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Summary Table

Category	Details
Risk Factors	Immunocompromised patients (prolonged neutropenia, hematopoietic stem cell transplant, solid organ transplant, high-dose corticosteroids, AIDS with CD4 <100), pre-existing lung cavities (TB, sarcoidosis), chronic asthma or cystic fibrosis (for ABPA)
Etiology	Aspergillus fumigatus (most common species); acquired via inhalation of airborne conidia (spores) found in soil, decaying vegetation, and construction dust
Patient Presentation	Varies by form: (1) ABPA: recurrent asthma exacerbations with productive cough and brown mucus plugs; (2) Aspergilloma: hemoptysis in a patient with a pre-existing lung cavity; (3) Invasive pulmonary aspergillosis (IPA): fever unresponsive to broad-spectrum antibiotics in a neutropenic patient, pleuritic chest pain, dyspnea, hemoptysis
Classic Physical Exam	ABPA: wheezing, signs of bronchiectasis; Aspergilloma: often asymptomatic or hemoptysis only; IPA: fever, tachypnea, focal crackles, may have skin lesions from dissemination
Key Diagnostic Results	ABPA: elevated total IgE (>1000 IU/mL), eosinophilia, positive Aspergillus-IgE and IgG, central bronchiectasis on CT; Aspergilloma: CXR/CT showing intracavitary mass with "air crescent sign"; IPA: CT chest with "halo sign" (early) or "air crescent sign" (late), positive serum galactomannan, positive BAL culture
Management	ABPA: systemic corticosteroids + itraconazole; Aspergilloma: observation if asymptomatic, surgical resection if significant hemoptysis; IPA: voriconazole (first-line), alternatives include isavuconazole or liposomal amphotericin B
Keywords	"Fungus ball," "air crescent sign," "halo sign," "neutropenic fever not responding to antibiotics," "central bronchiectasis," "brown mucus plugs," "galactomannan," "septate hyphae with acute-angle (45-degree) branching"

1. Pathophysiology

Aspergillosis is caused by Aspergillus species, most commonly A. fumigatus, a ubiquitous mold found in the environment. The organism produces small conidia (2 to 3 micrometers) that are easily inhaled deep into the airways. The clinical syndrome that develops depends entirely on the host immune status and pre-existing lung architecture, which is why the same organism produces vastly different diseases.

In immunocompetent individuals with pre-existing lung cavities (such as old tuberculosis cavities, sarcoidosis, or emphysematous bullae), the inhaled conidia colonize the cavity without invading tissue. The fungus proliferates within the cavity, forming a dense mass of hyphae, mucus, and cellular debris called an aspergilloma (fungus ball). Because the fungus does not invade the parenchyma, patients are typically asymptomatic unless the fungus ball erodes into a bronchial vessel, causing hemoptysis, which can be life-threatening.

In atopic patients (those with asthma or cystic fibrosis), the immune system mounts an exaggerated type I (IgE-mediated) and type III (immune complex) hypersensitivity response to Aspergillus antigens colonizing the airways. This is allergic bronchopulmonary aspergillosis (ABPA). The allergic inflammation causes bronchial wall damage, mucus impaction, and progressive central bronchiectasis. The hallmark is recurrent asthma exacerbations that are difficult to control, peripheral eosinophilia, and markedly elevated serum IgE. The fungus does not invade tissue in ABPA; the damage is immunologically driven.

In severely immunocompromised patients, particularly those with prolonged neutropenia (>10 days) or those on high-dose immunosuppressive therapy after transplantation, the innate immune defenses (neutrophils and macrophages) fail to kill the inhaled conidia. The hyphae then invade blood vessel walls (angioinvasion), causing thrombosis, tissue infarction, and hemorrhagic necrosis. This is invasive pulmonary aspergillosis (IPA), the most lethal form. Angioinvasion explains the characteristic CT findings: the "halo sign" (ground-glass opacity surrounding a nodule, representing hemorrhage around the infarct) seen early in the disease, and the "air crescent sign" (a crescent of air between the necrotic lung and surrounding parenchyma) seen later as neutrophils recover and the necrotic tissue retracts. From the lungs, the fungus can disseminate hematogenously to the brain, kidneys, skin, and other organs.

The histopathological hallmark across all invasive forms is septate hyphae with dichotomous branching at 45-degree angles (acute angles), which distinguishes Aspergillus from Mucor (which has ribbon-like, pauciseptate hyphae branching at 90-degree angles).

