Multisystem Processes & Disorders

Aspergillosis: invasive, ABPA, aspergilloma

Clinical Overview and When to Suspect Aspergillosis

— Invasive pulmonary aspergillosis (IPA): profound, prolonged neutropenia (ANC <500 >10 days), allogeneic HSCT, solid-organ transplant (lung > heart > liver), high-dose corticosteroids (>0.3 mg/kg prednisone equivalent ≥3 weeks), advanced AIDS, ibrutinib, GVHD, decompensated cirrhosis, severe influenza/COVID-19 in ICU (influenza-associated and CAPA)

— Allergic bronchopulmonary aspergillosis (ABPA): hypersensitivity reaction in poorly controlled asthma or cystic fibrosis — not infection

— Aspergilloma (mycetoma/"fungus ball"): saprophytic colonization of a pre-existing cavity (post-TB, sarcoid, bullae, ankylosing spondylitis apical fibrosis, prior abscess)

— Febrile neutropenia unresponsive to ≥4–7 days of broad-spectrum antibiotics → think mold, get CT chest

— Transplant recipient with new pulmonary nodule, pleuritic chest pain, or hemoptysis

— Asthmatic with recurrent infiltrates, central bronchiectasis, brown mucus plugs, persistently elevated IgE

— Hemoptysis in a patient with old TB cavity on CXR

Aspergillus is a ubiquitous, thermotolerant, septate, acute-angle (45°) branching mold; A. fumigatus causes most human disease, with A. flavus, A. niger, A. terreus in specific niches

Three classic syndromes board-tested as a triad — recognize by host immune status:

Less common: chronic pulmonary aspergillosis (CPA, including chronic cavitary and chronic fibrosing forms), tracheobronchitis (lung transplant anastomosis), Aspergillus sinusitis, cerebral aspergillosis (hematogenous or contiguous), cutaneous (burns, IV sites), endophthalmitis

When to suspect on Step 3:

Board pearl: The host phenotype tells you the syndrome before the imaging does — neutropenic = invasive, atopic asthmatic = ABPA, old TB cavity = aspergilloma. Mismatched host-syndrome pairings are usually wrong-answer distractors

Key distinction: Aspergillus colonization (sputum culture in COPD) ≠ disease; clinical, radiographic, and serologic correlation is mandatory before treatment

Presentation Patterns and Key History

— Persistent fever despite broad-spectrum antibiotics in a neutropenic or transplant patient

— Pleuritic chest pain (from infarction by angioinvasion), dry cough, hemoptysis (often as neutrophils recover and cavitate the infarct)

— Dyspnea, hypoxemia; can be remarkably subtle in the steroid-suppressed host (no fever, only malaise)

— Sinus symptoms (unilateral facial pain, epistaxis, black eschar on turbinate) suggest rhinocerebral/sinus aspergillosis — neutropenic leukemia patients

— CNS: focal deficit, seizure, altered mentation → hematogenous brain abscess

— Long-standing asthma or CF with recurrent exacerbations, low-grade fever, malaise

— Expectoration of brownish mucus plugs (high-yield buzzword), occasional hemoptysis

— Episodic wheeze despite adherent inhaler therapy; weight loss in severe disease

— Ask about: childhood asthma severity, prior steroid bursts, CF status, environmental mold exposure (compost, hay, construction)

— Often asymptomatic and found incidentally on imaging

— Hallmark complaint = hemoptysis (50–90%), can be life-threatening/massive (>200 mL/24h) due to erosion into bronchial arteries

— Chronic cough, weight loss, fatigue suggest progression to chronic pulmonary aspergillosis

— History clues: prior TB, sarcoidosis, ankylosing spondylitis (apical fibrobullous disease), prior cavitary pneumonia, lung cancer cavity

Invasive pulmonary aspergillosis (IPA)

ABPA

Aspergilloma

CCS pearl: When the stem mentions a febrile leukemia patient on day 10 of cefepime who now has pleuritic chest pain and a single new nodule, do not wait — order CT chest without contrast (or with, if PE on differential), serum galactomannan, and infectious disease consult in the same time-step. Empiric voriconazole should be initiated before culture confirmation in high-probability hosts

Board pearl: The triad of asthma + central bronchiectasis + brown mucus plugs is ABPA until proven otherwise

Physical Exam Findings (and Hemodynamic Assessment when relevant)

— Often paucity of findings disproportionate to imaging — classic teaching point in the neutropenic host on steroids

— Tachypnea, tachycardia, hypoxia; localized rales or a pleural rub (over infarcted parenchyma) can be a tip-off

— Hemodynamic instability suggests dissemination, superimposed bacteremia, or massive hemoptysis — assess airway, breathing, circulation first

— Sinus disease: necrotic black turbinate, periorbital swelling, proptosis, ophthalmoplegia, palatal eschar (overlaps with mucormycosis — biopsy distinguishes)

— CNS: focal neurologic deficits, cranial nerve palsies, papilledema

— Skin: violaceous or necrotic nodules at IV sites or under occlusive dressings (cutaneous inoculation, especially neonatal ICU)

— Wheezing, prolonged expiratory phase; may have signs of chronic airflow obstruction

— Coarse crackles over upper lobes if bronchiectasis advanced

— Clubbing in late/fibrotic disease or CF substrate

— Frequently normal exam

— May hear coarse crackles or amphoric breath sounds over apical cavity

— During hemoptysis: signs of volume loss, anemia, airway compromise — protect airway, lateral decubitus with bleeding lung down to protect the contralateral lung

— Continuous SpO2, two large-bore IVs, type and crossmatch ≥2 units pRBCs

— Reverse coagulopathy (vitamin K, FFP, platelets to >50k, hold antiplatelets)

— Early interventional radiology for bronchial artery embolization and thoracic surgery consult

Invasive pulmonary aspergillosis

ABPA

Aspergilloma

Hemodynamic assessment in suspected massive hemoptysis:

