Chronic Pulmonary Aspergillosis

Chronic Pulmonary Aspergillosis 

• Chronic pulmonary aspergillosis is a disease caused by various species of Aspergillus, a common mold
• Aspergillus species are ubiquitous in soil, water, air, and food
• Aspergillus spores are regularly inhaled and normally are cleared by ciliary and other mechanisms without harmful consequences; however, in some patients, colonization or saprophytic growth occurs without tissue invasion
• Saprophytic growth may occur in preexisting lung cavities. If patient is asymptomatic and cavity size of single aspergilloma does not progress over 6 to 24 months, continue to observe
• A spectrum of disease is recognized and may be influenced by the existence of subtle immune deficiency (eg, diabetes mellitus, alcohol use disorder malnutrition). In some patients, periodic monitoring reveals increasing symptoms and radiographic evidence of progressive (locally invasive) disease that warrants treatment
  • Medical treatment with antifungals may suffice in some patients, but surgical intervention is sometimes required, especially if hemoptysis occurs

• Chronic pulmonary aspergillosis is a disease caused by various species of Aspergillus, a common mold 
  • Aspergillus spores are ubiquitous. They are regularly inhaled and normally cleared by ciliary and other mechanisms without harmful consequences; however, in some patients, colonization or saprophytic growth occurs without tissue invasion
  • Chronic infection caused by Aspergillus occurs almost exclusively in patients with cavitary lung disease, in whom Aspergillus also may invade surrounding lung parenchyma

Classification

• Classified by presence (and degree) or absence of tissue invasion
• Saprophytic
  • Aspergilloma (also called fungus ball or fungal ball)
    • Pulmonary
      • Hyphal elements and mucinous material form a mass in a preformed cavity resulting from tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, or other chronic cavitary lung disease
  • Chronic pulmonary aspergillosis
    • Characterized by pulmonary nodules and/or slowly evolving or enlarging single or multiple cavities, with or without aspergillomas
      • By definition, symptoms (chronic cough with or without hemoptysis, dyspnea, and constitutional symptoms) and radiographic findings have been present for at least 3 months
      • Aspergillus-specific IgG or serum-precipitating antibodies may be detected 
      • Chronic cavitary pulmonary aspergillosis may progress to chronic fibrosing pulmonary aspergillosis, an end-stage complication of chronic cavitary pulmonary aspergillosis
    • There is believed to be a continuum of chronic pulmonary Aspergillus with subacute invasive pulmonary aspergillosis 
• Invasive
  • Subacute invasive pulmonary aspergillosis (chronic necrotizing aspergillosis) 
    • May evolve from chronic cavitary pulmonary aspergillosis, with direct invasion of Aspergillus into the surrounding lung parenchyma, causing cavity enlargement and progressive lung damage
    • May occur de novo, usually in patients with some degree of immune dysfunction, beginning as pulmonary nodules or consolidation and progressing over weeks to months to cavitary disease
    • Respiratory and constitutional symptoms are usually present, and Aspergillus-specific IgG or serum-precipitating antibodies may be detected

Diagnosis

Clinical Presentation

History

• Medical history may reveal underlying conditions that foster colonization or invasive disease. Unifying factor in almost all aspergillosis is presence of chronic structural pulmonary disease and/or an immune defect
  • Pulmonary aspergilloma requires presence of immunologically protected cystic lung spaces typically from prior infection, chronic obstructive pulmonary disease, malignancy, or inflammatory lung disease 
  • Chronic cavitary pulmonary aspergillosis and subacute invasive cavitary pulmonary aspergillosis (chronic necrotizing aspergillosis) are associated with subtle immunocompromised states, including chronic steroid use, diabetes, and alcohol use disorder
• Patient may have a history of likely exposure or inoculation (eg, gardening, composting, excavation or building renovation)
• Symptoms
  • Noninvasive disease
    • Aspergilloma
      • Pulmonary disease is often asymptomatic, but hemoptysis may occur if there is invasion of a blood vessel and may be severe
      • Sinus disease may be asymptomatic or associated with nasal obstruction and discharge, headache, or facial pain
    • Chronic cavitary pulmonary aspergillosis
      • Persistent (3 months or more) respiratory symptoms (productive or nonproductive cough, wheezing, dyspnea), which may be progressive
  • Invasive disease
    • May be characterized by constitutional symptoms (fever, diaphoresis, weight loss, fatigue) in addition to localizing symptoms
    • Pulmonary or tracheobronchial symptoms include cough, dyspnea and—with angioinvasive disease—pleuritic pain and/or hemoptysis

