Spectrum of pulmonary disease caused by Aspergillus species: invasive in neutropenic hosts, allergic in asthma/CF, and aspergilloma in pre-existing cavities.
Also known as: invasive aspergillosis, ABPA, allergic bronchopulmonary aspergillosis, aspergilloma, fungus ball, Aspergillus fumigatus
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Risk factors
- Invasive: prolonged neutropenia (ANC <500 for >10 days), allogeneic HSCT, lung transplant, high-dose corticosteroids, advanced AIDS
- Invasive: severe influenza or COVID-19 (influenza-associated and COVID-associated pulmonary aspergillosis)
- ABPA: poorly controlled asthma, cystic fibrosis
- Aspergilloma: pre-existing cavity from tuberculosis, sarcoidosis, bullous emphysema
- Voriconazole prophylaxis breakthrough infections raise concern for azole-resistant Aspergillus
Pathophysiology
Invasive disease: inhaled conidia germinate into hyphae that invade blood vessels, producing infarction, hemorrhage, and necrosis. ABPA: type I and type III hypersensitivity to Aspergillus antigens colonizing the airways, causing eosinophilic inflammation, mucus plugging, and central bronchiectasis. Aspergilloma: saprophytic growth of a fungal mass within a pre-existing cavity without tissue invasion.
Clinical presentation
Symptoms
- Invasive pulmonary: persistent fever despite broad-spectrum antibiotics, pleuritic chest pain, hemoptysis, dyspnea in neutropenic patient
- ABPA: poorly controlled asthma, productive cough with brownish mucus plugs, wheezing, recurrent infiltrates
- Aspergilloma: chronic cough, hemoptysis (sometimes massive), often discovered incidentally on imaging
- Invasive sinus disease: facial pain, epistaxis, nasal congestion, palatal eschar in immunocompromised host
- Disseminated invasive disease: CNS lesions with focal deficits, seizures, or stroke
Signs / physical exam
- Often nonspecific; fever and tachypnea in invasive disease
- Wheezing and prolonged expiration in ABPA
- Cavitary lesions with intracavitary mass on imaging in aspergilloma
- Sinus tenderness, palatal necrosis in invasive sinus disease
- Focal neurologic deficits in CNS disease
Classic findings
Halo sign and air crescent sign on chest CT in invasive aspergillosis. Mobile intracavitary mass with 'Monod sign' in aspergilloma. Eosinophilia, markedly elevated IgE, and central bronchiectasis in ABPA.
Differential diagnosis
- Mucormycosis — Diabetic ketoacidosis, iron overload, deferoxamine; rhino-orbital-cerebral or pulmonary necrosis; broad non-septate hyphae with right-angle branching on biopsy
- Pseudomonas or other bacterial pneumonia in neutropenic host — Often coexists; bacterial cultures, response to broad-spectrum antibiotics
- Pneumocystis pneumonia — HIV with CD4 <200, ground-glass on CT, hypoxia out of proportion to imaging; beta-D-glucan elevated in both
- Active tuberculosis — Chronic cavitary disease; AFB workup needed alongside fungal evaluation
- Lung cancer — Mass lesion can resemble aspergilloma; biopsy distinguishes
- Asthma exacerbation without ABPA — No central bronchiectasis, normal IgE; ABPA suggested by IgE >1000, peripheral eosinophilia, positive Aspergillus skin test or IgE/IgG
Diagnostic workup
Diagnostic criteria
EORTC/MSGERC criteria for invasive aspergillosis combine host factors, clinical/imaging features, and mycologic evidence (proven, probable, possible). ABPA: ISHAM/CFF criteria. Aspergilloma: imaging plus serology.
Labs
- Serum galactomannan antigen — elevated in invasive aspergillosis (less sensitive on prophylaxis)
- BAL galactomannan more sensitive than serum
- Serum beta-D-glucan (non-specific; positive in many invasive fungal infections except mucormycosis and cryptococcosis)
- Aspergillus PCR on serum or BAL (emerging utility)
- ABPA criteria: total IgE >1000 IU/mL, Aspergillus-specific IgE and IgG, peripheral eosinophilia >500, positive Aspergillus skin test
- Culture and histopathology of tissue (definitive — narrow septate hyphae with acute-angle 45-degree branching)
Imaging
- Chest CT invasive: nodules with halo sign (early), air crescent sign (later as neutrophils recover), cavitation
- Chest CT ABPA: central bronchiectasis (upper lobe), mucus plugging, fleeting infiltrates
- Chest CT aspergilloma: intracavitary mass with crescent of air (Monod sign), most often in upper lobes
- MRI brain for CNS lesions
- Sinus CT/MRI for invasive fungal sinusitis
Treatment
First-line
- Invasive aspergillosis: voriconazole 6 mg/kg IV BID x 2 doses, then 4 mg/kg IV BID, or isavuconazole 200 mg IV TID x 6 doses then 200 mg daily — both preferred over amphotericin
- Liposomal amphotericin B 3-5 mg/kg/day as alternative or for voriconazole-intolerant patients
- Echinocandin — caspofungin, micafungin, anidulafungin — as second-line monotherapy or in combination
- Continue therapy at least 6-12 weeks and until imaging and immune recovery support cure
- ABPA: oral corticosteroids (prednisone 0.5 mg/kg/day taper over 3-6 months) is mainstay; itraconazole 200 mg PO BID or voriconazole as steroid-sparing adjunct
- Aspergilloma: observation if asymptomatic; surgical resection for recurrent hemoptysis; bronchial artery embolization for life-threatening bleeding; itraconazole has modest benefit
Second-line / adjunct
- Posaconazole — prophylaxis and salvage therapy
- Combination voriconazole plus echinocandin in severe disease (limited evidence)
- Therapeutic drug monitoring of voriconazole trough (target 1-5 microg/mL) — variable metabolism via CYP2C19
- Surgical resection for localized invasive disease near great vessels, in pericardium, or with massive hemoptysis
- Reduction of immunosuppression and G-CSF support to recover neutrophils
Complications
- Massive hemoptysis (aspergilloma and invasive disease)
- Disseminated infection to brain, sinuses, skin, and other organs
- Bronchiectasis and progressive lung damage in ABPA
- Voriconazole toxicity: hepatotoxicity, visual disturbances, photosensitivity, QT prolongation, periostitis with long-term use
- Azole-resistant Aspergillus fumigatus (emerging concern from environmental fungicide exposure)
PANCE pearls
- Voriconazole is first-line for invasive aspergillosis — superior survival versus amphotericin in randomized trials.
- Beta-D-glucan is positive in invasive aspergillosis but NEGATIVE in mucormycosis and cryptococcosis — use this to help differentiate.
- Galactomannan can be falsely positive with piperacillin-tazobactam (older formulations) and falsely negative on prophylaxis.
- ABPA is suspected in any asthmatic or CF patient with new infiltrates, eosinophilia, and very high IgE.
- Aspergilloma rarely disseminates; the principal danger is hemoptysis, which can be massive and fatal.
References
- IDSA 2016 — Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America (Patterson et al., Clin Infect Dis 2016)
- ECIL/EORTC — European guidelines for the diagnosis and management of invasive aspergillosis (Ullmann et al., Clin Microbiol Infect 2018)
- CDC — CDC — Aspergillosis: types, clinical features, and treatment overview
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