Aspergillosis¶
Chapter 223 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Fungal · Chapter 223
Key Clinical Points¶
- Aspergillosis encompasses disease entities caused by ~50 pathogenic Aspergillus species.
- Only thermotolerant species (e.g., A. fumigatus) cause invasive infection; A. fumigatus accounts for >95% of chronic cases and is the primary driver of allergic syndromes.
- The 'halo sign' on thoracic CT (ground-glass nodule with surrounding consolidation) is a critical prognostic marker in neutropenic patients (7-day window).
- Morphology: Hyaline, septate mold with 45° branching hyphae; definitive diagnosis requires sterile site culture or histology + PCR.
- Voriconazole, posaconazole, and isavuconazole are first-line for invasive disease; Amphotericin B lacks activity against A. terreus and A. nidulans.
- Chronic pulmonary aspergillosis (CPA) requires 12+ months of therapy; corticosteroids increase mortality by 240% in these cases.
- Allergic Bronchopulmonary Aspergillosis (ABPA) is characterized by IgE >1000 IU/mL and Aspergillus-specific IgE.
- HEPA filtration reduces infection risk in high-risk settings.
- Chronic granulomatous sinusitis (often A. flavus) is rare outside the Middle East and India.
1. DEFINITION & OVERVIEW¶
• Scope: Aspergillosis encompasses disease entities caused by ~50 Aspergillus species, including invasive, chronic, and allergic forms. • Pathogenicity: Only thermotolerant species (e.g., A. fumigatus) cause invasive infection; other species typically trigger allergic syndromes.
• Species Characteristics: • A. fumigatus: Most common in invasive, chronic disease, and allergic syndromes. • A. flavus: Predominant in sinus/cutaneous infections and keratitis. • A. niger: Colonizes respiratory tract; causes external otitis. • A. terreus: Invasive only; associated with poor prognosis. • A. nidulans: Rare invasive cases, specifically in CGD patients.
• Pathogen Morphology: • Structure: Hyaline, septate mold. • Branching: 45° branching hyphae. • Reproduction: Produces conidia on stalks above mycelial growth. • Presence: Ubiquitous in air, water, and organic matter.
2. EPIDEMIOLOGY¶
• Exposure: Daily exposure to 10^4–10^6 conidia is common in high-risk environments. • Global Burden: • Invasive: ~2.1 million cases; mortality >95% without treatment. • Chronic: 6.1 million cases; 50% mortality without therapy. • Allergic: 11.7 million cases; <1% mortality.
• Risk Factors: • Immune Status: Neutropenia, glucocorticoid use, CGD, and NK cell deficiency. • Comorbidities: Chronic lung disease (TB, COPD, bronchiectasis), severe liver disease. • Medications: Ibrutinib or infliximab use.
Table 223-1: Disease Frequency and Diagnostic Sensitivity¶
• Invasive: Incidence 27.6/100,000; Mortality ~100%; Respiratory Diagnosis (Antigen sqrt{surd}, PCR sqrt{surd}); Blood Diagnosis (β-D-Glucan sqrt{surd}, IgG sqrt{surd}). • Chronic: Incidence 23.6/100,000; Mortality ~50%. • Allergic: Incidence ?; Mortality <1%.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Immune Determinants: Genetic susceptibility and immune status dictate disease manifestation. • Chronic pulmonary aspergillosis: Characterized by suboptimal T1-like inflammation. • ABPA: Driven by T2 immunity with IgE >1000 IU/mL. • Corticosteroid Impact: Accelerates disease progression in ABPA; increases mortality by 240% in chronic cases.
• Pathogenesis Cascade: • Environmental exposure → sensitization → COPD exacerbations. • Incubation period: 2–90 days post-exposure. • Nosocomial risk: Outbreaks linked to construction or contaminated air.
4. CLINICAL FEATURES¶
• Invasive Pulmonary Aspergillosis: • Symptoms: Fever, cough, hemoptysis. • Radiology: Halo sign (ground-glass nodule with surrounding consolidation) within a 7-day window. • Diagnostics: Tracheobronchial lavage antigen detection is critical in ICU patients.
• Chronic Pulmonary Aspergillosis: • Presentation: Expanding pulmonary cavities, fatigue, weight loss. • Serology: 90% IgG antibody positivity. • Complications: Hemoptysis (major complication) → progresses to fibrosing lung disease.
• Allergic Bronchopulmonary Aspergillosis (ABPA): • Presentation: Recurrent bronchial obstruction with mucus plugs, eosinophilia. • Serology: IgE >1000 IU/mL and Aspergillus-specific IgE. • Imaging: Characteristic bronchiectasis and hyperattenuated mucus on CT.
Table 223-2: Major Manifestations of Aspergillosis¶
• Lung: • Invasive: Angioinvasive (in neutropenia), nonangioinvasive, granulomatous. • Chronic: Cavitary, fibrosing, bronchitis, Aspergillus nodule. • Saprophytic: Aspergilloma (single), airway colonization. • Allergic: ABPA, severe asthma with fungal sensitization, hypersensitivity pneumonitis.
