Fellow's quick read · Infectious Disease
Invasive aspergillosis
IDSA 2016 (Patterson, Clin Infect Dis 2016;63:e1–e60) · reviewed 2026-06-30
Personal study digest for a new ID fellow. Recommendations are from the cited IDSA 2016 guideline; the "What's changed since 2016" box is reviewer synthesis of newer evidence, each claim cited. Not a substitute for the full guideline.
In one line
Mold infection of the profoundly immunocompromised — prolonged neutropenia, allo-HSCT, GVHD on steroids, advanced SOT — now also severe influenza and COVID in the ICU. Voriconazole is the anchor azole; start it early on suspicion, don't wait for proof.
When to suspect / diagnose
- Host first. Prolonged neutropenia, allogeneic HSCT (especially GVHD on corticosteroids), SOT, high-dose steroids, advanced cellular immunodeficiency, ibrutinib/BTK inhibitors. Post-2016: severe influenza or COVID in the ICU — even without classic immunosuppression.
- Image on suspicion. Chest CT for any clinical suspicion of IPA, regardless of CXR (rec 13, strong/high). Classic = nodule with halo; contrast only if a nodule/mass abuts a large vessel (rec 14).
- Markers. Serum + BAL galactomannan (GM) is validated in hematologic malignancy / HSCT (rec 9, strong/high). β-D-glucan is sensitive but not Aspergillus-specific (rec 12). Blood PCR is adjunctive, case-by-case (recs 7–8).
Workup the fellow drives
- Bronchoscopy + BAL in suspected IPA (rec 16) — send culture, cytology, and GM. Defer for severe hypoxemia, bleeding, or platelet-refractory thrombocytopenia. Peripheral nodules have low BAL yield → percutaneous or endobronchial biopsy.
- GM caveat: mold-active azole prophylaxis/therapy lowers serum GM sensitivity → screen with BAL GM, not serum (rec 10). GM is not validated for screening in SOT or CGD (rec 11).
- Don't routinely send susceptibility testing (rec 24) — reserve for suspected azole resistance, non-response, or epidemiology.
Empiric & definitive therapy
| Scenario | Drug / dose / route | Duration | Strength |
|---|---|---|---|
| Primary IPA | Voriconazole 6 mg/kg IV q12h ×2 doses (day 1), then 4 mg/kg IV q12h; PO 200–300 mg q12h. TDM at steady state. | ≥6–12 wk | strong / high |
| First-line alternatives | Isavuconazole 200 mg q8h ×6 doses, then 200 mg daily · or liposomal AmB 3–5 mg/kg/day IV | ≥6–12 wk | strong / mod |
| Posaconazole (post-2016) | IV or DR tablet 300 mg BID day 1, then 300 mg daily — now first-line (see box) | ≥6–12 wk | NEW · Lancet 2021 |
| Documented IPA, select | Voriconazole + an echinocandin (combination) — not routine | — | weak / mod |
| Salvage | Switch class: lipid AmB, micafungin, caspofungin, posaconazole, or itraconazole | — | weak / mod |
| Empiric (neutropenic fever) | Lipid AmB, an echinocandin (caspofungin/micafungin), or voriconazole — for persistent fever despite broad-spectrum abx | — | strong |
| Prophylaxis (AML/MDS, GVHD) | Posaconazole (DR tablet 300 mg daily; oral susp 200 mg TID) | through risk period | strong |
Echinocandin monotherapy is NOT recommended for primary therapy (rec 29). Voriconazole TDM: keep trough <5–6 µg/mL to limit CNS toxicity; aim ≥1–1.5 for efficacy.
Duration & stopping
- IPA: minimum 6–12 weeks, driven by degree/duration of immunosuppression, site, and radiographic response (rec 30). No fixed stop date — treat to immune recovery + resolution.
- Follow-up chest CT after ≥2 weeks (rec 15, sooner if deteriorating). Serial serum GM tracks response in those with an elevated baseline GM (rec 43).
- Secondary prophylaxis when immunosuppression resumes after treated IPA (rec 31).
- Other forms: chronic cavitary PA ≥6 months (rec 83); invasive tracheobronchial ≥3 months or until resolved (rec 48); CNS aspergillosis = voriconazole, highest mortality of all IA (rec 50).
Key decisions a fellow owns
- Reduce or withdraw immunosuppression wherever feasible (rec 32) — as decisive as the antifungal.
- Reverse neutropenia: consider G-CSF/GM-CSF and granulocyte transfusions in refractory neutropenic IA (recs 33–34).
- Azole drug interactions + TDM. All mold-active azoles are CYP3A4 players — co-manage tacrolimus, sirolimus, cyclosporine, vinca alkaloids, TKIs (recs 21–22).
- Surgery for localized accessible disease (invasive sinus, cutaneous, selected CNS) and for endocarditis (rec 36).
- Don't over-empiricize. Skip empiric antifungals if neutropenia is expected to be short (<10 days) without other IFI findings (rec 75); biomarker-driven (pre-emptive) therapy is an accepted alternative to fever-driven empiric coverage (rec 76).
