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Invasive Pulmonary Aspergillosis

Pneumonia

Source: IDMP View antifungal coverage →
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Patient
Clinical scenario / source

Annotations only — chart still shows the full chemistry of each drug.

1. Clinical Syndrome

Invasive infection by Aspergillus species, most commonly pulmonary in immunocompromised hosts. Hallmarks: persistent fever despite broad-spectrum antibiotics in neutropenic host; CT chest with halo sign (early) or air-crescent sign (recovery / late); hemoptysis. Diagnostics: serum / BAL galactomannan (BAL more sensitive), 1,3-β-D-glucan, BAL culture and PCR, tissue biopsy with septate hyphae at acute angles.

2. Pathogens

Consider the patient: Prolonged neutropenia (HSCT recipients, induction chemo for AML/MDS), allogeneic HSCT (esp. with severe GVHD on steroids), solid organ transplant (lung transplant highest risk), chronic high-dose corticosteroids, biologics (ibrutinib, ruxolitinib), advanced HIV with neutropenia, ICU patients with severe influenza or severe COVID-19 (CAPA / IAPA).

Consider the case: Galactomannan trends are more useful than single values. CT findings evolve — halo sign early (vascular invasion, hemorrhage), air-crescent sign late (cavitation). Send BAL galactomannan, BDG, fungal culture, PCR. Biopsy if accessible.

Common

    • Aspergillus fumigatus

      Most common species. Watch for environmental azole resistance (TR34/L98H, TR46/Y121F).

3. Empiric Therapy

TierFirst choiceAlternativesDurationComments
Admitted to ward
  • 6 mg/kg q12h × 2 doses → 4 mg/kg q12h · q12h · IV · ≥6–12 weeks (extend per clinical response and imaging)

    FIRST-LINE per IDSA 2016. Switch to PO 200 mg q12h once stable. **Trough 1–5.5 mg/L target — TDM mandatory** at day 5 and during therapy.

  • 200 mg q8h × 6 doses → 200 mg daily · q8h then daily · IV/PO · ≥6–12 weeks

    Non-inferior to voriconazole (SECURE trial). NO TDM required, fewer interactions, less hepatotoxicity. Preferred when transplant drug interactions are a concern.

≥6–12 weeks (extend per imaging response and clinical course; some patients require months–years)Confirmed or probable invasive pulmonary aspergillosis in stable host. Voriconazole or isavuconazole are first-line interchangeable choices (IDSA 2016 / ECIL).
Acute / severe
  • 6 mg/kg q12h × 2 → 4 mg/kg q12h · q12h · IV

    First-line. Add second agent (caspofungin or LiAmB) for refractory disease per CRTI / clinician judgment.

  • 3–5 mg/kg · q24h · IV

    Salvage / azole-refractory / azole-intolerant / pregnancy. Or initial therapy in severely ill / azole-resistance suspected.

  • 200 mg q8h × 6 → 200 mg daily · q8h then daily · IV/PO

    Equivalent to voriconazole; preferred in severe transplant interactions or hepatic concerns.

  • 300 mg q12h × 2 → 300 mg daily · q12h then daily · IV/PO

    Salvage option; delayed-release tablets preferred over suspension.

  • 70 mg load → 50 mg · q24h · IV

    Salvage adjunct; limited monotherapy data.

≥12 weeks; longer based on imaging + immune recoverySevere / refractory invasive aspergillosis, ICU-level care, neutropenia not improving. Combination therapy (voriconazole + echinocandin) considered for refractory; IDSA 2016 recommends mono first-line.

4. Directed Therapy

Voriconazole TDM mandatory — target trough 1–5.5 mg/L at steady-state day 5; sub-therapeutic → treatment failure; supra-therapeutic (>5.5) → visual disturbances, hepatotoxicity, encephalopathy. Re-check after dose adjustments.

Isavuconazole does NOT require TDM (linear PK).

Treatment duration ≥6–12 weeks as a starting point; extend until:

  • Clinical resolution
  • CT imaging showing significant resolution / lesion stability
  • Galactomannan trend toward negative
  • Underlying immunosuppression reduced (ANC recovery, GVHD steroid reduction, transplant immunosuppression weaning)

Many patients require months–years. Consider step-down to oral isavuconazole or posaconazole tablets for prolonged outpatient courses.

Surgical resection considered for:

  • Hemoptysis from cavitary lesion
  • Lesion abutting great vessels / pericardium / spine
  • Persistent focal lesion despite optimal medical therapy
  • Mycetoma in pre-existing cavity
  • Pre-HSCT consolidation if mass present

5. Monitoring

Drug levels (mandatory):

  • Voriconazole trough at day 5; target 1–5.5 mg/L; recheck after dose changes / interacting drug starts
  • Isavuconazole: not required

Toxicity:

  • Voriconazole: LFTs weekly initially; visual disturbances (transient flashes — common; resolves); QTc; periostitis (long-term high-dose); skin cancer with chronic use; encephalopathy at high troughs
  • Isavuconazole: shortened QT (yes, shortened); LFTs
  • Liposomal amphotericin B: BMP daily (Cr, K, Mg); infusion reactions
  • Caspofungin: LFTs

Disease tracking:

  • Galactomannan trend (twice-weekly initially, then weekly) — falling trend supports response
  • CT chest q2 weeks initially, then per response
  • Clinical (fever curve, oxygen requirement, hemoptysis)

Pearls

Voriconazole is first-line; isavuconazole non-inferior (SECURE). Choose isavuconazole when transplant interactions matter or hepatic concerns dominate.

TDM for voriconazole is MANDATORY — trough 1–5.5 mg/L. Sub-therapeutic → failure; supra-therapeutic → toxicity. CYP2C19 polymorphisms cause large inter-patient variability.

Visual disturbances (voriconazole) — flashing lights / color-vision changes; transient, dose-related; usually resolves; not a stop-drug AE.

Treatment duration ≥6–12 weeks; many require months. Step-down to oral azole when stable. Continue until clinical + imaging + immune recovery.

Galactomannan trend > snapshot. Falling trend supports response; rising trend suggests progression.

Surgery for hemoptysis, lesions adjacent to great vessels, refractory focal disease.

Environmental azole resistance (TR34/L98H from agricultural triazole use, esp. Netherlands, India) — emerging concern; consider susceptibility testing in suspected resistant strains or treatment failure.

References