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).
Try two board-style Aspergillosis questions
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Question 1Infectious DiseaseMedium
A 47-year-old man who is day 14 of induction chemotherapy for acute myeloid leukemia has persistent fever to 39.1°C despite 6 days of broad-spectrum antibiotics. His absolute neutrophil count is 80/microL. He reports new pleuritic right-sided chest pain and one episode of blood-streaked sputum. Chest CT shows a 2.5-cm right upper lobe nodule surrounded by a rim of ground-glass opacity. Which of the following is the most appropriate next diagnostic test?
ASerum galactomannan antigen
BSerum cryptococcal antigen test
CUrine Histoplasma antigen test
DSputum acid-fast bacilli smear
Reveal answer & full explanation
Correct answer: A — Serum galactomannan antigen
ASerum galactomannan antigen✓
BSerum cryptococcal antigen test
CUrine Histoplasma antigen test
DSputum acid-fast bacilli smear
Why Serum galactomannan antigen is correct
The picture is classic invasive pulmonary aspergillosis: prolonged neutropenia, persistent fever through broad-spectrum antibiotics, pleuritic pain, hemoptysis, and a nodule with a surrounding "halo sign" on CT.
Serum galactomannan (a cell-wall polysaccharide of Aspergillus) is the recommended non-invasive mycologic test in this setting and is part of the EORTC/MSGERC criteria for probable invasive aspergillosis; BAL galactomannan is even more sensitive if bronchoscopy is feasible.
Sensitivity falls with mold-active prophylaxis, so a positive result strongly supports the diagnosis and a negative result does not exclude it.
Why the others are wrong
Sputum acid-fast bacilli smear is appropriate for tuberculosis, which can cause cavitary disease, but the halo sign in an acutely neutropenic AML patient points to angioinvasive mold, not TB.
Serum cryptococcal antigen test fits T-cell-deficient hosts (advanced HIV, transplant) with meningitis or scattered pulmonary nodules without a halo sign; it does not fit profound neutropenia.
Urine Histoplasma antigen test is useful for disseminated histoplasmosis, which presents with hepatosplenomegaly, cytopenias, and exposure history rather than an acute neutropenic halo-sign nodule.
Question 2Infectious DiseaseMedium
A 58-year-old man with a history of pulmonary tuberculosis treated 15 years ago presents with intermittent cough and small-volume hemoptysis. He is otherwise well, with no fever and a normal white blood cell count. Chest CT shows a 4-cm rounded soft-tissue mass within a fibrotic upper-lobe cavity, separated from the cavity wall by a crescent of air that shifts when he is repositioned prone. Serum Aspergillus IgG is positive. Which of the following complications is most likely to develop in this patient?
ARhino-orbital-cerebral tissue necrosis
BMassive, potentially fatal hemoptysis
CCentral bronchiectasis with mucus plugging
DAngioinvasive dissemination to the brain
Reveal answer & full explanation
Correct answer: B — Massive, potentially fatal hemoptysis
ARhino-orbital-cerebral tissue necrosis
BMassive, potentially fatal hemoptysis✓
CCentral bronchiectasis with mucus plugging
DAngioinvasive dissemination to the brain
Why Massive, potentially fatal hemoptysis is correct
The CT findings (a mobile intracavitary mass with a surrounding air crescent, the Monod sign, that shifts with positioning) plus positive Aspergillus IgG in an old tuberculous cavity establish an aspergilloma (fungus ball).
An aspergilloma is saprophytic, non-invasive growth within a pre-existing cavity. It rarely disseminates; its principal and potentially fatal danger is hemoptysis from erosion of bronchial-artery vessels in the cavity wall, which can be massive.
Management of recurrent or massive bleeding is bronchial artery embolization or surgical resection; observation is appropriate while the patient is asymptomatic.
Why the others are wrong
Angioinvasive dissemination to the brain is the hallmark of INVASIVE aspergillosis in neutropenic or transplant patients; this immunocompetent host with a non-invasive fungus ball is not at meaningful risk for angioinvasion.
Central bronchiectasis with mucus plugging is the complication of allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity disease in patients with asthma or cystic fibrosis who have very high IgE and eosinophilia, not of an aspergilloma.
Rhino-orbital-cerebral tissue necrosis describes mucormycosis and invasive fungal sinusitis, classically in diabetic ketoacidosis or iron overload; it is not a complication of a cavitary aspergilloma.
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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 IgE >1000, 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: total IgE >1000 IU/mL, Aspergillus-specific IgE and IgG, peripheral eosinophilia >500, positive Aspergillus skin test
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
Echinocandin — caspofungin, micafungin, anidulafungin — as second-line monotherapy or in combination
Continue therapy at least 6-12 weeks and until imaging and immune recovery support cure
ABPA: oral corticosteroids (prednisone 0.5 mg/kg/day taper over 3-6 months) is mainstay; itraconazole 200 mg PO BID or voriconazole as steroid-sparing adjunct
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)
ECIL/EORTC — European guidelines for the diagnosis and management of invasive aspergillosis (Ullmann et al., Clin Microbiol Infect 2018)
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