2. Classification and Clinical Manifestation

Form	Immune Status	Lung Anatomy	Mechanism	Key Clinical Features
ABPA	Immunocompetent, atopic (asthma, cystic fibrosis)	Normal or with bronchiectasis	Type I and III hypersensitivity to Aspergillus antigens	Recurrent wheezing, productive cough with brown/golden mucus plugs, proximal (central) bronchiectasis, fleeting pulmonary infiltrates, peripheral eosinophilia, markedly elevated total IgE
Aspergilloma	Immunocompetent	Pre-existing cavity (TB, sarcoidosis, emphysema)	Saprophytic colonization of a cavity without tissue invasion	Often asymptomatic; hemoptysis (can be severe/fatal); mobile intracavitary mass on imaging
Chronic Pulmonary Aspergillosis (CPA)	Mildly immunocompromised or chronic lung disease (COPD, prior TB)	Cavitary or fibrotic lung	Slowly progressive infection, semi-invasive	Chronic productive cough, weight loss, fatigue over months; single or multiple cavities that may enlarge; positive Aspergillus IgG
Invasive Pulmonary Aspergillosis (IPA)	Severely immunocompromised (neutropenia, transplant, high-dose steroids)	Normal (no pre-existing cavity needed)	Angioinvasion with thrombosis and hemorrhagic infarction	Fever refractory to broad-spectrum antibiotics, pleuritic chest pain, dyspnea, hemoptysis; rapid clinical deterioration; halo sign on CT
Disseminated / Extrapulmonary	Severely immunocompromised	Any	Hematogenous spread from lungs	CNS abscess (ring-enhancing lesions), skin nodules/eschars, renal or hepatic involvement; very high mortality

3. Diagnostic Workup

Test	Form of Aspergillosis	Role	Key Finding
Chest X-ray	All forms	Initial imaging	Aspergilloma: round mass in a cavity; ABPA: fleeting infiltrates, "finger-in-glove" sign (mucoid impaction); IPA: nodules, wedge-shaped infiltrates
CT Chest (HRCT)	All forms	Best initial imaging for characterization	Aspergilloma: intracavitary mass with air crescent sign, mobile with position change; ABPA: central bronchiectasis, mucoid impaction; IPA: halo sign (early), air crescent sign (late)
Serum total IgE	ABPA	Screening and monitoring	>1000 IU/mL (strongly suggestive); used to track treatment response
Aspergillus-IgE (skin prick test or serum)	ABPA	Diagnostic criterion	Positive (confirms sensitization)
Aspergillus-IgG (precipitins)	ABPA, Aspergilloma, CPA	Supportive	Positive in aspergilloma and CPA; part of ABPA diagnostic criteria
Peripheral eosinophil count	ABPA	Supportive	>500 cells/microL
Serum galactomannan (GM)	IPA	Biomarker for invasive disease	Elevated (index >0.5); high sensitivity in neutropenic patients; false positives with piperacillin-tazobactam
Serum (1,3)-beta-D-glucan	IPA	Nonspecific biomarker for invasive fungal infection	Elevated; not unique to Aspergillus (also positive in Candida, Pneumocystis)
BAL culture and galactomannan	IPA	Confirmatory	Culture of Aspergillus from BAL; BAL GM index >1.0 is highly suggestive
Tissue biopsy with histopathology	IPA, CPA	Gold standard (most accurate test)	Septate hyphae with 45-degree branching; evidence of tissue invasion

ABPA Workup: When a patient with poorly controlled asthma or cystic fibrosis presents with recurrent exacerbations, peripheral eosinophilia, and fleeting pulmonary infiltrates, ABPA should be suspected. The best initial step is to measure serum total IgE (a level >1000 IU/mL is a key threshold). The diagnosis is then supported by demonstrating Aspergillus sensitization via positive skin prick test or elevated Aspergillus-IgE, along with positive Aspergillus-IgG (precipitins), elevated peripheral eosinophils, and central bronchiectasis on HRCT. There is no single confirmatory test; ABPA is diagnosed by meeting a constellation of criteria (the Rosenberg-Patterson or revised ISHAM criteria). The total IgE level is also used to monitor treatment response and detect flares.

Aspergilloma Workup: A patient with a known lung cavity (particularly from prior TB) who presents with hemoptysis should raise suspicion. Chest CT is the best initial test and characteristically shows a solid, round mass within a cavity with a surrounding crescent of air (air crescent sign). The mass classically moves with changes in patient position ("rolling ball" on decubitus imaging). Aspergillus IgG (precipitating antibodies) is positive in over 90% of cases, making it a highly reliable serologic marker. Sputum cultures may grow Aspergillus, but this is not always reliable. Biopsy is rarely needed because the imaging and serology are usually sufficient.

