ASPERGILLOSIS 

Definition:
Aspergillosis refers to a spectrum of diseases caused by fungi of the genus Aspergillus, most commonly Aspergillus fumigatus, but also A. flavus, A. niger, A. terreus, and A. nidulans.

These fungi are ubiquitous saprophytes found in soil, decaying vegetation, and indoor air. Infection occurs by inhalation of airborne conidia (spores).

 

CLASSIFICATION OF ASPERGILLOSIS

Form

Host Immunity

Site / Features

1. Allergic bronchopulmonary aspergillosis (ABPA)

Asthma or CF; hypersensitivity reaction

Bronchial

2. Aspergilloma (Fungal ball)

Structurally abnormal lung (cavity, bronchiectasis, TB cavity, etc.)

Intracavitary colonization

3. Chronic pulmonary aspergillosis (CPA)

Mild immunocompromise, prior lung disease

Chronic necrotizing infection

4. Invasive pulmonary aspergillosis (IPA)

Profound immunosuppression (neutropenia, HSCT, transplant, ICU)

Angioinvasive disease

5. Disseminated aspergillosis

Severe immunocompromise

Hematogenous spread to brain, kidney, heart, etc.

6. Cutaneous / sinus / orbital aspergillosis

Local invasion or dissemination

Skin, sinuses, orbits

 

ETIOLOGY & RISK FACTORS

Common species:

  • A. fumigatus (most frequent)
  • A. flavus (sinus/orbital infections)
  • A. terreus (intrinsically resistant to amphotericin B)
  • A. niger (ear infections, aspergilloma)

Predisposing factors:

  • Prolonged neutropenia (ANC < 500/µL)
  • Hematologic malignancies
  • Hematopoietic stem cell or solid organ transplant
  • High-dose corticosteroids
  • Chronic granulomatous disease (CGD)
  • Prolonged ICU stay, mechanical ventilation
  • Influenza or COVID-19 associated pulmonary aspergillosis (IAPA/CAPA)

 

PATHOGENESIS

  1. Inhalation of conidia → alveoli
  2. Macrophages normally kill spores; neutrophils kill hyphae.
  3. In immunocompromised hosts, spores germinate into hyphae, causing:
    • Angioinvasion → thrombosis, infarction, hemorrhage
    • Dissemination to CNS, kidneys, skin, etc.

 

CLINICAL MANIFESTATIONS

1. Invasive Pulmonary Aspergillosis (IPA)

  • Occurs in profoundly immunocompromised or ICU patients.
  • Symptoms: Fever unresponsive to antibiotics, pleuritic chest pain, cough, hemoptysis, dyspnea.
  • Signs: Pulmonary infiltrates, sometimes cavitary or nodular.
  • Complications: Hemoptysis (vessel erosion), dissemination (CNS, skin).

2. Chronic Pulmonary Aspergillosis

  • Occurs in COPD, TB, sarcoidosis.
  • Symptoms: Chronic cough, weight loss, hemoptysis, fatigue.
  • Radiology: Cavitary lesions ± fungal ball; slow progression over months.

3. Aspergilloma

  • Colonization of pre-existing cavity.
  • Symptoms: Recurrent hemoptysis (may be massive), minimal systemic symptoms.
  • CT: Mobile intracavitary mass with an air crescent sign.

4. Allergic Bronchopulmonary Aspergillosis (ABPA)

  • Hypersensitivity to A. fumigatus in asthma or cystic fibrosis.
  • Symptoms: Recurrent wheeze, cough with brown mucus plugs.
  • Lab: ↑ IgE, eosinophilia.
  • Radiology: Central bronchiectasis, fleeting infiltrates.

5. Sinus / Orbital / CNS Aspergillosis

  • Sinus involvement: Facial pain, proptosis, necrotic nasal mucosa.
  • CNS involvement: Brain abscesses (ring-enhancing lesions), meningitis, infarcts.

