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id.invasive-aspergillosis.core.v1PRODUCTION
id.invasive-aspergillosis.core.v1

Invasive aspergillosis

infectious_diseaseacutesubacuteadult
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Encounter flow

12/12 authored

Canonical 12-phase frame with authored status for this dossier.

Current phase

Frame

Detailed

Adult invasive pulmonary / disseminated aspergillosis (IDSA 2016). ABPA / chronic pulmonary aspergillosis covered by sibling engines

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Patient inputs (10)

Posaconazole / isavuconazole prophylaxis affects empiric switch (IDSA 2016 / ECIL-6 2017)

Diagnosis is host-defined (EORTC/MSGERC 2020): prolonged neutropenia, HCT, SOT, high-dose steroids, biologics, advanced HIV

Halo / reverse-halo / air-crescent / nodules — EORTC/MSGERC 2020 imaging criteria; IDSA 2016 Class I

Voriconazole / isavuconazole hepatotoxicity monitoring (IDSA 2016 / ESCMID 2018)

Hypoxia drives ICU triage (IDSA 2016)

Voriconazole IV cyclodextrin vehicle accumulates if eGFR <50 (IDSA 2016); lipid AmB nephrotoxicity monitoring

Voriconazole has wide-ranging CYP2C19/3A4-mediated DDIs — cyclosporine, tacrolimus, sirolimus, warfarin (IDSA 2016 / ESCMID 2018)

EORTC/MSGERC 2020 mycology criterion; serial trend for treatment response (IDSA 2016)

Higher sensitivity than serum in non-neutropenic hosts (IDSA 2016 — BAL GM index ≥1.0)

Adjunct — positive in many invasive fungal infections; non-specific (IDSA 2016)

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (10)

10 need judgement
  • informationallife_threateningcns_invasive_aspergillosis (IDSA 2024)
    Brain lesion / meningitis / focal deficit with positive GM or biopsy (IDSA 2016)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningmassive_hemoptysis
    Hemoptysis from cavitary IA — especially angioinvasive disease (IDSA 2016)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningcapa_or_iapa_features
    COVID-19 or severe influenza on ICU corticosteroids + new pulmonary infiltrate + BAL galactomannan ≥ 1.0 OR serum galactomannan ≥ 0.5 OR Aspergillus on BAL culture/PCR (Verweij Lancet ID 2020 CAPA criteria; Schauwvlieghe Lancet RM 2018 IAPA)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningcns_aspergillosis
    CNS imaging (MRI brain) showing ring-enhancing mass, abscess, or compatible lesion + biopsy/BAL or compatible mycology + host criterion (IDSA 2016)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningdisseminated_aspergillosis_with_immunocompromise
    Multi-organ involvement (≥ 2 non-contiguous sites — e.g., pulmonary + CNS + skin / liver / spleen / kidney) on imaging or biopsy in immunocompromised host (HSCT, SOT, prolonged neutropenia, high-dose steroids, biologics) (IDSA 2016 — proven/probable disseminated IA)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverebreakthrough_on_mold_prophylaxis
    IA developing on posaconazole or isavuconazole prophylaxis (ECIL-6 2017)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverepersistent_neutropenia
    ANC <500 not recovering with cytokine support (IDSA 2016)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereazole_resistance_suspected
    Environmental azole-resistance exposure (agriculture, paint, compost) + treatment failure on appropriate voriconazole / isavuconazole dosing with confirmed TDM in range, OR Aspergillus fumigatus isolate with elevated MIC, OR known TR34/L98H or TR46/Y121F/T289A mutation (IDSA 2016; Lestrade CID 2019; WHO 2022 fungal priority pathogens)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatetdm_outside_therapeutic_range
    Voriconazole trough <1 (subtherapeutic) or >5 ug/mL (toxicity) — IDSA 2016 / ESCMID 2018
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderateqtc_prolongation_voriconazole
    QTc >500 ms or >60 ms increase from baseline on voriconazole (ESCMID 2018)
    Trigger could not be auto-evaluated — needs clinician judgement.

