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Pathogen
- Aspergillus species â A. fumigatus #1 cause (~ 85%), A. flavus, A. niger, A. terreus
- Ubiquitous â soil, decaying vegetation, dust, water, construction sites
- Spores (conidia) inhaled
- 5 clinical forms based on host immunity + lung structure
Diagnosis
Imaging
- Chest CT:
- Halo sign (ground-glass around nodule) â early invasive
- Air crescent sign â recovering invasive (neutrophil recovery)
- Cavitary mass with intracavitary âfungal ballâ â aspergilloma
- Nodules, consolidation, infiltrates
- MRI brain: for suspected CNS aspergillosis
- Paranasal CT: for sinus disease
Biomarkers
- β-D-glucan: elevated in IA, Candida, PJP (not specific)
- Galactomannan (GM):
- Aspergillus cell wall component
- Serum GM screening in high-risk neutropenic
- BAL GM more sensitive than serum for pulmonary
- CSF GM for CNS
- False positives: pip-tazo (lots, especially old), other molds, some lab issues
Microbiology
- Sputum / BAL culture + microscopy
- PCR of BAL fluid (emerging)
- Tissue biopsy: definitive â hyphae 45° branching with septations in tissue (Aspergillus characteristic)
- Aspergillus colonization vs invasion: tissue invasion is key
Pulmonary Function (ABPA)
- Total IgE > 1000 IU/mL
- Aspergillus-specific IgE elevated
- Aspergillus precipitins (IgG)
- Peripheral eosinophilia
- Central bronchiectasis on CT
- Mucous plugging
Treatment
Invasive Aspergillosis
- First-line: Voriconazole 6 mg/kg IV q12h à 2 doses then 4 mg/kg IV q12h (or oral 200 mg bid)
- TDM: trough 1-5.5 mg/L
- Alternative: Isavuconazole (oral or IV â lower toxicity, linear PK)
- Salvage: Liposomal Amphotericin B 3-5 mg/kg/d
- Combination: voriconazole + echinocandin in severe (controversial; no clear mortality benefit)
- Duration: ⥠6-12 weeks; longer for cavitary / severe / CNS / disseminated
- Reduce immunosuppression if possible
- Surgical resection for localized cavity / persistent disease / hemoptysis
ABPA
- Systemic corticosteroids (prednisone 0.5 mg/kg/d â taper)
- Itraconazole (or voriconazole) 200 mg bid à 16 wk
- Anti-IgE therapy (omalizumab) for recurrent / severe
- Optimal asthma + CF management
Aspergilloma
- Observation if asymptomatic
- Surgical resection for hemoptysis + symptomatic + lobar disease (high-risk surgery)
- Bronchial artery embolization for hemoptysis
- Antifungal limited efficacy in established aspergilloma
Chronic Pulmonary Aspergillosis
- Itraconazole or voriconazole long-term (months-years)
- Posaconazole alternative
- Surgical resection for symptomatic single cavity
- Management of underlying lung disease
Cutaneous + Sinus
- Voriconazole + surgical debridement
- Source control critical
Resistance
- Azole-resistant Aspergillus fumigatus (TR34/L98H mutation in CYP51A) â Netherlands first, now Asia + Europe + USA
- Mechanism: agricultural azole fungicide use â environmental selection
- Voriconazole MIC ⥠4 mg/L = resistant
- Alternative: liposomal AmB, isavuconazole (variable activity), olorofim (Phase 3)
- Surveillance recommended
1ïžâ£ Microbiology + Epidemiology
Species
- A. fumigatus (#1 cause invasive aspergillosis, ~ 85%)
- A. flavus (sinus, cutaneous; mycotoxin aflatoxin)
- A. niger (otomycosis common)
- A. terreus (rare invasive; intrinsic AmB resistance)
- A. nidulans (chronic granulomatous disease association)
- 250+ species; few cause human disease
Habitat
- Ubiquitous in environment
- Soil, decaying vegetation, dust, water
- Construction sites (high spore release)
