfection in persistent cavities—treat concurrently when present. 2