Spectrum of pulmonary disease caused by Aspergillus species: invasive in neutropenic hosts, allergic in asthma/CF, and aspergilloma in pre-existing cavities.
Also known as: invasive aspergillosis, ABPA, allergic bronchopulmonary aspergillosis, aspergilloma, fungus ball, Aspergillus fumigatus
Overview
Spectrum of disease caused by Aspergillus species, most commonly A. fumigatus. Three principal syndromes: invasive aspergillosis (angioinvasive infection in immunocompromised hosts), allergic bronchopulmonary aspergillosis (ABPA, a hypersensitivity disease in patients with asthma or cystic fibrosis), and aspergilloma (a saprophytic fungus ball in a pre-existing cavity).
Epidemiology
Aspergillus conidia are ubiquitous in the environment. Invasive aspergillosis is the most common invasive mold infection in patients with hematologic malignancy and allogeneic stem cell transplantation. ABPA affects approximately 1-2% of asthmatics and 2-15% of patients with cystic fibrosis. Aspergilloma develops in patients with pre-existing pulmonary cavities (e.g., from TB or sarcoid).
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Question 1PulmonaryMedium
A 42-year-old man with advanced HIV (CD4 count 60/µL despite antiretroviral therapy) has fever and productive cough. Chest CT shows a right upper lobe cavitary lesion with surrounding satellite nodules. Acid-fast bacilli sputum smears are negative on three samples, serum galactomannan is positive, and serum β-D-glucan is elevated. Which of the following is the most likely diagnosis?
ATuberculosis
BPulmonary aspergillosis
CBacterial lung abscess
DPneumocystis jirovecii pneumonia
EPulmonary mucormycosis
Reveal answer & full explanation
Correct answer: B — Pulmonary aspergillosis
ATuberculosis
BPulmonary aspergillosis✓
CBacterial lung abscess
DPneumocystis jirovecii pneumonia
EPulmonary mucormycosis
Why Pulmonary aspergillosis is correct
In advanced AIDS, invasive pulmonary aspergillosis can present as upper-lobe cavitary disease that may be mistaken for tuberculosis. This is not the halo sign (a nodule >1 cm with a rim of ground-glass opacity, seen mainly in neutropenic patients); a cavity or air crescent is usually a later finding.
Serum galactomannan, an Aspergillus cell-wall antigen, is the marker that points to Aspergillus; an elevated β-D-glucan supports an invasive fungal infection but is not specific for Aspergillus.
Three negative AFB smears do not exclude tuberculosis (smear sensitivity is low, especially in advanced HIV), so sputum NAAT and mycobacterial culture should still be sent; what TB cannot explain is the positive galactomannan together with the elevated β-D-glucan.
Invasive aspergillosis is treated with voriconazole first-line, with isavuconazole or liposomal amphotericin B as alternatives.
Why the others are wrong
Pneumocystis jirovecii pneumonia — CD4 <200 plus an elevated β-D-glucan does not equal PCP: β-D-glucan also rises in invasive aspergillosis, and galactomannan is not positive in PCP. PCP typically causes a dry cough and diffuse bilateral ground-glass opacities, not a focal cavitary lesion (the buzzword-matching trap).
Bacterial lung abscess — can cavitate, often with an air-fluid level, but would not explain a positive galactomannan or an elevated β-D-glucan (premature closure on "cavity = abscess").
Tuberculosis — upper-lobe cavitation is the classic picture and negative smears do not exclude TB, but TB does not explain a positive galactomannan or an elevated β-D-glucan (anchoring on the classic cavitary-TB picture).
Pulmonary mucormycosis — an angioinvasive mold that can cause cavitary lung lesions in immunocompromised hosts, so it mimics aspergillosis, but Mucorales do not produce galactomannan and have little β-D-glucan, so both markers are typically negative; the positive galactomannan points to Aspergillus (the trap is treating all molds as interchangeable).
Additional high-yield points
Invasive aspergillosis is a rare complication of HIV, seen mostly in advanced AIDS, often with added risk factors such as neutropenia or corticosteroid use; here it is the fungal markers, not the TB-like imaging, that point to it.
Question 2PulmonaryMedium
A 58-year-old man who completed treatment for cavitary pulmonary tuberculosis 6 years ago presents with intermittent hemoptysis and a chronic cough. He denies fever, night sweats, or weight loss. Three sputum AFB smears are negative, and a tuberculosis NAAT is negative. Chest CT shows a rounded soft-tissue mass within a pre-existing right upper lobe cavity that shifts position when he is moved to the prone position, surrounded by a crescent of air. Which of the following complications is he most likely developing?