- Air conditioning systems
- Aspergillus spores ubiquitous in air â most healthy people donât develop disease
Spore Inhalation
- Conidia (spores) 2-3 µm diameter â fine enough to reach alveoli
- Most cleared by alveolar macrophages
- Disease when:
- Immunocompromise
- Pre-existing lung disease (cavity, bronchiectasis)
- Allergic predisposition (asthma, CF, atopy)
- Mucous obstruction
Pathogenesis
- Tissue invasion in immunocompromise
- Angioinvasion â vascular damage + thrombosis + infarction + hemorrhage
- Hyphae morphology: 45° branching with septations (Aspergillus)
- Cell wall components: galactomannan, β-glucan (used for diagnosis)
2ïžâ£ Invasive Aspergillosis (IA)
Risk Factors
Major Immune Compromise
- Neutropenia (< 500/µL, especially prolonged > 10 days)
- Anti-cancer chemotherapy
- HSCT (especially allogeneic, prolonged engraftment)
- Solid organ transplant (especially lung; less heart, kidney, liver)
- Severe COPD on high-dose inhaled corticosteroids
- Anti-CD20 therapy (rituximab, ocrelizumab)
- Anti-TNF therapy
- High-dose corticosteroids ⥠20 mg prednisone for weeks
- Advanced HIV (CD4 < 50)
- Chronic granulomatous disease (CGD â genetic; A. nidulans + fumigatus)
- Severe influenza + COVID-19 (post-viral immunosuppression â increased recognition)
Imaging â Chest CT (Diagnostic)
Halo Sign
- Ground-glass opacity around solid nodule
- Reflects angioinvasion + surrounding hemorrhage
- Early invasive aspergillosis (especially neutropenic)
- Sensitivity 60-90% in early IA
Air Crescent Sign
- Crescent of air between dying parenchyma + cavity wall
- Appears days-weeks later
- Often during neutrophil recovery
- Distinctive for invasive aspergillosis
Other CT Findings
- Nodules + cavitations
- Wedge-shaped peripheral infarcts
- Consolidation
- Pleural-based lesions
- Halo sign + air crescent sign = pathognomonic combination
Diagnosis
Galactomannan (GM)
- Aspergillus cell wall component (mannan)
- Serum GM screening in high-risk neutropenic (q3-5 days during neutropenia)
- BAL GM more sensitive than serum (especially in non-neutropenic)
- CSF GM for CNS aspergillosis
- Cutoff: serum index > 0.5 or BAL > 1.0
- False positives: piperacillin-tazobactam (older lots; now less of an issue), Penicillium, Histoplasma, blastomycosis, other molds, lab issues
- False negatives: posaconazole prophylaxis, voriconazole therapy, mild disease
β-D-Glucan
- Elevated in IA + Candida + PJP (not specific for Aspergillus)
- Adjunctive
PCR
- BAL Aspergillus PCR
- Emerging diagnostic
- High sensitivity + specificity in research settings
Microbiology + Histology
- BAL culture (Aspergillus growth)
- Sputum less reliable (colonization vs invasion)
- Tissue biopsy: definitive â hyphae 45° branching with septations (Aspergillus characteristic; differential from Mucor â broader, irregular, less septate, 90° branching)
Treatment
First-Line
- Voriconazole:
- 6 mg/kg IV q12h à 2 doses then 4 mg/kg IV q12h (loading + maintenance)
- Or oral 200 mg bid
- TDM: trough 1-5.5 mg/L
- Adjust dose based on trough
Alternative First-Line
- Isavuconazole (oral or IV):
- 200 mg loading à 6 doses then 200 mg/day
- Linear pharmacokinetics (less TDM)
- Lower hepatotoxicity than voriconazole
- Less drug interactions
- Less photosensitivity
- Comparable efficacy (SECURE trial)
Salvage / Alternative
- Liposomal Amphotericin B 3-5 mg/kg/day
- For voriconazole intolerance / failure
- Higher dose (5 mg/kg) for severe disease
Combination Therapy
- Voriconazole + Echinocandin (caspofungin, anidulafungin)