Step 3 management: In a stable patient with suspected aspergilloma and small-volume hemoptysis, do not start systemic antifungals reflexively — they penetrate the fungus ball poorly. Stratify hemoptysis severity, optimize the underlying lung disease, and consult pulmonology/thoracic surgery for definitive planning

Key distinction: A patient with a necrotic palatal eschar — Aspergillus vs Mucor — Mucor is non-septate, wide, ribbon-like, 90° branching; treatment differs (amphotericin + surgery for Mucor; voriconazole is ineffective against Mucor)

Diagnostic Workup — Initial Labs / Imaging / ECG / Biomarkers

— Halo sign (nodule surrounded by ground-glass) — early, transient, ~7–10 days, high specificity in neutropenic host

— Air crescent sign — later (neutrophil recovery), cavitation around a sequestrum, also classic for aspergilloma

— Wedge-shaped pleural-based consolidations, multiple nodules, cavitation

— ABPA: central bronchiectasis (inner two-thirds of lung), finger-in-glove opacities (mucoid impaction), upper-lobe predominance, fleeting infiltrates

— Aspergilloma: mobile intracavitary mass with crescent of air, movement on prone imaging is diagnostic

— Galactomannan (GM): cell wall antigen; serum GM optical density ≥0.5 supports IPA in at-risk hosts; BAL GM ≥1.0 is more sensitive than serum (especially in non-neutropenic and steroid-treated patients)

— (1→3)-β-D-glucan: pan-fungal, not specific (also positive in Candida, Pneumocystis); useful as a screen

— False-positive GM: piperacillin-tazobactam (older formulations), amoxicillin-clavulanate, plasmalyte, certain enteral feeds

— False-negative GM: prior mold-active prophylaxis (posaconazole/voriconazole)

— Total serum IgE ≥1000 IU/mL (cornerstone)

— Aspergillus-specific IgE and IgG elevated

— Positive Aspergillus skin prick (type I hypersensitivity)

— Peripheral eosinophilia, precipitating Aspergillus antibodies

CBC with diff: confirm neutropenia depth/duration (key risk substrate); eosinophilia (>500/µL, often >1000) in ABPA

CMP, LFTs, coags: baseline before voriconazole (hepatotoxicity), bilirubin guides IV vehicle issues

Inflammatory markers: elevated CRP/ESR — nonspecific; useful as trend

ABG/SpO2: assess hypoxemia severity

Imaging — CT chest (without contrast unless PE on differential) is the single most useful initial test in suspected IPA

Serum biomarkers

ABPA-specific labs (mandatory combination):

ECG: baseline QTc before starting voriconazole, posaconazole, isavuconazole — azoles prolong QT (isavuconazole shortens it — distinctive)

Board pearl: A neutropenic patient on pip-tazo with a "positive" serum GM and otherwise unimpressive CT — consider antibiotic-related false positive; repeat after switching antibiotics and confirm with BAL GM

Diagnostic Workup — Advanced or Confirmatory Studies

— Send: fungal smear (KOH, calcofluor), fungal culture, BAL galactomannan (≥1.0 strongly supports IPA), Aspergillus PCR, bacterial culture, AFB, PJP DFA/PCR, viral PCR

— Histopathology of biopsy specimens: septate hyphae with acute-angle (45°) dichotomous branching — definitive when present

— Differentiate from Fusarium, Scedosporium (look similar histologically — culture is essential)

— Sputum culture has poor sensitivity (~30%) but high specificity in the right host; a positive culture in a transplant or neutropenic patient is never ignored

— Blood cultures are almost always negative in Aspergillus (unlike Fusarium, which is bacteremia-like) — a useful distinguishing fact

— Sinus CT for unilateral sinus symptoms in neutropenic host

— MRI brain with contrast if CNS symptoms — ring-enhancing lesions, hemorrhagic infarcts in Aspergillus cerebritis

— Echocardiogram if endocarditis suspected (prosthetic valve, IV drug use is uncommon for Aspergillus — think more in immunocompromised with indwelling lines)

— CT chest defines cavity, mass mobility, vascular supply

— Aspergillus IgG (precipitins) is the most useful serology — distinguishes colonization vs disease

— Sputum culture often positive; pulmonary function tests prior to any surgical consideration

— Predisposing condition (asthma/CF) + obligatory criteria (elevated total IgE, Aspergillus-specific IgE) + other criteria (precipitins, eosinophilia, consistent radiology)

— Stages: acute, remission, exacerbation, steroid-dependent, fibrotic

Bronchoscopy with bronchoalveolar lavage (BAL) is the highest-yield confirmatory test for IPA

Tissue biopsy (transbronchial, CT-guided, or surgical wedge) — gold standard for proven invasive disease, but often deferred due to thrombocytopenia/coagulopathy; pursue when diagnosis would change management or empiric therapy is failing

Cultures

Imaging — extended evaluation

Aspergilloma workup

ABPA staging (Rosenberg-Patterson / ISHAM revised criteria)

CCS pearl: Order bronchoscopy with BAL in suspected IPA when serum GM is negative or equivocal and the host is high-risk — sensitivity of BAL GM substantially exceeds serum GM in non-neutropenic patients (steroid-treated, transplant)

Key distinction: Septate, acute-angle branching = Aspergillus/Fusarium/Scedosporium; non-septate, ribbon-like, 90° = Mucorales — biopsy plus culture distinguishes and treatment diverges sharply

Risk Stratification or First-Line Management Logic

— Proven: histopathology + culture from sterile site

— Probable: host factor + clinical/radiologic feature + mycologic evidence (GM, culture, PCR)

— Possible: host factor + clinical feature, no mycology

— Treat probable and proven as invasive disease; "possible" warrants further workup and often empiric therapy in high-risk hosts

— Disseminated disease (CNS, multifocal pulmonary, skin)

— Respiratory failure / mechanical ventilation

— Persistent profound neutropenia, uncontrolled GVHD

— Co-infections (CMV, PJP, bacterial superinfection)