Workflow calculators

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Recommended regimen

Invasive aspergillosis — voriconazole / isavuconazole first-line (IDSA 2024)
axis: invasive_aspergillosis_initial_treatment
Selected axis "Invasive aspergillosis — voriconazole / isavuconazole first-line (IDSA 2024)" by default fallback (first axis)
  • voriconazole
    first line
    azole
    6 mg/kg IV q12h × 2 doses (loading) then 4 mg/kg IV q12h; PO 200-300 mg q12h once stable • IV→PO • q12h
    triggers: proven_or_probable_invasive_aspergillosis
    Herbrecht NEJM 2002 — superior to AmB; CYP-mediated DDIs; TDM target trough 1-5 µg/mL
    rxcui 121243
  • isavuconazole
    first line
    azole
    200 mg IV/PO q8h × 6 doses (loading) then 200 mg daily • IV/PO • daily after load
    triggers: proven_or_probable_invasive_aspergillosis, voriconazole_intolerant_or_DDI
    SECURE Lancet 2016 — non-inferior to voriconazole, fewer DDIs, no QTc prolongation, no photosensitivity
    rxcui 1720882
  • posaconazole
    second line
    azole
    300 mg IV/PO BID × 1 d then 300 mg daily • IV/PO • daily after load
    triggers: salvage, prophylaxis_step_up, voriconazole_isavuconazole_alternative
    Approved alternative; best as DR tablets; TDM target ≥1 µg/mL (IDSA 2024)
    rxcui 282446
  • liposomal_amphotericin_B
    rescue
    polyene
    3-5 mg/kg IV daily • IV • daily
    triggers: azole_intolerant, pregnant, mucormycosis_concern_co_treatment
    IDSA 2016 alternative for refractory or intolerance; nephrotoxicity, hypokalemia, hypomagnesemia monitoring
    rxcui 236594
  • caspofungin
    add on
    echinocandin
    70 mg IV load then 50 mg/d • IV • daily
    triggers: salvage_combination_with_voriconazole
    Marr Ann Intern Med 2015 — combo with voriconazole considered for severe disease; not monotherapy
    rxcui 140108

outpatient playbook — drug actions (5)

  1. 1. PO voriconazole (continuation)
    rxcui 121243
    200-300 mg PO q12h (TDM-adjusted; target trough 1-5 µg/mL or 2-5 µg/mL for CNS) • PO • q12h
    trigger: Patient stable + tolerating PO + GM trending down + repeat HRCT showing improvement + completing total ≥ 6-12 wk + through immunosuppression duration
    IDSA 2016 Patterson — PO voriconazole has good bioavailability; TDM-guided dosing achieves therapeutic exposure; preferred OPAT modality vs IV
  2. 2. PO isavuconazole (continuation alternative)
    rxcui 1720882
    200 mg PO daily (no further load after IV→PO transition) • PO • daily
    trigger: Voriconazole-intolerant (hepatotoxicity, photosensitivity, neurotoxicity, QTc prolongation) OR baseline CYP-DDI burden OR preference for once-daily dosing + no TDM requirement
    SECURE Maertens Lancet 2016 — non-inferior to voriconazole, fewer DDIs, no QTc prolongation, no photosensitivity; preferred for prolonged outpatient therapy
  3. 3. PO posaconazole (continuation, salvage)
    rxcui 282446
    300 mg PO daily (DR tablets); target TDM trough ≥ 1 µg/mL • PO • daily
    trigger: Voriconazole + isavuconazole intolerant OR salvage after voriconazole/isavuconazole failure OR secondary prophylaxis post-IA in high-risk HSCT
    IDSA 2016 alternative; ECIL-6 2017 first-line for secondary prophylaxis in high-risk HSCT
  4. 4. OPAT L-AmB (refractory / azole-intolerant)
    rxcui 236594
    3-5 mg/kg IV daily (3 mg/kg most common for continuation; up to 5 mg/kg for CNS or refractory) • IV • daily
    trigger: Refractory IA on azole OR azole-intolerant (severe hepatotoxicity, QTc prolongation, neurotoxicity) OR continued mucormycosis differential — OPAT IV for prolonged continuation
    IDSA 2016 Patterson — L-AmB alternative for prolonged outpatient continuation; OPAT delivery with weekly creatinine + K + Mg monitoring
  5. 5. Secondary prophylaxis (post-engraftment HSCT or ongoing immunosuppression)
    Posaconazole 300 mg PO daily (DR tablet) OR isavuconazole 200 mg PO daily OR voriconazole 200 mg PO q12h with TDM • PO • daily
    trigger: Post-IA HSCT recipient + ongoing GVHD with high-dose steroids OR continued immunosuppression OR SOT with high-risk net state of immunosuppression
    ECIL-6 2017 — secondary prophylaxis through immunosuppression duration prevents relapse; posaconazole preferred per ECIL-6 evidence