- Controversial â no clear mortality benefit (some trials negative)
- May be considered for severe / progressing disease
- Long-term outcomes unclear
Duration
- ⥠6-12 weeks minimum
- Until:
- Clinical resolution
- Radiographic improvement
- Galactomannan trends negative
- Resolution of immune compromise
- Longer for:
- Cavitary disease (months)
- CNS aspergillosis
- Disseminated disease
- Persistent immunosuppression
Surgical
- Resection for:
- Localized disease with persistent imaging finding
- Hemoptysis (cavitary)
- Failure of medical management
- Pulmonary aspergilloma
- Approach near large vessels (close monitoring)
Reduce Immunosuppression
- Critical adjunct
- Recovery from neutropenia
- Reduce corticosteroids
- Hold chemotherapy when feasible
- Granulocyte transfusion historic (rare now)
Prognosis
- Mortality 30-50% in invasive
- Reduced with voriconazole + earlier diagnosis
- Worse outcomes:
- Persistent neutropenia
- CNS involvement
- Disseminated disease
- High initial galactomannan
- Delayed treatment
3ïžâ£ Allergic Bronchopulmonary Aspergillosis (ABPA)
Background
- IgE-mediated allergic response to Aspergillus colonization of airways
- Asthma + cystic fibrosis (CF) primary host populations
- ~ 1-2% asthma; ~ 7-10% CF
Pathogenesis
- Aspergillus colonizes bronchi (especially central)
- Persistent antigenic stimulation
- Mixed Type I + Type III hypersensitivity
- Eosinophilic + IgE-mediated inflammation
- Mucous plugging + bronchiectasis (central)
Clinical
- Worsening / recalcitrant asthma
- Recurrent pulmonary infiltrates
- Cough + wheeze + dyspnea
- Sometimes severe with respiratory failure
- Chronic productive cough (mucus plugs â brown/black)
- Mucous plug âcastsâ expectorated
Diagnosis (ISHAM 2024 Criteria)
Required
- Asthma OR cystic fibrosis
- Aspergillus IgE positive + Total IgE > 1000 IU/mL
Major Criteria (⥠2)
- Aspergillus IgG positive (precipitins)
- Peripheral eosinophilia
- Central bronchiectasis on CT (cylindrical, varicose, cystic)
- Mucous plugging
- Pulmonary infiltrates on CXR
- Reversible bronchoconstriction
- Mucoid impaction on CT
Stages
- Acute: above criteria + active disease
- Remission: ⥠6 months without symptoms/lab changes
- Exacerbation: relapse with above features
- Steroid-dependent: requires chronic steroid
- Fibrocavitary: end-stage with fibrosis + cavities
Treatment
Corticosteroids
- Prednisone 0.5 mg/kg/day à 2 weeks â taper over 3-6 months
- Mainstay for active disease
- Severe / refractory: higher initial dose
Itraconazole
- 200 mg PO bid à 16 weeks standard
- Voriconazole alternative
- Reduces fungal burden â reduces antigenic stimulation
- TDM for itraconazole (variable absorption)
Anti-IgE (Omalizumab)
- For severe / steroid-dependent ABPA
- Especially in CF
- Reduces IgE levels + steroid requirement
- Off-label for ABPA but commonly used
Optimal Asthma + CF Management
- Long-acting bronchodilators
- Inhaled corticosteroids
- CF: airway clearance, pancreatic enzymes
- Manage exacerbations
Monitoring
- Total IgE (reflects disease activity)
- Imaging
- Symptoms
- Eosinophilia
4ïžâ£ Aspergilloma (âFungal Ballâ)
Background
- Saprophytic colonization of pre-existing lung cavity
- Aspergillus hyphae + cellular debris form ball within cavity
- No tissue invasion
- Often A. fumigatus
Predisposing Conditions
- Post-tuberculosis cavity
- Sarcoidosis (especially fibrocystic)
- COPD/Emphysema bullae
- Lung abscess cavity
- Pneumoconiosis (silicosis cavities)
- Cystic fibrosis bronchiectasis