• Sinus: • Invasive: Acute invasive. • Chronic: Chronic invasive, chronic granulomatous. • Saprophytic: Maxillary fungal ball.
• Brain: • Invasive: Abscess, hemorrhagic infarction, meningitis; Acute disseminated, locally invasive (trauma, burns, IV access). • Chronic: Granulomatous, meningitis.
• Skin: • Saprophytic: External otitis, onychomycosis.
• Heart: • Invasive: Endocarditis (native or prosthetic), pericarditis.
• Eye: • Invasive: Keratitis, endophthalmitis.
6. INVESTIGATIONS & DIAGNOSIS¶
- Radiologic Imaging: • Halo Sign: Ground-glass nodule with surrounding consolidation; marker of early invasive aspergillosis in neutropenic patients (7-day window). • Fungal Ball: Hyperattenuating on CT (T2 hypointense); identifies saprophytic growth.
- Antigen & Molecular Testing: • Galactomannan/Aspergillus Antigen: Serum is sensitive; respiratory samples are critical in ICU patients. • Real-time PCR: Faster and more sensitive than culture.
- Definitive Diagnosis: • Requires sterile site culture or histology + molecular confirmation.
7. MANAGEMENT & TREATMENT¶
- Pharmacologic Selection: • First-line (Invasive): Voriconazole, posaconazole, or isavuconazole. • Second-line: Caspofungin or micafungin. • Specific Exclusion: Amphotericin B is ineffective against A. terreus and A. nidulans.
- Treatment Duration & Monitoring: • Chronic Pulmonary Aspergillosis: Requires 12+ months of therapy. • Corticosteroid Management: Avoid in ABPA (accelerates progression) and chronic cases (increases mortality by 240%).
8. PROGNOSIS & COMPLICATIONS¶
• Invasive Forms: >95% mortality without treatment. • Chronic Disease: Progresses to fibrosing lung disease. • Disseminated Aspergillosis: Often presents with negative blood cultures; requires localization to brain or skin.
10. KEY PEARLS & CLINICAL TRAPS¶
• ABPA vs. Allergic Fungal Sinusitis: Differentiate by IgE levels (>1000 IU/mL) and bronchial thickening. • Fungal Ball vs. Invasive Sinusitis: Fungal ball shows no tissue invasion; invasive sinus shows tissue involvement. • Halo Sign Timing: Represents a 7-day window for early invasive aspergillosis in neutropenic patients. • Species Resistance: A. terreus and A. nidulans are resistant to Amphotericin B. • Prevention: HEPA filtration reduces infection risk in high-risk settings. • Geographic Note: Chronic granulomatous sinusitis (often A. flavus) is rare outside the Middle East and India.
Reference Tables¶
TABLE 223-1 Disease Frequency and Diagnostic Sensitivity for Different Manifestations of Aspergillosis PARAMETER…¶
Harrison's 22e, p.1713
| 223 | Aspergillosis David W. Denning |
|---|---|
TABLE 223-1 Disease Frequency and Diagnostic Sensitivity for Different Manifestations of Aspergillosis
| PARAMETER | TYPE OF DISEASE | ||
|---|---|---|---|
| INVASIVE | CHRONIC | ALLERGIC | |
| Incidence/100,000a | 27.6 | 23.6 | ?b |
| — | 55.4 | ||
| Global burdena | ~2,116,000 | ~6,141,000 | ~11,690,000 |
| ~100% | ~50% | ||
| Respiratory Diagnostic Sensitivityd | |||
| Culturee | √ | √-√√e | √-√√e |
| √ | √ | ||
| Antigen | √√√ | √√ | ? |
| √√ | √√ | ||
| Blood Diagnostic Sensitivityd | |||
| Culture | x | x | x |
| √√ | √ | ||
| β-D-Glucan | √√ | √ | ? |
| √√ | x | ||
| IgG antibodyf | √√f | √√√ | √√√ |
| x | √√ |
TABLE 223-2 Major Manifestations of Aspergillosis ORGAN Lung Sinus Brain Skin Heart Eye¶
Harrison's 22e, p.1714
| ORGAN | TYPE OF DISEASE | |||
|---|---|---|---|---|
| INVASIVE (ACUTE AND SUBACUTE) | CHRONIC | SAPROPHYTIC | ALLERGIC | |
| Lung | Angioinvasive (in neutropenia), nonangioinvasive, granulomatous |
Chronic cavitary, chronic fibrosing, bronchitis, Aspergillus nodule |
Aspergilloma (single), airway colonization |
Allergic bronchopulmonary, severe asthma with fungal sensitization, hypersensitivity pneumonitis |
| Acute invasive | Chronic invasive, chronic granulomatous |
Maxillary fungal ball | ||
| Brain | Abscess, hemorrhagic infarction, meningitis |
Granulomatous, meningitis | None | None |
| Acute disseminated, locally invasive (trauma, burns, IV access) |
External otitis, onychomycosis | None | ||
| Heart | Endocarditis (native or prosthetic), pericarditis |
None | None | None |
| Keratitis, endophthalmitis | None | None |