Physical examination

• Patients may appear chronically or acutely ill
• Fever may be present in invasive disease
• Lung examination may be unremarkable or findings may reflect the predisposing pulmonary condition (eg, wheezing, rhonchi, decreased air movement); signs of localized consolidation (percussion dullness, rales) may be present

Causes and Risk Factors

Causes

• Most common cause is inhalation of the Aspergillus species of mold
  • Aspergillus species are ubiquitous in air, water, food, and soil and regularly are inhaled without ill effect
    • Marijuana has been shown to contain Aspergillus spores
  • Patients who develop pulmonary disease often have a predisposing abnormality of lung architecture or a subtle immune defect

Risk factors and/or associations

Age

• Chronic pulmonary aspergillosis usually occurs in middle age 

Sex

• Chronic cavitary pulmonary aspergillosis shows a male predominance 

Other risk factors/associations

• Aspergilloma
  • Pulmonary
    • Occurs in preexisting lung cavity, as occurs in the following:
      • Chronic obstructive pulmonary disease (bullous emphysema)
      • Sarcoidosis
      • Tuberculosis
      • Histoplasmosis
      • Bacterial lung abscess
      • Congenial cyst
      • Bleb from pneumocystic pneumonia in AIDS
• Chronic cavitary and subacute invasive aspergillosis
  • Immune defects, some of which are relatively subtle (eg, diabetes mellitus, alcohol use disorder, malnutrition)
  • Underlying lung disease (eg, chronic obstructive pulmonary disease, current or previous tuberculosis or other mycobacterial disease, sarcoidosis)

Diagnostic Procedures

Primary diagnostic tools

• Diagnosis of aspergillosis is complicated by its myriad clinical presentations and the ubiquitous presence of the organism in the environment. These factors make it difficult, in some circumstances, to distinguish pathogenicity from colonization or contamination 
• One essential tool for diagnosing Aspergillus is maintaining a high suspicion in susceptible patients. Chronic pulmonary symptoms and a history of cavitary lung disease should raise suspicion for chronic pulmonary aspergillosis spectrum 
• Conversely, the diagnosis is often suggested by radiographic findings or results of culture and histopathology studies obtained during work-up of pulmonary or other localized symptoms
• Aspergilloma
  • In an asymptomatic patient, aspergilloma may be an incidental finding on chest radiography 
  • Presence of Aspergillus IgG or precipitins can be detected in 90% of patients with aspergilloma; this presence confirms Aspergillus as the cause 
• Chronic cavitary pulmonary aspergillosis diagnostic criteria include:
  • 3-month history of progressive pulmonary or systemic symptoms
  • Presence of 1 or more pulmonary cavities on plain radiographs or CT, which progress in size or in extent of surrounding parenchymal changes
  • Serologic (Aspergillus-specific IgG or precipitins) or microbiologic evidence of Aspergillus
  • Chronic fibrosing cavitary aspergillosis is a complication of chronic cavitary pulmonary fibrosis in which there is severe fibrosis of at least 2 lobes, with significant loss of lung function
• Subacute invasive aspergillosis
  • Definitive diagnosis requires histologic demonstration of tissue invasion with hyphal elements. Serologic evidence of infection (positive Aspergillus IgG or precipitins) may support diagnosis of invasive disease
  • Plain radiographs or CT scans may reveal typical or suggestive findings of various conditions associated with Aspergillus and may serve to guide needle biopsy or aspiration
  • Growth of Aspergillus species from nonsterile sites is not proof of etiology, but it may provide suggestive evidence in some circumstances
  • Galactomannan antigen may be detected in blood or respiratory secretions of patients with subacute invasive aspergillosis
• Patients with chronic pulmonary aspergillosis should undergo pulmonary function testing to guide management of airway disease and to provide a baseline for yearly monitoring 