ACavitary aspergilloma
BBronchogenic carcinoma
CCavitary histoplasmosis
DAnaerobic lung abscess
ERasmussen pseudoaneurysm
Reveal answer & full explanation
Correct answer: A — Cavitary aspergilloma
ACavitary aspergilloma✓
BBronchogenic carcinoma
CCavitary histoplasmosis
DAnaerobic lung abscess
ERasmussen pseudoaneurysm
Why Cavitary aspergilloma is correct
An aspergilloma (fungus ball) is a classic late complication that colonizes a residual cavity left by prior pulmonary TB, the most common predisposing lesion.
The imaging is characteristic: a mobile intracavitary soft-tissue mass that shifts with patient positioning, surrounded by an air-crescent sign.
Hemoptysis (sometimes massive) is the hallmark symptom, and serum Aspergillus IgG is typically elevated, supporting saprophytic colonization rather than invasive disease.
Why the others are wrong
Bronchogenic carcinoma — hemoptysis with a lung mass is plausible, but a fixed parenchymal tumor cannot move freely within an air-filled cavity or create an air-crescent sign.
Cavitary histoplasmosis — chronic cavitary histoplasmosis can follow granulomatous lung disease and cause hemoptysis, but it produces thick-walled cavities with adjacent infiltrates rather than a mobile intracavitary mass.
Rasmussen pseudoaneurysm — a pulmonary artery branch pseudoaneurysm within an old TB cavity can cause hemoptysis, but it enhances with contrast on CT and does not produce a mobile soft-tissue mass with an air-crescent sign.
Anaerobic lung abscess — an upper-lobe cavity with contents inside it can suggest an abscess, which also causes cough and hemoptysis, but a lung abscess is typically a febrile illness with purulent, often foul-smelling sputum, usually after aspiration, and shows a thick-walled cavity with an air-fluid level, not a mobile soft-tissue ball outlined by an air crescent in an afebrile man.
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Invasive: prolonged neutropenia (ANC <500 for >10 days), allogeneic HSCT, lung transplant, high-dose corticosteroids, advanced AIDS
Invasive: severe influenza or COVID-19 (influenza-associated and COVID-associated pulmonary aspergillosis)
ABPA: poorly controlled asthma, cystic fibrosis
Aspergilloma: pre-existing cavity from tuberculosis, sarcoidosis, bullous emphysema
Voriconazole prophylaxis breakthrough infections raise concern for azole-resistant Aspergillus
Pathophysiology
Invasive disease: inhaled conidia germinate into hyphae that invade blood vessels, producing infarction, hemorrhage, and necrosis. ABPA: type I and type III hypersensitivity to Aspergillus antigens colonizing the airways, causing eosinophilic inflammation, mucus plugging, and central bronchiectasis. Aspergilloma: saprophytic growth of a fungal mass within a pre-existing cavity without tissue invasion.
Disseminated invasive disease: CNS lesions with focal deficits, seizures, or stroke
Signs / physical exam
Often nonspecific; fever and tachypnea in invasive disease
Wheezing and prolonged expiration in ABPA
Cavitary lesions with intracavitary mass on imaging in aspergilloma
Sinus tenderness, palatal necrosis in invasive sinus disease
Focal neurologic deficits in CNS disease
Classic findings
Halo sign and air crescent sign on chest CT in invasive aspergillosis. Mobile intracavitary mass with 'Monod sign' in aspergilloma. Eosinophilia, markedly elevated IgE, and central bronchiectasis in ABPA.
Differential diagnosis
Mucormycosis — Diabetic ketoacidosis, iron overload, deferoxamine; rhino-orbital-cerebral or pulmonary necrosis; broad non-septate hyphae with right-angle branching on biopsy
Pseudomonas or other bacterial pneumonia in neutropenic host — Often coexists; bacterial cultures, response to broad-spectrum antibiotics
Pneumocystis pneumonia — HIV with CD4 <200, ground-glass on CT, hypoxia out of proportion to imaging; beta-D-glucan elevated in both
Lung cancer — Mass lesion can resemble aspergilloma; biopsy distinguishes
Asthma exacerbation without ABPA — No central bronchiectasis, normal IgE; ABPA suggested by total IgE >=500, peripheral eosinophilia, positive Aspergillus skin test or IgE/IgG
Diagnostic workup
Diagnostic criteria
EORTC/MSGERC criteria for invasive aspergillosis combine host factors, clinical/imaging features, and mycologic evidence (proven, probable, possible). ABPA: ISHAM/CFF criteria. Aspergilloma: imaging plus serology.