Invasive Pulmonary Aspergillosis Workup: In a neutropenic patient with persistent fever despite broad-spectrum antibacterial therapy, the best initial step is to obtain a CT chest, which may show the halo sign (a ground-glass halo surrounding a pulmonary nodule, representing hemorrhage around an area of infarction) in early disease. This finding in the right clinical context is highly suggestive and should prompt empiric antifungal therapy even before culture confirmation. Serum galactomannan (a cell wall component of Aspergillus released during hyphal growth) should be sent as a biomarker; it has good sensitivity in neutropenic patients but performs less well in non-neutropenic hosts. Be aware that piperacillin-tazobactam can cause false-positive galactomannan results, a frequently tested fact. BAL with culture and galactomannan improves diagnostic yield. The most accurate test (gold standard) is tissue biopsy demonstrating septate hyphae with acute-angle branching invading tissue, but this is often impractical in critically ill, thrombocytopenic patients.

4. Management and Treatment

Form	First-Line Treatment	Alternative / Adjunct	Duration	Key Considerations
ABPA	Oral prednisolone 0.5 mg/kg/day for 2 weeks, then taper over 3 to 5 months	Itraconazole 200 mg twice daily (steroid-sparing agent) for 16 weeks or longer	Months; guided by IgE levels and symptoms	Monitor total IgE every 6 to 8 weeks; consider omalizumab in refractory cases
Aspergilloma (asymptomatic)	Observation (no treatment needed)	N/A	Indefinite monitoring	Intervene only if symptomatic
Aspergilloma (hemoptysis)	Surgical resection (lobectomy)	Bronchial artery embolization for acute life-threatening hemoptysis as a bridge to surgery	Definitive with surgery	Antifungals alone are ineffective for aspergilloma because the fungus ball is avascular and drug penetration is poor
Invasive Pulmonary Aspergillosis	Voriconazole: loading dose 6 mg/kg IV every 12 hours on day 1, then 4 mg/kg IV every 12 hours; switch to oral 200 mg twice daily when stable	Isavuconazole 200 mg IV/PO every 8 hours for 6 doses (loading), then 200 mg daily; or liposomal amphotericin B 3 to 5 mg/kg/day IV	Minimum 6 to 12 weeks; until clinical and radiographic resolution and immune reconstitution	Voriconazole requires therapeutic drug monitoring (target trough 1 to 5.5 mcg/mL); visual disturbances and hepatotoxicity are common side effects; contraindicated with certain CYP450 interactions
Disseminated / CNS Aspergillosis	Voriconazole (good CNS penetration)	Liposomal amphotericin B (poor CNS penetration but used if voriconazole contraindicated)	Prolonged (months to over a year)	Neurosurgical consultation for abscess drainage if accessible

ABPA: The cornerstone of ABPA management is systemic corticosteroids to suppress the immunologic response driving airway damage. Prednisolone is started at 0.5 mg/kg/day for 1 to 2 weeks, then gradually tapered over 3 to 5 months. Itraconazole is added as a steroid-sparing agent, reducing the fungal antigen burden in the airways and allowing lower steroid doses. Total IgE should be monitored regularly; a doubling of the baseline IgE level (after initial decline) suggests a flare requiring retreatment. In patients with steroid-dependent or refractory ABPA, omalizumab (anti-IgE monoclonal antibody) has shown benefit and may be considered.

Aspergilloma: The key management principle is that asymptomatic aspergillomas do not require treatment. Antifungal drugs do not penetrate the avascular fungus ball effectively. Intervention is warranted only for symptomatic hemoptysis. For life-threatening hemoptysis, bronchial artery embolization provides temporizing control of bleeding. Definitive treatment is surgical resection (lobectomy or segmentectomy) in patients with adequate pulmonary reserve. The decision to operate must weigh the risk of surgery against the risk of recurrent fatal hemorrhage.

Invasive Pulmonary Aspergillosis: This is a medical emergency. The next best step whenever IPA is suspected (neutropenic fever + halo sign on CT) is to start empiric voriconazole immediately, even before culture results return. Delay in antifungal therapy increases mortality. Voriconazole is the first-line agent based on landmark trial data (superior survival compared to amphotericin B deoxycholate). Isavuconazole is an acceptable alternative with fewer drug interactions and no need for cyclodextrin vehicle (therefore safer in renal impairment). Liposomal amphotericin B is the alternative for patients who cannot tolerate or have contraindications to azoles. Echinocandins (caspofungin, micafungin) are used as salvage combination therapy but are not first-line monotherapy. Equally important is immune reconstitution: reducing immunosuppression and using G-CSF to recover neutrophil counts whenever possible. Treatment continues for a minimum of 6 to 12 weeks and should not stop until imaging shows resolution and the patient's immune status has recovered.