Laboratory

• Culture
  • Aspergillus generally grows well on standard media
    • Sometimes an unanticipated finding from specimens submitted for routine culture. Because Aspergillus is ubiquitous in the environment, positive cultures from sputum must be interpreted in light of clinical context and supporting laboratory and radiographic evidence
• Galactomannan antigen is a major cell wall component of Aspergillus, although it is not specific for Aspergillus species versus other fungi. Sensitivity is significantly higher in bronchoalveolar lavage fluid than in serum 
• Aspergillus IgG antibody by ELISA and anti-IgG precipitins supports diagnosis of invasive disease
  • Positive in greater than 90% of patients with chronic pulmonary aspergillosis 
• Histology is definitive, showing typical hyphal elements within lung tissue 

Imaging

• Chronic pulmonary aspergillosis
  • Aspergillus nodule
    • Chest radiograph or CT
      • One or several nodules; may cavitate or remain solid 
  • Aspergilloma
    • Pulmonary
      • Chest radiograph or chest CT shows a thick-walled cavity, typically in upper lobe, containing a mass, which may move with position change
      • Crescent-shaped air pocket (air crescent) is often visible between aspergilloma and cavity wall
      • Chest CT is more sensitive than plain radiograph
  • Chronic cavitary pulmonary aspergillosis
    • Chest radiograph or CT
      • Single or multiple thin- or thick-walled cavities, which may or may not contain an aspergilloma
      • Cavities expand over time
  • Chronic fibrosing pulmonary aspergillosis
    • Chest radiograph or CT
      • Fibrosis appears as consolidation of the parenchyma; large cavities with surrounding fibrosis may be seen
      • At least 2 lobes of the lung must be involved to make the diagnosis
• Subacute invasive pulmonary aspergillosis (chronic necrotizing pulmonary aspergillosis)
  • Constellation of changes that includes nodules, consolidation, and cavitation; progresses over 1- to 3-month period 
  • Usually involves upper lobes 

Differential Diagnosis

Most common

• Aspergilloma
  • Pulmonary
    • Often asymptomatic unless bleeding or hemoptysis occurs, and differential diagnosis is largely radiographic. Conditions with a similar appearance on chest imaging (and which also may be associated with hemoptysis) include:
      • Cavitating hematoma
      • Malignant neoplasm
      • Wegener granulomatosis
      • Hydatid (echinococcal) cyst
    • Distinction is most often made by bronchoscopic examination (with or without biopsy) or by needle aspiration. Other distinguishing features include:
      • Pulmonary hematoma may be associated with known coagulopathy, embolic event, trauma, or procedure
      • Cavitary neoplasm may be clinically indistinguishable from pulmonary aspergilloma, although cavitary neoplasm may be more commonly associated with constitutional symptoms (eg, weight loss) and with a smoking history
      • Wegener granulomatosis is an autoimmune disease of the lungs (sometimes with kidney involvement) in which autoantibodies (eg, antineutrophil cytoplasmic autoantibodies, antinuclear antibodies) often are detected. Biopsy shows granulomatous inflammation and necrotizing small vessel vasculitis 
      • Echinococcosis
• Other forms of chronic pulmonary aspergillosis (chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis) and subacute invasive pulmonary aspergillosis and chronic necrotizing pulmonary aspergillosis 
  • Progressive pulmonary diseases that, like chronic pulmonary aspergillosis, may appear as infiltrates, multiple small cavities or nodules, or areas of fibrosis on imaging and clinically present as cough, dyspnea, weight loss and/or general fatigue and malaise, similar to forms of chronic pulmonary aspergillosis:
    • Malignant neoplasm
      • Diagnosis is made by bronchoscopic image-guided needle or by open-lung biopsy with histopathologic identification of malignant cells and characteristic architectural changes in tissue
    • Sarcoidosis
      • Chronic multisystem disease of unknown cause; pulmonary involvement is usual
      • May be associated with hypercalcemia, elevated serum levels of angiotensin converting enzyme. Biopsy reveals noncaseating granulomas
    • Wegener granulomatosis
      • Distinguished by biopsy findings of granulomatous inflammation and necrotizing small vessel vasculitis
      • Noninvasive evidence may include autoantibodies (eg, antineutrophil cytoplasmic antibodies, antinuclear antibodies), although they are not invariably detected
    • Tuberculosis
      • Distinguished from pulmonary aspergillosis by culture or polymerase chain reaction demonstration of Mycobacterium tuberculosis in sputum or tissue
      • Microscopic examination of sputum reveals acid-fast organisms, which also can be seen (along with caseating granulomas) in histopathology of biopsied tissue
    • Histoplasmosis
      • Occurs in certain geographic areas (Ohio and Mississippi River Valleys), so history may be helpful in excluding likelihood. 
      • Histoplasma antigen may be detected in urine, although this is not a sensitive test in chronic disease
      • Definitive diagnosis is made by demonstrating organism in sputum or tissue
    • Bacterial lung abscess
      • Unlike chronic pulmonary aspergillosis, characterized by halitosis and production of copious amounts of foul-smelling purulent secretions
      • Culture of sputum or (ideally) bronchoscopic aspirate usually reveals polymicrobial mixture of anaerobes. Response to antibacterial antibiotics is a further distinguishing factor