What's changed since 2016
Reviewer synthesis — not the guideline. Each item cited; flags where the 2016 text lags practice.
- Posaconazole is now first-line. Posaconazole was noninferior to voriconazole for primary IA — day-42 mortality 15% vs 21%, fewer drug-related AEs (30% vs 40%). The first-line azole trio is now voriconazole / isavuconazole / posaconazole. Maertens, Lancet 2021;397:499–509; PMID 33549194; doi:10.1016/S0140-6736(21)00219-1.
- Isavuconazole elevated to co-first-line. SECURE showed noninferiority to voriconazole (42-day mortality 19% vs 20%) with fewer hepatobiliary/eye/skin AEs (drug-related AEs 42% vs 60%), plus no routine TDM, fewer interactions, and QT-neutral dosing. ESCMID-ECMM-ERS 2017 lists isavuconazole and voriconazole as co-preferred. SECURE: Maertens, Lancet 2016;387:760–769; PMID 26684607. Ullmann, Clin Microbiol Infect 2018;24(S1):e1–e38; PMID 29544767.
- Two new ICU host groups. Influenza-associated PA (IAPA): IPA in 19% of ICU influenza patients (~3 d after admission), influenza an independent risk factor (aOR 5.2); 90-day mortality 51% vs 28%. COVID-associated PA (CAPA): ECMM/ISHAM consensus definition; first-line voriconazole or isavuconazole, liposomal AmB if azole resistance is a concern. The 2016 guideline predates both. IAPA: Schauwvlieghe, Lancet Respir Med 2018;6:782–792; PMID 30076119. CAPA: Koehler, Lancet Infect Dis 2021;21:e149–e162; PMID 33333012.
- Environmental azole resistance. TR34/L98H A. fumigatus is spreading; ESCMID-ECMM-ERS 2017 advises liposomal AmB when voriconazole MIC >2, and combination (echinocandin) or LAmB at intermediate MIC (2). Where local resistance is high, azole monotherapy can't be assumed to work. Ullmann, Clin Microbiol Infect 2018; PMID 29544767.
- Newer society guidance — but 2016 IDSA still governs diagnosis/treatment. ESCMID-ECMM-ERS 2017 is the contemporary peer guideline. An IDSA 2026 update exists but covers prevention in adult SOT recipients only — it does not replace the 2016 diagnosis/management document. IDSA 2026 SOT-prophylaxis update, idsociety.org.
- Pipeline (investigational). Olorofim (orotomide) and fosmanogepix (Gwt1 inhibitor) target azole-resistant/refractory mold. Olorofim remains FDA-UNAPPROVED as of mid-2026 (complete response letter 2023; Phase 3 OASIS read-out pending) — recency flag, confirm current status. F2G/FDA filings; clinicaltrials.gov NCT05101187.
Anki cards minted this run
- Posaconazole = post-2016 first-line azole for invasive aspergillosis (Maertens, Lancet 2021).
- Galactomannan under mold-active prophylaxis — serum GM goes falsely negative, send BAL GM (IDSA recs 9–10).
- IAPA — influenza is an independent risk factor for IPA in the ICU (~19%; Schauwvlieghe 2018).
- CAPA — first-line voriconazole/isavuconazole; liposomal AmB if azole resistance (ECMM/ISHAM 2021).
Held (already in deck or under the 4-card cap): voriconazole primary + TDM, halo sign, β-D-glucan sensitivity, echinocandin-not-primary, 6–12-week duration, azole-resistance→LAmB, ABPA cluster.
Sources: 1. Patterson TF, et al. IDSA Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update. Clin Infect Dis 2016;63(4):e1–e60. PMID 27365388; doi:10.1093/cid/ciw326. 2. Maertens JA, et al. Posaconazole vs voriconazole for primary treatment of invasive aspergillosis (phase 3, noninferiority). Lancet 2021;397:499–509. PMID 33549194; doi:10.1016/S0140-6736(21)00219-1. 3. Maertens JA, et al. Isavuconazole vs voriconazole (SECURE). Lancet 2016;387:760–769. PMID 26684607; doi:10.1016/S0140-6736(15)01159-9. 4. Schauwvlieghe AFAD, et al. Invasive aspergillosis in ICU patients with severe influenza. Lancet Respir Med 2018;6:782–792. PMID 30076119; doi:10.1016/S2213-2600(18)30274-1. 5. Koehler P, et al. Defining and managing COVID-19-associated pulmonary aspergillosis: 2020 ECMM/ISHAM consensus. Lancet Infect Dis 2021;21:e149–e162. PMID 33333012; doi:10.1016/S1473-3099(20)30847-1. 6. Ullmann AJ, et al. Diagnosis and management of Aspergillus diseases: ESCMID-ECMM-ERS guideline (2017). Clin Microbiol Infect 2018;24(Suppl 1):e1–e38. PMID 29544767; doi:10.1016/j.cmi.2018.01.002.