Invasive Aspergillosis
Summary
Invasive Aspergillosis (IA) is a life-threatening opportunistic fungal infection caused predominantly by Aspergillus fumigatus. It primarily affects gravely immunocompromised hosts, particularly those with prolonged Neutropenia (e.g., Acute Leukaemia) or Haematopoietic Stem Cell Transplant (HSCT) recipients. The mould is ubiquitous in the environment (spores in air/soil). In vulnerable hosts, inhaled spores germinate into hyphae which invade pulmonary blood vessels (Angioinvasion), causing thrombosis, ischaemic necrosis, and cavitation. Mortality exceeds 50% if untreated. [1,2]
Key Facts
- The Spectrum of Aspergillus:
- Aspergilloma: Fungus ball in old cavity (TB). Non-invasive.
- ABPA: Allergic reaction (Asthma/CF).
- Invasive Aspergillosis: The lethal form discussed here.
- Galactomannan: A polysaccharide component of the Aspergillus cell wall released into blood/fluids during growth. High specificity. It is often detectable before clinical symptoms or radiologic changes.
- Voriconazole: The drug of choice. Superior survival to Amphotericin B, but has unique side effects (visual disturbances, photosensitivity, liver toxicity).
Clinical Pearls
The "Halo Sign": On CT chest, a nodule surrounded by ground-glass opacity. This represents the fungal nodule surrounded by haemorrhage (angioinvasion). While classic, it is transient (early phase only).
The "Air Crescent Sign": A crescent of air appearing within the nodule. This represents recovery (the immune system clearing out the necrotic centre). It is a good sign but appears late (2-3 weeks).
The "Empiric" Rule: In a neutropenic patient with persistent fever despite 5-7 days of appropriate antibiotics (e.g. Tazocin), start antifungal therapy empirically. Do not wait for proof.
Risk Factors
- Prolonged Neutropenia: less than 0.5 x 10^9/L for >10 days (e.g. AML induction chemo).
- HSCT: Especially Allogeneic with Graft vs Host Disease (GVHD).
- Steroids: High dose prolonged use (>0.3mg/kg/day for >3 weeks).
- Solid Organ Transplant: Lung/Heart.
Mechanism
- Inhalation: Conidia (spores) inhaled into alveoli.
- Germination: In absence of alveolar macrophages (steroids) or neutrophils (neutropenia), spores germinate into hyphae.
- Angioinvasion: Hyphae have a predilection for blood vessels. They penetrate vessel walls.
- Thrombosis: Fungal invasion causes clotting -> Pulmonary Infarction (tissue death).
- Dissemination: Haematogenous spread to Brain, Kidneys, Heart.
Pulmonary (85% of cases)
Extra-Pulmonary
- Chest: Often non-specific. Pleural rub may be heard.
- Skin: Occasional necrotic skin nodules (disseminated).
- Eyes: Endophthalmitis?
Imaging
- CT Thorax (HRCT): Essential.
- Early: Halo Sign (Ground glass around nodule).
- Late: Air Crescent Sign (Cavitation).
- Note: CXR is insensitive (often normal).
Microbiology
- Galactomannan Antigen:
- Serum: Sensitivity ~70% in haematology patients.
- BAL (Bronchoalveolar Lavage): Higher sensitivity/specificity. Gold Standard.
- Beta-D-Glucan: Pan-fungal marker. High sensitivity, low specificity (false positives with IVIG, albumin, gauze).
- Culture: Sputum often negative. BAL fluid required.
- PCR: Increasing utility.
Management Algorithm
SUSPECTED ASPERGILLOSIS
(Neutropenia + Refractory Fever
or Positive CT Halo Sign)
↓
START VORICONAZOLE (IV)
(Loading dose: 6mg/kg BD x 1 day)
+ ARRANGE URGENT BAL
↓
┌─────────────┴─────────────┐
RESPONDS / CONFIRMED INTOLERANT / FAILURE
↓ ↓
Continue Voriconazole Switch to LIPOSOMAL
(Switch to PO when AMPHOTERICIN B
stable) or ISAVUCONAZOLE
Min Total: 6-12 wks
1. Antifungal Therapy
- First Line: Voriconazole.
- Loading: Required to reach steady state.
- Monitoring: Trough levels (Target 2-5.5 mg/L). Genetic variability in metabolism (CYP2C19).
- Side Effects: Hepatotoxicity, Visual hallucinations (transient), Photosensitivity (burn easily).
- Second Line / Salvage:
- Liposomal Amphotericin B (AmBisome). Less nephrotoxic than conventional Amphotericin.
- Isavuconazole: Newer azole with fewer side effects and predictable pharmacokinetics (no levels needed).
- Salvage: Caspofungin (Echinocandin).
2. Surgical
- Lobectomy may be required for Massive Haemoptysis (vessel erosion) or localized disease prior to further chemotherapy/transplant.
3. Prophylaxis
- Posaconazole: Often given to AML/MDS patients during chemotherapy to prevent IA.
- Massive Haemoptysis: Major cause of death.
- Cerebral Aspergillosis: High mortality.
- Chronic Pulmonary Aspergillosis (CPA): If host immunity recovers but fungus not cleared.
- Mortality: 30-50% even with treatment (up to 90% in CNS disease).
- Recovery: Depends on recovery of neutrophil count. If marrow doesn't recover, fungus usually wins.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Aspergillosis | IDSA (2016) / ESCMID | Voriconazole is superior to Amphotericin B. CT Chest is primary diagnostic modality. |
| ECIL-6 | Euro Conf Infect Leuk | Galactomannan monitoring recommended. |
Landmark Trials
1. Herbrecht Trial (NEJM 2002)
- Comparison: Voriconazole vs Amphotericin B deoxycholate.
- Findings: Voriconazole had significantly higher survival (71% vs 58%) and fewer severe side effects.
- Impact: Established Voriconazole as global Gold Standard.
What is this infection?
Aspergillus is a common mould found in soil, compost, and air. We breathe it in every day without knowing. In healthy people, the immune system cleans it out instantly. In patients whose immune system is "switched off" by chemotherapy, the mould can grow into the lungs and blood vessels.
Is it dangerous?
Yes, extremely. It can destroy lung tissue and spread to other organs.
What is the treatment?
Strong antifungal drugs, usually Voriconazole. We often have to give these for months.
Can it be cured?
Yes, but it relies on your immune system (white blood cells) recovering from the chemotherapy. The drugs hold the fungus back until your body can finish the fight.
Primary Sources
- Patterson TF, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America (IDSA). Clin Infect Dis. 2016;63:e1-e60.
- Herbrecht R, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408-415. PMID: 12167683.
- Maertens J, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease (SECURE). Lancet. 2016.
Common Exam Questions
- Radiology: "Recent BMT + Fever + Nodule with Halo Sign?"
- Answer: Invasive Aspergillosis.
- Pharmacology: "Side effects of Voriconazole?"
- Answer: Visual disturbances (flashing lights), Liver toxicity, Photosensitivity.
- Microbiology: "Test for Aspergillus?"
- Answer: Galactomannan (or Beta-D-Glucan - less specific).
- Medicine: "Difference between Aspergilloma and Invasive Aspergillosis?"
- Answer: Aspergilloma = Ball in cavity (Non-invasive). Invasive = Tissue invasion (Immunocompromised).
Viva Points
- Isavuconazole: Why use it? Shortens QT (Voriconazole prolongs it). No liver/visual issues. No loading dose. Expensive.
- Air Crescent Sign: Why is it a good prognostic sign? It means the neutrophil count has recovered enough to wall off and cavitate the necrosis ("Neutrophil rescue").
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.