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: CT chest halo or air-crescent sign in immunocompromised host (EORTC/MSGERC 2020 imaging criterion); Serum / BAL galactomannan elevated (EORTC/MSGERC 2020 mycology criterion); Persistent neutropenic fever despite broad antibacterials (IDSA 2016 / ECIL-6 2017).

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Invasive aspergillosis** (id.invasive-aspergillosis.core.v1).
Phenotype framing: Mucormycosis — reverse halo more typical, GM negative (ESCMID 2018); Pneumocystis; bacterial pneumonia; viral pneumonitis; tumor
Scope: Adult invasive pulmonary / disseminated aspergillosis (IDSA 2016). ABPA / chronic pulmonary aspergillosis covered by sibling engines

No severity triggers fired against current inputs.

Plan

Regimen axis: **Invasive aspergillosis — voriconazole / isavuconazole first-line (IDSA 2024)**.
1. voriconazole 6 mg/kg IV q12h × 2 doses (loading) then 4 mg/kg IV q12h; PO 200-300 mg q12h once stable IV→PO q12h (azole, first line) — Herbrecht NEJM 2002 — superior to AmB; CYP-mediated DDIs; TDM target trough 1-5 µg/mL
2. isavuconazole 200 mg IV/PO q8h × 6 doses (loading) then 200 mg daily IV/PO daily after load (azole, first line) — SECURE Lancet 2016 — non-inferior to voriconazole, fewer DDIs, no QTc prolongation, no photosensitivity
3. posaconazole 300 mg IV/PO BID × 1 d then 300 mg daily IV/PO daily after load (azole, second line) — Approved alternative; best as DR tablets; TDM target ≥1 µg/mL (IDSA 2024)
4. liposomal_amphotericin_B 3-5 mg/kg IV daily IV daily (polyene, rescue) — IDSA 2016 alternative for refractory or intolerance; nephrotoxicity, hypokalemia, hypomagnesemia monitoring
5. caspofungin 70 mg IV load then 50 mg/d IV daily (echinocandin, add on) — Marr Ann Intern Med 2015 — combo with voriconazole considered for severe disease; not monotherapy