 

DIAGNOSIS

1. Radiologic Findings (CT Chest)

Finding

Description

Significance

Halo sign

Ground-glass opacity around nodule

Early angioinvasion

Air crescent sign

Cavitation with crescent of air

Late, neutrophil recovery

Reverse halo sign

Central ground-glass with peripheral consolidation

Seen in CAPA/IAPA

2. Microbiological Diagnosis

Test

Specimen

Interpretation

Microscopy (KOH / Calcofluor)

BAL, sputum

Septate, acute-angle branching hyphae

Culture

BAL, tissue biopsy

Confirms genus/species

Histopathology

Lung or sinus biopsy

Tissue invasion confirms proven disease

Galactomannan (GM) antigen

Serum or BAL

Positive ≥0.5 in serum, ≥1.0 in BAL

β-D-glucan (BDG)

Serum

Nonspecific fungal marker (positive in Aspergillus, Candida, etc.)

PCR

Blood or BAL

High sensitivity but not standardized

Diagnostic criteria (EORTC/MSGERC):

  • Proven: Histopathologic or cultural evidence of tissue invasion.
  • Probable: Compatible host factor + clinical features + mycologic evidence.
  • Possible: Host + clinical but no mycologic evidence.

 

SPECIAL FORMS

COVID-Associated Pulmonary Aspergillosis (CAPA)

  • Occurs in severe COVID-19 on steroids or mechanical ventilation.
  • Diagnosis: BAL GM ≥1.0, CT with nodules or cavitation.
  • Often overlaps with bacterial co-infection.

Influenza-Associated Pulmonary Aspergillosis (IAPA)

  • Similar to CAPA, occurs within 3–7 days of severe influenza.
  • Poor prognosis.

 

TREATMENT

1. First-line therapy

Drug

 

Notes

Voriconazole

 

First-line (IDSA 2016). Monitor trough 1–5 µg/mL.

Isavuconazole

 

Alternative first-line; less QT prolongation.

Liposomal Amphotericin B

 

Alternative if azole resistance/intolerance.

2. Salvage therapy

  • Echinocandins (caspofungin, micafungin): For salvage or combination.
  • Combination therapy (voriconazole + echinocandin): For refractory or disseminated disease.

3. Duration

  • At least 6–12 weeks; guided by clinical, radiologic, and immunologic recovery.

4. Surgical therapy

  • Indicated for localized disease (e.g., aspergilloma with massive hemoptysis, sinus aspergillosis).

5. ABPA

Goal

Therapy

Reduce inflammation

Oral corticosteroids (prednisolone  )

Reduce fungal burden

Itraconazole or voriconazole 

Monitor

Total IgE (should fall by ≥35% in 6 weeks)

 

PREVENTION & PROPHYLAXIS

  • HEPA-filtered rooms for neutropenic patients.
  • Prophylaxis:
    • Posaconazole or voriconazole in HSCT or AML induction chemotherapy.
  • Avoid exposure to construction dust, potted plants.

 

PROGNOSIS

Form

Mortality

Invasive pulmonary aspergillosis

30–60%

Disseminated disease

>80%

ABPA / aspergilloma

Good with treatment

 

KEY DIFFERENTIALS

Disease

Key Differences

Mucormycosis

Broad, ribbon-like, right-angle hyphae; resistant to voriconazole

Nocardiosis

Filamentous bacteria; weakly acid-fast; treat with TMP-SMX

Candidiasis

Yeast forms; non-septate; different risk profile

 

CRITICAL CARE PEARLS

  • In ICU patients with CAPA/IAPA, suspicion should rise with new cavitary lesions or hemoptysis despite broad-spectrum antibiotics.
  • Serum GM may be negative in non-neutropenic ICU patients — BAL GM is more sensitive.
  • Empiric antifungal therapy (voriconazole) may be life-saving in high-risk ventilated patients with compatible CT findings.

 

REFERENCES

  1. Harrison’s Principles of Internal Medicine, 21st Edition.
  2. IDSA Clinical Practice Guidelines for Aspergillosis (2016).
  3. Ullmann AJ et al., Clin Infect Dis. 2018;66(10):1618–1621.
  4. BJA Education 2021;21(8):286–294.
  5. Critical Care Medicine 2021;49(3):e279–e289 (CAPA consensus).
  6. EMCrit Project: Invasive Aspergillosis, 2024 update.