— Start voriconazole as soon as IPA is probable; do not wait for culture

— Reverse immunosuppression where possible: taper steroids, treat neutropenia (consider G-CSF), reduce calcineurin inhibitor dosing in transplant

— Source control: debride necrotic sinus tissue, remove infected lines/devices, surgical resection of single accessible lesions near great vessels or in cavities with refractory hemoptysis

— Treat acute disease and exacerbations with systemic corticosteroids (e.g., prednisone 0.5 mg/kg/day with taper over 2–3 months)

— Add itraconazole (or voriconazole/posaconazole) for 16 weeks as steroid-sparing and to reduce fungal burden

— Optimize asthma/CF baseline therapy (ICS-LABA, airway clearance, biologics where indicated)

— Monitor total IgE — expect ~35% drop with treatment; rising IgE heralds exacerbation

— Asymptomatic / minimal hemoptysis: observe with serial imaging

— Significant or recurrent hemoptysis: surgical resection (lobectomy/segmentectomy) is definitive when pulmonary reserve permits

— Poor surgical candidate with hemoptysis: bronchial artery embolization ± intracavitary amphotericin instillation; oral itraconazole/voriconazole has limited efficacy (poor cavity penetration) but is used adjunctively

EORTC/MSGERC categories guide therapy in IPA

Severity drivers for IPA

First-line management logic — IPA

ABPA management logic

Aspergilloma management logic

Step 3 management: Choose voriconazole over amphotericin B for first-line IPA — survival benefit demonstrated in the landmark trial — unless contraindicated (severe hepatic dysfunction, QT prolongation, drug interactions)

Board pearl: Antifungal prophylaxis with posaconazole is standard in AML induction and GVHD on high-dose steroids

Pharmacotherapy — First-Line Drug Regimen

— Loading: 6 mg/kg IV q12h × 2 doses → maintenance 4 mg/kg IV q12h; PO 200 mg q12h when stable

— Therapeutic drug monitoring (TDM): target trough 1–5.5 mg/L; check after 5–7 days, then weekly

— Adverse effects: transient visual disturbances (photopsia, altered color perception — pathognomonic), hepatotoxicity, QT prolongation, periostitis (fluoride-mediated, long-term use, painful bones with elevated ALP), photosensitivity → squamous cell skin cancer (sun protection mandatory), CNS effects, peripheral neuropathy

— Pharmacogenomics: CYP2C19 polymorphisms drive levels — poor metabolizers have high levels/toxicity; ultra-rapid metabolizers have subtherapeutic troughs (common in young, otherwise healthy)

— Drug interactions (CYP3A4/2C9/2C19): avoid with rifampin, carbamazepine, St. John's wort, long-acting barbiturates (induce voriconazole); sirolimus contraindicated; tacrolimus/cyclosporine reduce dose ~by half; warfarin INR rises

— Isavuconazole — non-inferior to voriconazole, fewer drug interactions, shortens QT (use if baseline long QT), no TDM required, well-tolerated; covers some Mucorales (useful when diagnosis unclear)

— Liposomal amphotericin B (L-AmB) 3–5 mg/kg/day IV — when azoles contraindicated, suspected mixed mold infection, or breakthrough on azole prophylaxis; nephrotoxicity, infusion reactions, hypokalemia/hypomagnesemia

— Posaconazole — primarily prophylaxis (AML, GVHD); delayed-release tablet or IV preferred (better bioavailability than suspension); also salvage therapy

— Echinocandins (caspofungin, micafungin) — not first-line monotherapy; used as salvage or in combination; fungistatic against Aspergillus

Voriconazole — first-line for invasive aspergillosis

Alternatives for IPA

Duration of IPA therapy: minimum 6–12 weeks, often longer; continue until clinical resolution, radiologic improvement (not necessarily full clearance), and reversal of immunosuppression

ABPA pharmacotherapy: prednisone 0.5 mg/kg/day × 2 weeks, taper over 2–3 months + itraconazole 200 mg BID × 16 weeks (TDM target trough >1 mg/L); biologics (omalizumab, mepolizumab, dupilumab) increasingly used in refractory/steroid-dependent disease

CCS pearl: Always document baseline LFTs, ECG/QTc, and a medication reconciliation for interactions before initiating voriconazole, and schedule a trough at day 5–7

Procedures and Adjunctive Management

— Indications: lesion abutting great vessels, pericardium, or major airway; refractory hemoptysis; single accessible pulmonary lesion; persistent disease despite optimal antifungal therapy; debridement of necrotic sinus or cutaneous tissue

— Pre-op: optimize platelets (>50k), correct coagulopathy, continue antifungal perioperatively, multidisciplinary planning with thoracic surgery and ID

— Lobectomy is gold standard for symptomatic disease in patients with adequate pulmonary reserve

— Segmentectomy or cavernostomy when reserve limited

— Complications: bronchopleural fistula, empyema, prolonged air leak, hemorrhage (cavity often adherent to chest wall)

— Perioperative antifungal coverage (itraconazole or voriconazole) to reduce spillage/dissemination

— First-line for massive hemoptysis when patient is unstable or surgery not feasible

— Effective short-term control; recurrence common (up to 50% at 1 year) — definitive therapy still needed

— Complications: spinal cord ischemia (anterior spinal artery off intercostobronchial trunk), chest pain, dysphagia

— Amphotericin B paste or solution instilled into aspergilloma cavity under CT/bronchoscopic guidance

— Reserved for non-surgical candidates with persistent hemoptysis after BAE

— Position bleeding lung down (lateral decubitus) to protect contralateral lung

— Secure airway with large (≥8.0) ETT; consider selective mainstem intubation of unaffected side or double-lumen tube

— IV access × 2, type and cross, reverse coagulopathy, hold antiplatelets/anticoagulants if safe

— Urgent rigid bronchoscopy for localization and tamponade; IR for embolization; thoracic surgery on standby

— Taper corticosteroids to the lowest feasible dose

— Reduce calcineurin inhibitors in transplant — coordinate with transplant team

— G-CSF or granulocyte transfusions in profound neutropenia (selective use)