Setting playbook (outpatient) — Complete extended-duration mold-active therapy (≥ 6-12 wk and through immunosuppression duration) via OPAT-coordinated PO voriconazole or isavuconazole (preferred), IV L-AmB OPAT only when refractory; multidisciplinary review with primary team (transplant / heme-onc / rheumatology) for immunosuppression reduction; serial galactomannan trends + repeat HRCT for response; secondary mold-active prophylaxis through immunosuppression duration; long-term ID follow-up + photosensitivity / SCC surveillance on voriconazole; vaccination review per ACIP 2024 (IDSA 2016 Patterson; ECIL-6 2017; ESCMID 2018 Ullmann)
6. PO voriconazole (continuation) 200-300 mg PO q12h (TDM-adjusted; target trough 1-5 µg/mL or 2-5 µg/mL for CNS) PO q12h — Patient stable + tolerating PO + GM trending down + repeat HRCT showing improvement + completing total ≥ 6-12 wk + through immunosuppression duration (IDSA 2016 Patterson — PO voriconazole has good bioavailability; TDM-guided dosing achieves therapeutic exposure; preferred OPAT modality vs IV)
7. PO isavuconazole (continuation alternative) 200 mg PO daily (no further load after IV→PO transition) PO daily — Voriconazole-intolerant (hepatotoxicity, photosensitivity, neurotoxicity, QTc prolongation) OR baseline CYP-DDI burden OR preference for once-daily dosing + no TDM requirement (SECURE Maertens Lancet 2016 — non-inferior to voriconazole, fewer DDIs, no QTc prolongation, no photosensitivity; preferred for prolonged outpatient therapy)
8. PO posaconazole (continuation, salvage) 300 mg PO daily (DR tablets); target TDM trough ≥ 1 µg/mL PO daily — Voriconazole + isavuconazole intolerant OR salvage after voriconazole/isavuconazole failure OR secondary prophylaxis post-IA in high-risk HSCT (IDSA 2016 alternative; ECIL-6 2017 first-line for secondary prophylaxis in high-risk HSCT)
9. OPAT L-AmB (refractory / azole-intolerant) 3-5 mg/kg IV daily (3 mg/kg most common for continuation; up to 5 mg/kg for CNS or refractory) IV daily — Refractory IA on azole OR azole-intolerant (severe hepatotoxicity, QTc prolongation, neurotoxicity) OR continued mucormycosis differential — OPAT IV for prolonged continuation (IDSA 2016 Patterson — L-AmB alternative for prolonged outpatient continuation; OPAT delivery with weekly creatinine + K + Mg monitoring)
10. Secondary prophylaxis (post-engraftment HSCT or ongoing immunosuppression) Posaconazole 300 mg PO daily (DR tablet) OR isavuconazole 200 mg PO daily OR voriconazole 200 mg PO q12h with TDM PO daily — Post-IA HSCT recipient + ongoing GVHD with high-dose steroids OR continued immunosuppression OR SOT with high-risk net state of immunosuppression (ECIL-6 2017 — secondary prophylaxis through immunosuppression duration prevents relapse; posaconazole preferred per ECIL-6 evidence)

Non-pharmacologic actions:
- Line management plan: PICC removed before discharge if completing PO step-down; PICC continued for OPAT if IV-completion required (L-AmB) (Mermel IDSA CRBSI 2009)
- OPAT coordination with home infusion + ID clinic visit at week 1 + week 2 + monthly thereafter (Norris IDSA OPAT 2018)
- Immunosuppression coordination (transplant nephrology / heme-onc / rheumatology) — taper / hold / adjust per host and ongoing IA activity (IDSA 2016; ECIL-6 2017)
- Photosensitivity counselling if on voriconazole — broad-spectrum sunscreen, sun-protective clothing, avoid prolonged sun exposure; annual dermatology surveillance for cutaneous SCC if > 6 months voriconazole therapy (IDSA 2016)
- Patient / family education: signs of recurrence (new fever, hemoptysis, new respiratory symptoms, neurologic symptoms, sinus pain / visual changes), when to call OPAT / ID, when to return to ED (IDSA 2016)
- Vaccination administration if due: PCV20, influenza, COVID-19, herpes zoster (recombinant only — Shingrix is non-live), avoid live vaccines if transplant / biologic recipient (ACIP 2024)
- Advance-care planning / goals-of-care discussion if not addressed during admission (especially for high-mortality survivors and refractory disease) (IDSA 2016)
- Environmental risk reduction counselling — avoid construction sites, compost / mulch, gardening with soil, HEPA-filter home air if severely immunocompromised (IDSA 2016 / ECIL-6 2017)