Voriconazole monitoring: Therapeutic drug monitoring is essential because of its nonlinear pharmacokinetics. Target trough levels are 1 to 5.5 mcg/mL. Common adverse effects include transient visual disturbances (photopsia), hepatotoxicity, skin photosensitivity (long-term use increases risk of squamous cell carcinoma), and QT prolongation. Voriconazole is a potent CYP2C19 and CYP3A4 inhibitor, leading to numerous drug interactions (e.g., with sirolimus, which is contraindicated with concurrent voriconazole).

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Mucormycosis (Zygomycosis)	Also causes invasive pulmonary infection in immunocompromised patients; also causes angioinvasion and tissue necrosis	Mucor: ribbon-like, pauciseptate (few or no septa), 90-degree branching hyphae; classic risk factor is diabetic ketoacidosis or iron overload (deferoxamine use); rhinocerebral involvement with black eschar is characteristic; galactomannan is negative in mucormycosis
Tuberculosis	Both can cause upper lobe cavitary disease and hemoptysis	TB: constitutional symptoms (night sweats, weight loss), positive PPD/IGRA, acid-fast bacilli on sputum smear; aspergilloma may develop inside a pre-existing TB cavity (the two can coexist)
Granulomatosis with Polyangiitis (GPA)	Can cause pulmonary nodules and cavities with hemoptysis	GPA: involves upper airway (sinusitis, saddle nose), kidneys (glomerulonephritis with hematuria/proteinuria), positive c-ANCA / anti-PR3
Lung abscess (bacterial)	Cavity with air-fluid level on imaging; productive cough	Bacterial abscess: air-fluid level (aspergilloma shows solid mass, not fluid); foul-smelling sputum; responds to antibiotics; risk factors include aspiration
Pneumocystis jirovecii pneumonia (PJP)	Occurs in immunocompromised patients (HIV/AIDS); diffuse pulmonary infiltrates	PJP: bilateral ground-glass opacities (not nodules or halo sign); elevated LDH; CD4 <200; diagnosed by silver stain on BAL (showing cysts); beta-D-glucan is positive but galactomannan is negative
Eosinophilic pneumonia	Peripheral eosinophilia and pulmonary infiltrates, similar to ABPA	Eosinophilic pneumonia: no Aspergillus sensitization (negative IgE and IgG to Aspergillus); no central bronchiectasis; "photographic negative of pulmonary edema" pattern (peripheral infiltrates) on imaging
Lung cancer	Solitary pulmonary nodule or mass on imaging; can mimic aspergilloma	Lung cancer: solid mass that does not move with position change; no surrounding crescent of air; PET-avid; tissue biopsy shows malignant cells, not fungal hyphae

6. Traps and High-Yield Pearls

The most common way students get questions on aspergillosis wrong is by confusing the different clinical forms and applying the wrong management. Test-writers exploit this by presenting a neutropenic patient with IPA and offering itraconazole as an answer choice (wrong: itraconazole is for ABPA, not invasive disease) or by presenting an aspergilloma and offering voriconazole (wrong: antifungals do not penetrate the fungus ball). Always match the clinical form to the correct treatment.

A second frequent trap involves the halo sign versus air crescent sign timeline. The halo sign appears early in IPA (first 1 to 2 weeks) and may disappear as the disease progresses. The air crescent sign appears later, typically as neutrophils recover. A vignette showing a neutropenic patient whose CT initially showed a halo sign and now shows an air crescent sign after G-CSF administration is testing whether you recognize that this represents immune recovery and tissue cavitation, not worsening disease.

Another tested concept is the false-positive galactomannan with piperacillin-tazobactam. A vignette may describe a neutropenic patient on pip-tazo with a positive galactomannan, and the question tests whether you know this could be a false positive and whether you would still pursue further workup (the answer is yes: you should still treat empirically and obtain CT/BAL rather than dismissing the result).

For ABPA, the classic trap is a patient with "difficult-to-control asthma" where the vignette buries the clue of central bronchiectasis or brown mucus plugs in the history. Students who focus on adjusting asthma medications miss the diagnosis entirely. The core competency being tested is recognizing that refractory asthma with eosinophilia and elevated IgE should trigger evaluation for ABPA.

Finally, the histologic distinction between Aspergillus and Mucor is one of the most reliably tested facts in mycology. Remember: Aspergillus = septate, 45-degree acute-angle branching; Mucor = pauciseptate (ribbon-like), 90-degree wide-angle branching. If a biopsy description mentions "non-septate" or "ribbon-like" hyphae, the answer is mucormycosis regardless of how "Aspergillus-like" the clinical scenario appears.

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