Surgical resection — invasive aspergillosis

Surgical resection — aspergilloma

Bronchial artery embolization (BAE)

Intracavitary antifungal instillation

Airway management in massive hemoptysis (CCS sequence):

Reduction of immunosuppression

Step 3 management: Aspergilloma + massive hemoptysis in a poor surgical candidate → bronchial artery embolization first, then plan definitive therapy; antifungals alone will not stop the bleed

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher prevalence of comorbid COPD with chronic steroid exposure → increased risk of subacute invasive aspergillosis and chronic pulmonary aspergillosis (CPA)

— Polypharmacy magnifies azole drug interactions — statins, warfarin, amiodarone, opioids (methadone, oxycodone), proton pump inhibitors, benzodiazepines all affected

— Increased risk of QT prolongation from baseline conduction disease and concurrent QT-prolonging meds

— Falls/cognitive risk from voriconazole CNS effects (visual disturbance, encephalopathy at high troughs)

— Hepatotoxicity risk higher; check LFTs at baseline, week 1, week 2, then monthly

— Voriconazole IV vehicle contains sulfobutylether-β-cyclodextrin (SBECD) — accumulates with CrCl <50 mL/min, may worsen renal function

— Switch to oral voriconazole if CrCl <50 (oral has no SBECD), or use isavuconazole (no cyclodextrin vehicle — preferred in CKD)

— Liposomal amphotericin B — significant nephrotoxicity even in lipid formulation; pre-hydrate with saline, monitor Cr, K, Mg daily

— Echinocandins: no renal dose adjustment — useful in advanced CKD

— Posaconazole tablets/IV: IV form also contains cyclodextrin — same caution

— All azoles are hepatically metabolized → dose-reduce voriconazole maintenance by 50% in Child-Pugh A/B; avoid in Child-Pugh C (use isavuconazole or L-AmB)

— Monitor LFTs weekly initially; discontinue if transaminases rise >5× ULN or with symptomatic hepatitis

— Isavuconazole — no formal dose adjustment for mild-moderate hepatic impairment; caution in severe

— Voriconazole + amiodarone → QT additivity

— Voriconazole + opioids → respiratory depression, sedation

— Voriconazole + vincristine → severe neurotoxicity (contraindicated in leukemia patients receiving vincristine — swap antifungal or hold vincristine)

Elderly patients

Renal impairment

Hepatic impairment

Drug-disease interactions of note in elderly/comorbid hosts

Board pearl: In a transplant patient with CKD needing IV mold therapy, isavuconazole is the cleanest choice — no cyclodextrin, fewer drug interactions, no TDM required, and shortens QT

Key distinction: Renal dose adjustment applies to the IV vehicle, not the antifungal itself — oral azoles bypass this concern

Special Populations — Pregnancy, Pediatrics, and Other Subgroups

— Voriconazole, posaconazole, itraconazole, isavuconazole — pregnancy category D (formerly); teratogenic in animals (cleft palate, skeletal abnormalities)

— Liposomal amphotericin B is preferred for invasive aspergillosis in pregnancy — long human safety record

— Counsel reproductive-age women on azoles about effective contraception; switch off azoles if pregnancy planned

— ABPA in pregnancy: oral corticosteroids preferred; minimize azole exposure

— IPA risk: pediatric oncology (AML, ALL relapse), HSCT, chronic granulomatous disease (CGD — defective NADPH oxidase, classic Aspergillus susceptibility), severe combined immunodeficiency

— Voriconazole pediatric pharmacokinetics differ: higher mg/kg doses required (8–9 mg/kg q12h in children 2–12 yr); aggressive TDM essential

— Isavuconazole approved down to age 1; pediatric dosing data still maturing

— CGD prophylaxis: lifelong itraconazole plus TMP-SMX plus interferon-gamma

— ABPA prevalence ~10%; suspect with declining FEV1, new infiltrates, rising IgE

— Lower IgE threshold for diagnosis often used; co-managed with CF center

— Aspergillus tracheobronchitis can occur post-lung transplant — anastomotic site

— IPA in advanced disease (CD4 <50) — often presents with disseminated or CNS disease

— Start ART carefully — voriconazole + efavirenz has bidirectional interaction (avoid or dose-modify); raltegravir/dolutegravir-based regimens preferred

— Lung transplant highest risk — colonization → tracheobronchitis → invasive disease at anastomosis

— Prophylaxis with inhaled amphotericin or systemic voriconazole/itraconazole in many centers

— Calcineurin inhibitor levels rise with azoles — reduce tacrolimus by ~66%, cyclosporine by ~50%, monitor levels every 2–3 days during initiation

— Posaconazole prophylaxis during AML induction and prolonged GVHD on steroids — reduces invasive fungal infections

— Breakthrough on prophylaxis → switch antifungal class (amphotericin), pursue aggressive diagnostics

Pregnancy

Pediatrics

Cystic fibrosis

HIV/AIDS

Solid-organ transplant

Hematologic malignancy / HSCT

Step 3 management: A pregnant patient with probable IPA → liposomal amphotericin B, NOT voriconazole; involve maternal-fetal medicine and ID early

Complications and Adverse Outcomes

— Massive hemoptysis from angioinvasion — life-threatening, often during neutrophil recovery as infarcted tissue cavitates

— Dissemination: CNS (brain abscess, hemorrhagic infarcts, very high mortality), endocarditis, cutaneous, hepatic, splenic, renal, ophthalmic

— Cerebral aspergillosis: stroke-like presentations from septic emboli; mortality >90% historically, improving with voriconazole + surgery

— Aspergillus endocarditis: large bulky vegetations (mimic marantic/Libman-Sacks), embolic phenomena, blood cultures typically negative — surgical valve replacement usually required