AVOID / contraindication checks:
- Voriconazole CYP3A4 DDI cyclosporine tacrolimus sirolimus warfarin (IDSA 2024)
- Voriconazole TDM target 1 to 5 (IDSA 2024)
- Voriconazole photosensitivity SCC counsel (IDSA 2024)
- Voriconazole QTc baseline and K Mg correct (IDSA 2024)
- Isavuconazole no cyclodextrin safer renal (IDSA 2024)
- Amphotericin monitor creatinine K Mg (IDSA 2024)

Monitoring

Regimen monitoring:
- voriconazole TDM steady state day 5-7 then weekly (IDSA 2024)
- LFT weekly x4 then monthly (IDSA 2024)
- galactomannan twice weekly during induction (IDSA 2024)
- HRCT at 2-4 weeks for response (IDSA 2024)
- minimum duration 6-12 weeks through neutrophil recovery (IDSA 2024)

Setting (outpatient) monitoring:
- Weekly clinical + lab follow-up during induction phase (first 4-6 wk): CBC, BMP (renal trend for L-AmB), LFT (azole hepatotoxicity), voriconazole trough TDM (target 1-5 µg/mL; 2-5 µg/mL for CNS) (IDSA 2016)
- Bi-weekly to monthly clinical + lab during continuation phase: CBC, BMP, LFT, GM trend (IDSA 2016)
- Repeat HRCT chest at 4-6 wk + end-of-therapy for response assessment (IDSA 2016)
- Serial serum galactomannan: weekly to bi-weekly during induction, bi-weekly to monthly during continuation — downward trend confirms response (IDSA 2016)
- CYP-substrate drug-level monitoring: tacrolimus / cyclosporine / sirolimus / warfarin (INR) — q week to q 2 weeks during continuation (IDSA 2016; ESCMID 2018)
- Annual dermatology surveillance if voriconazole > 6 months (cutaneous SCC risk) (IDSA 2016)
- Recurrence surveillance: new fever / hemoptysis / cough / pleuritic chest pain / neurologic symptoms / sinus or facial pain / visual changes → return to ED + repeat HRCT + GM + clinical evaluation (IDSA 2016)

Follow-up plan: Step-down to oral voriconazole / isavuconazole (IDSA 2016); long-term secondary prophylaxis through immunosuppression duration (ECIL-6 2017); counsel photosensitivity / SCC risk on voriconazole (IDSA 2016)
- Close-out criterion: long-term mold-active plan documented

Monitoring phase: Voriconazole TDM steady-state day 5-7 (IDSA 2016), weekly LFT x 4 then monthly (ESCMID 2018), twice-weekly galactomannan trend during induction (IDSA 2016); repeat HRCT q1-2 wk

Disposition

Current setting: outpatient — Complete extended-duration mold-active therapy (≥ 6-12 wk and through immunosuppression duration) via OPAT-coordinated PO voriconazole or isavuconazole (preferred), IV L-AmB OPAT only when refractory; multidisciplinary review with primary team (transplant / heme-onc / rheumatology) for immunosuppression reduction; serial galactomannan trends + repeat HRCT for response; secondary mold-active prophylaxis through immunosuppression duration; long-term ID follow-up + photosensitivity / SCC surveillance on voriconazole; vaccination review per ACIP 2024 (IDSA 2016 Patterson; ECIL-6 2017; ESCMID 2018 Ullmann)

Disposition criteria:
- Completion: total duration met (≥ 6-12 wk for uncomplicated IPA; ≥ 6 months for CNS; longer if persistent immunosuppression) + clinical resolution + GM negative or stable low + HRCT improvement / stability + ophthalmologic / neurologic / sinus follow-up clear → completion of OPAT, transition to secondary prophylaxis if ongoing immunosuppression, return to standard primary care + relevant specialty (ID for chronic source; heme-onc / transplant for ongoing immunosuppression) (IDSA 2016; ECIL-6 2017)
- Discharge from IA-specific surveillance: no recurrence at 6 mo post-completion + immunosuppression stable + secondary prophylaxis appropriate to ongoing host risk + vaccinations up to date (IDSA 2016; ECIL-6 2017)