Labs
Serum galactomannan antigen — elevated in invasive aspergillosis (less sensitive on prophylaxis)
BAL galactomannan more sensitive than serum
Serum beta-D-glucan (non-specific; positive in many invasive fungal infections except mucormycosis and cryptococcosis)
Aspergillus PCR on serum or BAL (emerging utility)
ABPA criteria (ISHAM-AWG 2024): predisposing condition (e.g., asthma or CF) plus A. fumigatus sensitization (specific IgE >=0.35 kUA/L or positive skin test) and total IgE >=500 IU/mL, plus 2 of: Aspergillus-specific IgG, eosinophils >=500/microL, or CT showing bronchiectasis, mucus plugging, or high-attenuation mucus
Culture and histopathology of tissue (definitive — narrow septate hyphae with acute-angle 45-degree branching)
Imaging
Chest CT invasive: nodules with halo sign (early), air crescent sign (later as neutrophils recover), cavitation
Chest CT aspergilloma: intracavitary mass with crescent of air (Monod sign), most often in upper lobes
MRI brain for CNS lesions
Sinus CT/MRI for invasive fungal sinusitis
Treatment
First-line
Invasive aspergillosis: voriconazole 6 mg/kg IV BID x 2 doses, then 4 mg/kg IV BID, or isavuconazole 200 mg IV TID x 6 doses then 200 mg daily — both preferred over amphotericin
Liposomal amphotericin B 3-5 mg/kg/day as alternative or for voriconazole-intolerant patients
Echinocandins (caspofungin, micafungin, anidulafungin) are NOT recommended as primary monotherapy; use for salvage therapy or when azoles and amphotericin B are contraindicated
Continue therapy at least 6-12 weeks and until imaging and immune recovery support cure
ABPA (acute, symptomatic): oral prednisone/prednisolone 0.5 mg/kg/day for 2-4 weeks, tapered off over about 4 months, OR itraconazole 200 mg PO BID for 4 months as monotherapy; combine the two for recurrent exacerbations; asymptomatic ABPA is not routinely treated
Aspergilloma: observation if asymptomatic; surgical resection for recurrent hemoptysis; bronchial artery embolization for life-threatening bleeding; itraconazole has modest benefit
Second-line / adjunct
Posaconazole — prophylaxis and salvage therapy
Combination voriconazole plus echinocandin in severe disease (limited evidence)
Therapeutic drug monitoring of voriconazole trough (target 1-5 microg/mL) — variable metabolism via CYP2C19
Surgical resection for localized invasive disease near great vessels, in pericardium, or with massive hemoptysis
Reduction of immunosuppression and G-CSF support to recover neutrophils
Complications
Massive hemoptysis (aspergilloma and invasive disease)
Disseminated infection to brain, sinuses, skin, and other organs
Bronchiectasis and progressive lung damage in ABPA
Voriconazole toxicity: hepatotoxicity, visual disturbances, photosensitivity, QT prolongation, periostitis with long-term use
Azole-resistant Aspergillus fumigatus (emerging concern from environmental fungicide exposure)
PANCE pearls
Voriconazole is first-line for invasive aspergillosis — superior survival versus amphotericin in randomized trials.
Beta-D-glucan is positive in invasive aspergillosis but NEGATIVE in mucormycosis and cryptococcosis — use this to help differentiate.
Galactomannan can be falsely positive with piperacillin-tazobactam (older formulations) and falsely negative on prophylaxis.
ABPA is suspected in any asthmatic or CF patient with new infiltrates, eosinophilia, and very high IgE.
Aspergilloma rarely disseminates; the principal danger is hemoptysis, which can be massive and fatal.
References
IDSA 2016 — Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America (Patterson et al., Clin Infect Dis 2016)
ESCMID/ECMM/ERS 2017 — Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline (Ullmann et al., Clin Microbiol Infect 2018;24 Suppl 1:e1-e38)
ISHAM-ABPA Working Group 2024 — Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses (Agarwal et al., Eur Respir J 2024;63:2400061)
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