— Respiratory failure / ARDS; secondary bacterial superinfection

— Bronchopleural fistula, empyema post-surgery

— Central (proximal) bronchiectasis — irreversible

— Pulmonary fibrosis (end-stage stage V) — restrictive defect, cor pulmonale

— Chronic eosinophilic pneumonia overlap

— Steroid-related complications: weight gain, hyperglycemia, osteoporosis, adrenal suppression, cataracts — important on long-term therapy

— Massive hemoptysis (most feared) — can be fatal

— Progression to chronic cavitary pulmonary aspergillosis with constitutional symptoms, weight loss, fibrosis

— Surgical complications: empyema, bronchopleural fistula, prolonged air leak

— Voriconazole: hepatotoxicity, squamous cell carcinoma of skin (long-term use — counsel on SPF, dermatology surveillance), periostitis (bone pain, elevated ALP, fluoride accumulation), neurotoxicity at high troughs

— Amphotericin: nephrotoxicity, infusion reactions, electrolyte wasting (replete K, Mg)

— Azole-induced adrenal insufficiency and pseudohyperaldosteronism (especially posaconazole, itraconazole — hypertension, hypokalemia)

— Drug interactions: tacrolimus toxicity, statin myopathy, warfarin over-anticoagulation

Invasive aspergillosis complications

ABPA complications

Aspergilloma complications

Drug-related adverse outcomes

Board pearl: New bone pain + elevated ALP in a transplant patient on long-term voriconazole → fluoride-induced periostitis; switch antifungal class

CCS pearl: In Aspergillus endocarditis, surgical valve replacement plus prolonged voriconazole (often lifelong suppression) is standard — medical therapy alone fails

When to Escalate Care — ICU, Consult, and Inpatient Triage

— Respiratory failure (SpO2 <90% on supplemental O2, rising work of breathing)

— Massive hemoptysis (>200 mL/24h or any volume causing hemodynamic or gas exchange compromise)

— Hemodynamic instability, sepsis physiology with concurrent bacterial coinfection

— Altered mental status with suspected CNS aspergillosis

— Post-surgical airway issues, bronchopleural fistula with tension physiology

— Any new diagnosis of probable/proven IPA — admit for IV therapy initiation, diagnostic completion, immunosuppression adjustment

— ABPA exacerbation with hypoxemia, dehydration, or unable to tolerate oral therapy

— Aspergilloma with non-massive but recurrent hemoptysis needing workup and IR/surgical planning

— Infectious diseases: all proven/probable invasive disease — guides choice, TDM, duration

— Pulmonology and/or thoracic surgery: aspergilloma, cavitary disease, planned resection, bronchoscopy

— Interventional radiology: bronchial artery embolization for hemoptysis

— Hematology/Oncology or Transplant team: modify immunosuppression

— Otolaryngology: sinus disease, suspected rhinocerebral involvement

— Neurology / Neurosurgery: CNS disease, abscess drainage candidates

— Ophthalmology: if visual symptoms (voriconazole side effect vs ocular disease)

— Pharmacy/clinical pharmacology: TDM and drug interaction management

— Dermatology: skin lesions, long-term azole skin cancer surveillance

— Stable ABPA in remission, on maintenance therapy

— Asymptomatic aspergilloma under serial imaging surveillance

— Step-down oral voriconazole/isavuconazole after clinical improvement of IPA, with close outpatient follow-up

Immediate ICU triage

Inpatient admission (non-ICU)

Mandatory consults

Outpatient management acceptable

CCS pearl: In a CCS case of febrile neutropenic AML day 12, when you order CT chest and serum galactomannan, in the same time-step also consult Infectious Diseases and start empiric voriconazole — waiting for biopsy in this host loses points and worsens outcomes

Step 3 management: Threshold for admission is low in any immunocompromised host with suspected Aspergillus — the diagnostic yield, IV access needs, and rate of deterioration justify inpatient workup

Key Differentials — Same-Category (Other Molds and Fungal Mimics)

— Host: diabetic ketoacidosis (classic), iron overload/deferoxamine, neutropenia, hematologic malignancy, post-COVID with steroids

— Presentation: aggressive rhino-orbito-cerebral disease, palatal/nasal eschar, rapid progression hours-to-days

— Histology: non-septate (pauciseptate), wide ribbon-like hyphae, 90° branching

— Treatment: liposomal amphotericin B + aggressive surgical debridement + isavuconazole or posaconazole as step-down; voriconazole has no activity — a critical distinction

— Pulmonary mucor on imaging: reversed halo sign (central ground-glass surrounded by consolidation), >10 nodules

— Disseminated disease in neutropenic patients with positive blood cultures (unlike Aspergillus), painful skin lesions with central necrosis

— Histologically indistinguishable from Aspergillus — culture required; voriconazole active

— Look like Aspergillus histologically; intrinsically resistant to amphotericin; voriconazole preferred; Lomentospora prolificans highly drug-resistant

— Classic association: near-drowning (S. apiospermum), CF patients

— Histoplasmosis: Ohio/Mississippi River valleys, mediastinal lymphadenopathy, "buckshot" calcifications, urine antigen

— Blastomycosis: broad-based budding yeast, skin and bone involvement

— Coccidioidomycosis: Southwest US, erythema nodosum, spherules

— Distinguished by serology, antigen, geography, and yeast vs mold tissue forms

— HIV/CD4 <100, meningitis predominant, encapsulated yeast on India ink, serum/CSF cryptococcal antigen

— Pulmonary cryptococcoma can mimic nodule/aspergilloma — antigen testing distinguishes

— Overlap host (HIV, transplant, high-dose steroids) — bilateral ground-glass, elevated LDH, positive β-D-glucan (but galactomannan negative)

— Distinguished by BAL PCR/DFA; treat with TMP-SMX

Mucormycosis (Mucorales: Rhizopus, Mucor, Lichtheimia)

Fusariosis

Scedosporium / Lomentospora

Endemic mycoses (in the right geography/host)

Cryptococcosis

Pneumocystis jirovecii pneumonia (PJP)