Escalation triggers (move to higher acuity):
- New fever / hemoptysis / new respiratory symptoms during OPAT → return to ED for recurrent or progressive IA workup + repeat HRCT + GM + bronchoscopy if accessible (IDSA 2016)
- New neurologic symptoms (focal deficit, headache, altered MS, seizure) → emergent MRI brain + ID/neurosurgery consult; consider CNS aspergillosis dissemination (IDSA 2016)
- New sinus / facial / orbital pain / visual changes → emergent ENT + sinus CT/MRI; differential vs mucormycosis especially if reverse-halo (ESCMID 2018)
- Azole hepatotoxicity (AST/ALT > 5× ULN) → hold azole + switch to alternate azole or L-AmB; hepatology consult if severe (IDSA 2016)
- L-AmB nephrotoxicity (creatinine ≥ 1.5× baseline) → reduce dose / extend interval / switch back to PO azole if feasible (IDSA 2016)
- Drug-interaction event (tacrolimus trough > 15, INR > 5, rhabdomyolysis on statin) → adjust per DDI rules + safety consult (DailyMed labels)
- Voriconazole TDM out of range (trough < 1 or > 5 µg/mL) → dose adjustment + repeat TDM 5-7 d after change + consider CYP2C19 genotype if unexplained subtherapeutic (IDSA 2016; ESCMID 2018)
- GM trend rising or HRCT progression at 2-4 wk → reassess for azole resistance + adherence + drug levels + switch to L-AmB or combination (IDSA 2016)

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Brain lesion / meningitis / focal deficit with positive GM or biopsy (IDSA 2016)
- [LIFE_THREATENING] Hemoptysis from cavitary IA — especially angioinvasive disease (IDSA 2016)
- [LIFE_THREATENING] COVID-19 or severe influenza on ICU corticosteroids + new pulmonary infiltrate + BAL galactomannan ≥ 1.0 OR serum galactomannan ≥ 0.5 OR Aspergillus on BAL culture/PCR (Verweij Lancet ID 2020 CAPA criteria; Schauwvlieghe Lancet RM 2018 IAPA)

Citations

- IDSA 2016 Aspergillosis Guideline (Patterson et al, CID) + ESCMID/ECMM/ERS 2018 (Ullmann) + ECIL-6 2017 + EORTC/MSGERC 2020 definitions + Verweij Lancet ID 2020 CAPA criteria + Schauwvlieghe Lancet RM 2018 IAPA [PMID:27365388](https://pubmed.ncbi.nlm.nih.gov/27365388/)
- Cited evidence (PMID 12167683) [PMID:12167683](https://pubmed.ncbi.nlm.nih.gov/12167683/)
- Cited evidence (PMID 26684607) [PMID:26684607](https://pubmed.ncbi.nlm.nih.gov/26684607/)
- Cited evidence (PMID 33333012) [PMID:33333012](https://pubmed.ncbi.nlm.nih.gov/33333012/)
- Cited evidence (PMID 30076119) [PMID:30076119](https://pubmed.ncbi.nlm.nih.gov/30076119/)

Last reconciled with current guidelines: 2026-05-22.
References
  • IDSA 2016 Aspergillosis Guideline (Patterson et al, CID) + ESCMID/ECMM/ERS 2018 (Ullmann) + ECIL-6 2017 + EORTC/MSGERC 2020 definitions + Verweij Lancet ID 2020 CAPA criteria + Schauwvlieghe Lancet RM 2018 IAPA — PMID:27365388
  • Cited evidence (PMID 12167683) — PMID:12167683
  • Cited evidence (PMID 26684607) — PMID:26684607
  • Cited evidence (PMID 33333012) — PMID:33333012
  • Cited evidence (PMID 30076119) — PMID:30076119