Treatment Goals

• Goal is to prevent progressive tissue damage and to alleviate symptoms

Disposition

Admission criteria

Criteria for ICU admission

• Hemoptysis

Recommendations for specialist referral

• Refer patients who have suspected chronic pulmonary aspergillosis to a pulmonologist

Treatment Options

Treatment depends on the form of Aspergillus disease and the degree of clinical illness

• Aspergilloma
  • If patient is asymptomatic and cavity size of single aspergilloma does not progress over 6 to 24 months, continue to observe
  • If patient is symptomatic or size of aspergilloma is increasing, surgical resection is recommended (if feasible) with pre- and perioperative antifungal therapy (voriconazole or an echinocandin) if spillage occurs or is anticipated. If spillage does occur, 4 weeks minimum treatment is recommended
  • If surgery is not possible, antifungal therapy alone may mitigate progression and further hemoptysis
• Chronic cavitary pulmonary aspergillosis 
  • Stable patients without severe or systemic symptoms may not require therapy
  • Patients with significant pulmonary or systemic symptoms should receive itraconazole or voriconazole for at least 6 months
  • Hemoptysis may require administration of tranexamic acid or localized arterial embolization
• Subacute invasive pulmonary aspergillosis (chronic necrotizing pulmonary aspergillosis)
  • All patients require treatment, preferably with voriconazole, for at least 6 months or another regimen appropriate for patients with other forms of invasive aspergillosis (eg, immunocompromised patients) 

Drug therapy

• Antifungal agents
  • Voriconazole
    • Voriconazole Solution for injection; Adults: 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours; if maintenance dose not tolerated, decrease to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy after 7 days if clinical improvement. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks.
  • Itraconazole
    • Itraconazole Oral solution; Adults: 200 mg PO every 12 hours as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.
  • Treatment of some conditions (eg, chronic cavitary, fibrosing or subacute invasive pulmonary aspergillosis) may require prolonged or indefinite antifungal medication 

Nondrug and supportive care

Procedures

Surgical resection of pulmonary aspergilloma

General explanation

• Single pulmonary aspergillomas may be removed during open thoracotomy or video-assisted thoracoscopic surgery, usually as a sublobar segmentectomy or wedge resection, but removal occasionally requires lobectomy or even pneumonectomy 

Indication 

• Hemoptysis
• Progressive and symptomatic tissue destruction

Contraindications

• Poor pulmonary function precludes thoracotomy
• Uncorrected coagulopathy or thrombocytopenia

Complications

• Pneumothorax 
• Bronchopulmonary fistula 
• Spillage of Aspergillus into pleural space with potential empyema 
• Worsening of already-compromised pulmonary function 

Embolization of bronchial artery for hemoptysis in aspergilloma or invasive pulmonary aspergillosis