Key distinction: Halo sign (Aspergillus) vs reversed halo (Mucor) vs air crescent (Aspergillus, late) — high-yield CT imaging triad

Board pearl: Diabetic in DKA with facial pain, black turbinate eschar → start amphotericin empirically and call ENT for emergent debridement — do not wait for biopsy; voriconazole alone is the wrong choice and a classic trap

Key Differentials — Other-Category Causes

— Typical bacterial pneumonia in neutropenic host: gram-negatives (Pseudomonas), staph, strep — covered by empiric cefepime/pip-tazo

— Cavitary lesions: anaerobes, Klebsiella, Staph aureus (including MRSA), Nocardia

— Nocardia — weakly acid-fast filamentous bacterium in immunocompromised hosts; sulfonamides

— Tuberculosis — cavitary upper-lobe disease (the very substrate that leads to aspergilloma); always rule out active TB before starting steroids for ABPA-like presentation

— Nontuberculous mycobacteria (MAC) — chronic cavitary disease, indolent

— Right-sided endocarditis (IVDU), infected venous catheters, Lemierre syndrome — multiple peripheral nodules with cavitation, very mimics IPA

— Wedge-shaped pleural-based opacity (Hampton hump) can mimic IPA infarct; D-dimer, CTPA distinguishes

— Primary lung cancer in cavity, metastatic disease, lymphoma — biopsy when imaging atypical or unresponsive to therapy

— Post-transplant lymphoproliferative disorder (PTLD) in transplant patients

— GPA (Wegener's) — cavitary nodules, sinus disease, hemoptysis, c-ANCA/PR3 — important mimic of both IPA and aspergilloma

— EGPA (Churg-Strauss) — asthma + eosinophilia + pulmonary infiltrates → mimics ABPA; look for vasculitic features (mononeuritis multiplex, p-ANCA/MPO)

— Chronic eosinophilic pneumonia: "photographic negative of pulmonary edema" peripheral upper-lobe infiltrates, profound eosinophilia, dramatic steroid response; lacks Aspergillus serology

— Acute eosinophilic pneumonia: drug or smoking-related

— Inhaled organic antigen exposure (mold, bird, hot tub); ground-glass and mosaic attenuation; lacks IgE elevation typical of ABPA

— Migratory infiltrates, steroid-responsive — mimics ABPA migratory pattern but no Aspergillus serology

Bacterial pneumonia / lung abscess

Mycobacterial disease

Septic pulmonary emboli

Pulmonary infarction from PE

Malignancy

Vasculitis

Eosinophilic pneumonias

Hypersensitivity pneumonitis

Cryptogenic organizing pneumonia (COP)

Key distinction: EGPA vs ABPA — both feature asthma and eosinophilia, but EGPA has systemic vasculitis (neuropathy, sinus, cardiac, renal), ANCA positivity, and negative Aspergillus serologies

Step 3 management: In suspected ABPA, always rule out active TB before starting prednisone — chest imaging plus IGRA/PPD if any cavitary changes

Secondary Prevention / Discharge Medications / Long-Term Plan

— Transition IV → oral voriconazole (or isavuconazole) once clinically improved, afebrile, tolerating PO; total duration minimum 6–12 weeks, often longer

— Maintain secondary prophylaxis during ongoing immunosuppression (e.g., until ANC recovery, GVHD resolution, or transplant immunosuppression reduced) — risk of relapse without it

— Discharge meds: antifungal, electrolyte repletion as needed, dermatology sun-protection counseling, ophthalmology if visual changes occurred, calcium/vitamin D if on steroids

— Reconcile drug interactions every visit — new prescriptions can be catastrophic (e.g., starting rifampin will tank voriconazole levels)

— Itraconazole 200 mg BID for 16 weeks during acute treatment; consider longer in exacerbation-prone patients

— Taper prednisone over 2–3 months; lowest effective dose

— Optimize asthma: inhaled ICS-LABA, leukotriene modifiers, biologics (omalizumab for IgE-driven disease, mepolizumab/benralizumab for eosinophil-driven, dupilumab)

— Environmental control: avoid mold-rich environments (compost, hay, damp basements, water-damaged buildings), HEPA filtration

— Pulmonary rehab in established bronchiectasis; airway clearance techniques

— Bone protection on chronic steroids: calcium 1000–1200 mg/day, vitamin D 800–1000 IU/day, DEXA if >3 months prednisone ≥5 mg, bisphosphonate when indicated

— Vaccinations: annual influenza, PCV20 (or PCV15 + PPSV23), RSV when eligible, COVID-19 boosters per current guidance

— Post-resection: monitor for recurrence, optimize underlying lung disease (treat TB sequelae, sarcoid, CF)

— Non-surgical patients on observation: serial CT every 3–6 months, sputum surveillance, education on hemoptysis red flags (return immediately for any volume >30 mL or recurrent episodes)

— Smoking cessation, pulmonary rehab, vaccinations as above

— AML induction, HSCT, GVHD on high-dose steroids → posaconazole prophylaxis

— Lung transplant → center-specific (inhaled amphotericin or systemic azole)

— CGD → lifelong itraconazole + TMP-SMX + interferon-gamma

IPA — discharge and longitudinal plan

ABPA — long-term plan

Aspergilloma — long-term plan

Prophylaxis populations

Board pearl: ABPA management has three pillars — steroids, antifungal, asthma optimization; missing any pillar leads to relapse

Step 3 management: Schedule a structured medication-reconciliation visit within 1–2 weeks of discharge in any patient discharged on an azole — drug interactions and hepatotoxicity are the dominant readmission drivers

Follow-Up, Monitoring Parameters, and Rehab/Counseling

— Week 1–2: clinic or virtual check, voriconazole trough (target 1–5.5 mg/L), LFTs, CBC, BMP, ECG/QTc

— Every 2 weeks initially, then monthly: LFTs, drug levels, symptom assessment, drug interaction reconciliation

— Repeat CT chest at 2–4 weeks to assess response; cavitation often increases initially with neutrophil recovery (not failure!) — clinical and biomarker trends matter more