- Bronchiectasis secondary to other causes
Clinical
- Hemoptysis primary symptom (10-95%; can be massive + life-threatening)
- Cough
- Chest pain
- Sometimes asymptomatic
- Stable disease often
Imaging
- CXR / CT:
- Crescent sign (air-meniscus): air-fluid crescent between fungal ball + cavity wall
- Movement of fungal ball with patient position change
- Cavity within lung tissue
- Pre-existing cavity background
Diagnosis
- Imaging (characteristic appearance)
- Aspergillus IgG positive (precipitins) â most cases
- Sputum culture (variable; doesnât prove invasive)
- No invasion â no IA workup typically
Treatment
Observation
- Asymptomatic stable aspergilloma â observe + monitor
Surgical Resection
- For:
- Symptomatic (hemoptysis)
- Massive hemoptysis episode
- Lobar / segmental disease
- High-risk surgery (bleeding, lung function loss, complications in fibrotic background)
- Lobectomy / wedge resection
Bronchial Artery Embolization
- For acute massive hemoptysis
- Effective short-term
- Sometimes used as bridge or alternative to surgery
Antifungal Therapy
- Limited efficacy in established aspergilloma (fungal ball doesnât penetrate well)
- Itraconazole / voriconazole sometimes used pre-surgery or with embolization
- Not curative typically
Direct Cavity Instillation
- Amphotericin B paste or solution into cavity (rare)
- Historical for refractory disease
5ïžâ£ Chronic Pulmonary Aspergillosis (CPA)
Background
- Subacute / chronic Aspergillus lung disease
- Underlying lung disease common (COPD, post-TB, sarcoidosis, bronchiectasis)
- Borderline invasion (less aggressive than IA)
- ~ 3 million globally
Subtypes
Simple Aspergilloma
- Single cavity with fungal ball
- Stable disease
Chronic Cavitary Pulmonary Aspergillosis (CCPA)
- Multiple cavities expanding
- Symptomatic course
- Loss of lung function
Chronic Fibrosing Pulmonary Aspergillosis
- Progressive fibrosis
- Lung function decline
- Mimics IPF
Chronic Necrotizing Pulmonary Aspergillosis (CNPA / Semi-Invasive)
- Locally invasive
- Borderline IA
- Mild-moderate immune compromise
Clinical
- Chronic cough
- Hemoptysis
- Weight loss
- Fatigue
- Months-years course
- Mimics TB
Diagnosis
- Imaging (CT): cavitations, infiltrates, fibrosis
- Aspergillus IgG positive
- BAL culture sometimes
- Differential from IA, TB, malignancy
Treatment
- Long-term itraconazole or voriconazole (months-years)
- Posaconazole alternative
- TDM essential
- Surgical resection for select (localized cavitary disease, hemoptysis)
- Manage underlying lung disease
- Smoking cessation
6ïžâ£ Resistance + Newer Diagnostics
Azole-Resistant Aspergillus
- TR34/L98H mutation in CYP51A
- First identified Netherlands 2007
- Now widespread Europe, Asia, USA
- Caused by agricultural azole fungicides (mancozeb, others; environmental selection)
- Voriconazole MIC ⥠4 mg/L = resistant
- Other mutations: TR46/Y121F/T289A, others
Treatment of Azole-R Aspergillus
- Liposomal Amphotericin B
- Isavuconazole (variable activity â some isolates)
- Combination (echinocandin + voriconazole + liposomal AmB)
- Olorofim (Phase 3) â promising for resistant Aspergillus
Surveillance
- AST in clinical isolates (especially in high-risk patient)
- Environmental surveillance
- WHO + ECDC monitoring
- Implementation challenges + access issues
Newer Diagnostics
- PCR of BAL (commercial assays emerging)
- Lateral flow device (LFD) for galactomannan â rapid POC
- Plasma Aspergillus PCR in development
- Multi-marker panels combining BG + GM + PCR