General explanation

• Bronchial artery invaded by Aspergillus disease is injected with embolizing agent to stop bleeding
  • Unaffected lung is first preferentially intubated 
  • Bronchoscopy may be used to perform intrabronchial balloon tamponade to stabilize the patient before bronchial angiogram and embolization 
  • Once patient is stabilized, bronchial angiogram is performed and embolizing agent is injected into bleeding vessel 

Indication

• Hemoptysis from Aspergillus disease invading into bronchial vessel in patient for whom surgery is not currently feasible
  • Massive hemoptysis of 300 mL or more in 24 hours 
  • Moderate hemoptysis of 3 or more episodes of 100 mL or more within 1 week 
  • Mild hemoptysis with chronic or slowly increasing episodes 

Contraindications 

• Hemoptysis arising from a nonbronchial source (pulmonary artery or collateral systemic vessel)
• Concern that nontarget embolization may occur, especially to the spinal cord

Complications 

• Nontarget embolization
  • Can lead to lower extremity neurologic deficit
  • May cause transient chest pain or dysphagia if intercostals or esophageal branches are hit
• Pulmonary infarction
• Bronchial necrosis
• Contrast reaction

Interpretation of results

• Control of hemoptysis for up to 1 month after procedure is the usual outcome 
• Long-term recurrence rates of 10% to 52% have been reported in 4-year follow-up 

Comorbidities

• Numerous interactions between azole antifungal agents and other medications are documented; dosage adjustments or alternate drugs may be necessary 

Monitoring

• Therapeutic drug monitoring
  • There is some evidence that therapeutic drug monitoring in patients who have aspergillosis leads to improved patient outcomes and reduced toxicity
  • If voriconazole or itraconazole is used to treat chronic or invasive Aspergillus disease, therapeutic drug monitoring is recommended. Serum concentrations are measured at steady state (4-7 days after starting treatment); guidelines differ somewhat in defining optimal trough levels 
    • Infectious Diseases Society of America guidelines recommend target trough levels of 0.5 to 1 μg/mL for itraconazole and 1 to 1.5 μg/mL for voriconazole; toxicity may be associated with trough levels greater than 3 μg/mL of itraconazole and greater than 5 to 6 μg/mL for voriconazole. 
  • If patient is taking azoles, monitor with liver function tests
• Follow-up radiologic studies
  • Pulmonary aspergilloma
    • If asymptomatic, follow with CT or chest radiograph periodically for 6 to 24 months to determine rate of progression 
    • After surgery, monitor with radiographs every 4 to 6 months for up to 3 years if spillage has occurred; no evidence for radiologic monitoring if no spillage 
  • Chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis, and subacute invasive pulmonary aspergillosis
    • Low-dose chest CT or chest radiograph every 3 to 12 months 
• Serial pulmonary function tests
  • In chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis, and subacute invasive pulmonary aspergillosis, change in pulmonary function can add information regarding success of treatment and stability of disease 

Complications

• Aspergilloma
  • Hemoptysis may be severe, even life-threatening
  • Tissue destruction can be extensive
• Other noninvasive Aspergillus disease
  • Tissue destruction and fibrosis can be extensive
  • May advance to more invasive disease
  • May lead to respiratory failure
• Invasive Aspergillus
  • Progressive tissue necrosis, systemic decline (catabolic losses, respiratory compromise)

Prognosis

• Varies depending on type of Aspergillus disease and the site
  • Aspergilloma
    • In asymptomatic patients, has good outcome, generally depending more on underlying lung disease
    • In 1 series of patients treated surgically, 10-year survival for simple aspergilloma was 80% 
  • Chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis, and subacute invasive pulmonary aspergillosis
    • Antifungal treatment initially can stabilize or improve majority of patients (71% in one study), but relapse is common and appropriate length of treatment is unclear 
    • Antifungal therapy reduces mortality to 50% at 5 years 
    • Without antifungal therapy, mortality exceeds 50% at 1 year 

References

Thompson GR et al: Aspergillus species. In: Bennett JE et al, eds: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020:3103-116.e4