— Serial galactomannan trends — falling GM correlates with response; persistent or rising GM suggests failure or breakthrough

— Long-term: dermatology every 6–12 months (skin cancer surveillance on voriconazole), ophthalmology if visual symptoms, bone density if periostitis suspected

— Total IgE every 6–8 weeks initially → expect ~35% decrease with treatment; rising IgE precedes clinical exacerbation

— Spirometry every 3–6 months; asthma control questionnaires (ACT)

— Annual chest imaging to track bronchiectasis progression

— Eosinophil count, Aspergillus-specific IgE/IgG periodically

— Bone density at baseline if chronic steroids, then every 1–2 years

— Serial CT every 3–6 months for stable disease

— Hemoptysis diary; immediate evaluation for any new bleeding

— Pulmonary function annually

— Aspergillus IgG titers can be trended

— Pulmonary rehab — particularly in ABPA-bronchiectasis and post-aspergilloma resection patients

— Smoking cessation — every visit, document in chart

— Nutrition optimization — sarcopenia common in chronic pulmonary aspergillosis and immunocompromised patients

— Mental health screening — chronic disease, prolonged therapy, transplant patients have high depression/anxiety prevalence

— Patient education: medication adherence, photoprotection on voriconazole (broad-spectrum SPF 30+, sun-protective clothing), recognition of hepatotoxicity symptoms (jaundice, RUQ pain, nausea)

IPA follow-up cadence

ABPA follow-up

Aspergilloma follow-up

Rehabilitation and counseling

CCS pearl: Order voriconazole trough at steady state (day 5–7), not earlier; adjust dose and recheck in 5–7 days after any change; document interactions at every encounter

Key distinction: Radiographic worsening early in IPA therapy (especially with neutrophil recovery) is often expected; treatment failure is defined by clinical and mycologic non-response, not imaging alone

Ethical, Legal, and Patient Safety Considerations

— Voriconazole: disclose visual disturbances (transient but distressing), hepatotoxicity, photosensitivity and increased skin cancer risk (long-term), drug interactions, teratogenicity; document discussion

— Liposomal amphotericin: disclose nephrotoxicity, infusion reactions, electrolyte derangements, cost

— Surgical resection for aspergilloma: high morbidity in patients with poor pulmonary reserve — must include palliative non-surgical pathway in shared decision-making

— Azoles are teratogenic — counsel reproductive-age patients before initiation; document effective contraception plan

— Pregnancy testing prior to starting azole in any patient with reproductive capacity

— A patient declining contraception while on voriconazole is an ethics/safety conversation, not a refusal to treat

— IV → oral antifungal transition: confirm tolerance, recheck trough at new steady state

— Inpatient → outpatient: reconcile every drug interaction; pharmacy involvement reduces readmissions

— Hospital → SNF/LTC: provide explicit antifungal duration, monitoring schedule, contact for questions; many SNFs are unfamiliar with voriconazole TDM

— Transplant centers ↔ community providers: shared care plans with explicit responsibility for level monitoring

— Construction-associated Aspergillus outbreaks in hospitals are reportable events — infection prevention should be notified for any cluster of nosocomial invasive aspergillosis; HEPA filtration on protected wards is standard of care

— Adverse drug events (severe hepatotoxicity, periostitis, SCC) should be reported to FDA MedWatch

— Disseminated/CNS aspergillosis in a transplant or hematologic malignancy patient carries very high mortality — early goals-of-care discussions are mandatory, not optional

— Palliative care consult should be considered alongside aggressive therapy when prognosis is poor

— Voriconazole and isavuconazole are expensive — verify insurance coverage at discharge; help with prior authorization to prevent therapy interruption

— Lack of access to TDM in resource-limited settings affects safety profile

Informed consent for high-risk therapies

Reproductive counseling

Transitions of care — high-risk handoff zones

Patient safety reporting and infection control

End-of-life considerations

Health equity and access

Step 3 management: A neutropenic ICU patient with probable IPA requiring decisions about further escalation — convene a multidisciplinary goals-of-care meeting including oncology, ID, ICU, family within the first 72 hours; document surrogate decision-maker and advance directives

Board pearl: Hospital-acquired aspergillosis during construction is a sentinel event — engineering controls and surveillance cultures of high-risk units are part of patient-safety infrastructure

High-Yield Associations and Rapid-Fire Clinical Facts

Aspergillus morphology: septate hyphae, acute (45°) dichotomous branching — vs Mucor: non-septate, wide, 90° branching

Galactomannan: cell wall antigen; false positive with piperacillin-tazobactam (historical), amox-clav, plasmalyte; false negative with mold-active prophylaxis

β-D-glucan: positive in Aspergillus, Candida, Pneumocystis, Fusarium; NEGATIVE in Mucor and Cryptococcus (high-yield)

Halo sign — early IPA in neutropenic host; air crescent sign — late IPA OR aspergilloma; reversed halo — mucormycosis (and COP)

Voriconazole side effects mnemonic — "VORI": Visual disturbance, Osteo (periostitis with fluoride), Rash (photosensitivity, SCC), Interactions (CYP3A4)

Isavuconazole quirk: shortens QT (only azole that does); covers some Mucorales

Drug interactions: voriconazole + rifampin = contraindicated (subtherapeutic); voriconazole + vincristine = contraindicated (neurotoxicity); azoles + tacrolimus → reduce tacrolimus dose

ABPA diagnostic anchor: total IgE ≥1000 IU/mL plus elevated Aspergillus-specific IgE in an asthmatic/CF patient

Brown mucus plugs + central bronchiectasis + finger-in-glove imaging = ABPA buzzwords

Aspergilloma cavity substrates: prior TB (#1 worldwide), sarcoidosis, ankylosing spondylitis, bullous emphysema, prior lung abscess

Chronic granulomatous disease (CGD): defective NADPH oxidase, dihydrorhodamine flow test, Aspergillus is leading cause of mortality

Aspergillus endocarditis: blood cultures negative, large vegetations, embolic events — surgical replacement required

Posaconazole prophylaxis: AML induction, GVHD on high-dose steroids — reduces invasive fungal infection mortality

Voriconazole-associated SCC of skin — long-term users, fair skin, sun-exposed sites; mandate sun protection

CAPA (COVID-associated pulmonary aspergillosis) and influenza-associated pulmonary aspergillosis — emerging high-mortality syndromes in ICU; have a low threshold for BAL galactomannan in deteriorating ventilated patients

Pneumonia not improving on broad antibiotics in a neutropenic host = mold until proven otherwise — get CT and galactomannan

Lung transplant is the highest-risk solid organ transplant for aspergillosis (anastomotic disease)

Aspergillus niger — produces oxalate crystals, can cause otomycosis (external ear); A. flavus — aflatoxin, hepatocellular carcinoma; A. terreus — intrinsically amphotericin-resistant (use voriconazole)

CCS pearl: Remember the order in CCS for febrile neutropenia not responding to antibacterials: CT chest → galactomannan → BAL → empiric voriconazole → ID consult, all early

Board Question Stem Patterns

— Answer: Serum galactomannan and bronchoscopy with BAL; begin voriconazole empirically

— Distractors: switch antibiotics, repeat blood cultures only, observe

— Answer: Oral prednisone + itraconazole

— Distractors: voriconazole monotherapy, omalizumab as first-line, surgical resection

— Answer: Surgical resection (lobectomy)

— Distractors: oral voriconazole alone, observation, systemic amphotericin

— Answer: Liposomal amphotericin B and urgent ENT surgical debridement

— Distractor trap: voriconazole (ineffective against Mucor)

— Answer: Voriconazole-induced inhibition of CYP3A4 → elevated tacrolimus levels; reduce tacrolimus dose by ~66% at initiation

— Answer: EGPA (Churg-Strauss), not ABPA

— Answer: Antibiotic-related false positive; switch antibiotic, repeat GM, pursue BAL GM

— Answer: Voriconazole periostitis; switch antifungal

— Answer: BAL galactomannan + start voriconazole or isavuconazole

— Answer: Posaconazole

Stem 1 — Classic IPA: 52-year-old man, day 14 of AML induction, ANC 100, persistent fever despite cefepime and vancomycin, new pleuritic chest pain. CT chest shows a 3-cm nodule with surrounding ground-glass (halo sign). Best next step?

Stem 2 — ABPA: 28-year-old woman with long-standing asthma, recurrent exacerbations despite ICS-LABA, expectorates brownish mucus plugs, peripheral eosinophilia, total IgE 2400, CT shows central bronchiectasis. Most appropriate therapy?

Stem 3 — Aspergilloma: 60-year-old man with treated TB 20 years ago presents with intermittent hemoptysis. CXR shows a left upper-lobe cavity containing a rounded mass with surrounding crescent of air. Best management for moderate recurrent hemoptysis with adequate pulmonary reserve?

Stem 4 — Mucor vs Aspergillus distinguishing: Diabetic in DKA with facial pain, black eschar on palate. Best initial therapy?

Stem 5 — Drug interaction: Transplant patient on tacrolimus started on voriconazole develops tremor, AKI, hyperkalemia. Cause?

Stem 6 — Aspergillus mimic: Asthmatic with eosinophilia, mononeuritis multiplex, sinus disease, p-ANCA positive, negative Aspergillus serologies.

Stem 7 — Galactomannan false positive: Neutropenic patient on pip-tazo with positive serum GM but minimal CT findings.

Stem 8 — Voriconazole long-term effect: Transplant patient on voriconazole 3 years develops bone pain, elevated ALP, normal LFTs.

Stem 9 — CAPA: Ventilated COVID-19 patient on dexamethasone deteriorating in ICU; tracheal aspirate grows Aspergillus.

Stem 10 — Prophylaxis: AML undergoing induction — which antifungal prophylaxis?

Board pearl: When the stem features an asthmatic with brown mucus plugs and IgE >1000, the answer is ABPA — full stop; when it features prior TB cavity with hemoptysis, the answer is aspergilloma; when it features neutropenic AML with halo sign, the answer is IPA → voriconazole

One-Line Recap

Aspergillosis is one organism producing three syndromes defined by host immunity: invasive aspergillosis in the immunocompromised (treat with voriconazole or isavuconazole, confirm with CT halo sign, galactomannan, and BAL), ABPA in atopic asthmatics or CF patients (treat with prednisone plus itraconazole, anchored on IgE ≥1000 and central bronchiectasis), and aspergilloma in pre-existing lung cavities (treat hemoptysis with surgical resection or bronchial artery embolization, not systemic antifungals alone).

— IPA = neutropenic/transplant/steroid host + halo sign + galactomannan → voriconazole (isavuconazole if QT/CKD/interactions); duration ≥6–12 weeks; reduce immunosuppression; surgical resection for vascular-adjacent or refractory lesions; posaconazole prophylaxis in AML/GVHD

— ABPA = asthma/CF + brown mucus plugs + central bronchiectasis + IgE ≥1000 + Aspergillus-specific IgE → prednisone + itraconazole × 16 weeks; trend IgE; rule out TB before steroids; biologics for refractory disease

— Aspergilloma = prior TB cavity (or sarcoid, AS, bullae) + fungus ball with air crescent sign + hemoptysis → surgical resection if reserve adequate; bronchial artery embolization for massive hemoptysis or poor surgical candidates; antifungals adjunctive

— Distinguishing imperatives: Aspergillus (septate, 45°, halo sign, voriconazole-sensitive) vs Mucor (non-septate, 90°, reversed halo, voriconazole-resistant, needs amphotericin + surgery); EGPA mimics ABPA but has vasculitis and ANCA; voriconazole TDM trough 1–5.5 mg/L; watch periostitis, SCC, hepatotoxicity, drug interactions, QT; pregnancy → liposomal amphotericin B

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