Chronic Pulmonary Aspergillosis and Aspergilloma
Also known as: Aspergilloma, Fungal Ball, CPA, Chronic Cavitary Pulmonary Aspergillosis
Chronic pulmonary aspergillosis is a slowly progressive, destructive lung infection, nearly always caused by Aspergillus fumigatus. It affects people with pre-existing lung disease who are immunocompetent or mildly immunocompromised.
Diagnosis requires at least 3 months of symptoms, radiological evidence of progressive cavitation, and microbiological evidence of Aspergillus.
Prior pulmonary tuberculosis is the commonest cause, so the disease is a major problem in countries with a high tuberculosis burden. An estimated 3 million people live with chronic pulmonary aspergillosis worldwide, including more than 1 million after tuberculosis.
Five year survival is about 50 to 85 percent. Mortality is higher with:
- bilateral disease
- low body weight
- non tuberculous mycobacterial co-infection
- hypoalbuminaemia
| Form | Features |
|---|---|
| Simple aspergilloma | A single cavity containing a fungus ball (a mass of hyphae, mucus, and cell debris), with a stable course and few or no symptoms except haemoptysis; no progression of cavities over 3 months |
| Aspergillus nodule | One or more nodules, often mistaken for cancer, with or without cavitation; usually found at resection |
| Chronic cavitary pulmonary aspergillosis | One or more cavities, with or without a fungus ball, that expand or multiply over months, with surrounding pleural thickening and pericavitary infiltrates; the commonest form |
| Chronic fibrosing pulmonary aspergillosis | End stage of untreated cavitary disease, with fibrosis destroying 2 or more lobes and loss of lung function |
| Subacute invasive aspergillosis (chronic necrotising pulmonary aspergillosis) | Progression over 1 to 3 months with cavitation, consolidation, or nodules, in mild immunosuppression (diabetes, corticosteroids, alcoholism, malnutrition, connective tissue disease, chronic obstructive pulmonary disease); a link between the chronic and the invasive forms |
- Previous pulmonary tuberculosis (the commonest), non tuberculous mycobacterial infection (Mycobacterium avium complex), and bronchiectasis.
- Chronic obstructive pulmonary disease with emphysema and bullae, pneumothorax, and previous lung resection.
- Sarcoidosis (stage IV with fibrocystic changes), ankylosing spondylitis (apical fibrosis), pneumoconiosis, rheumatoid nodules, and radiation fibrosis.
- Allergic bronchopulmonary aspergillosis, which can lead to cavitation and chronic disease.
- Cystic fibrosis (colonisation and allergic disease more than chronic cavitary disease).
- Immune defects with a limited effect: diabetes, corticosteroids (including inhaled), malnutrition, alcohol misuse, HIV with moderate immunosuppression, and genetic variants affecting immunity.
Conidia that settle in a pre-existing cavity germinate and form hyphae. The hyphae proliferate in the cavity, and the local immune response cannot eradicate them.
Cavity wall inflammation, tissue destruction, and the release of fungal antigens drive symptoms, while the fungus ball stays in the lumen. The inflammatory process may spread to adjacent lung, pleura, and bronchial vessels. Haemoptysis arises from hypertrophied bronchial arteries lining the cavity wall. Over months the cavity enlarges and fibrosis develops.
Mild impairment of Th1 and Th17 responses, and a deficiency of mannose binding lectin and other innate proteins, have been associated with susceptibility.
- Weight loss, fatigue, and malaise (constitutional symptoms are common and can resemble tuberculosis).
- Chronic productive cough, breathlessness, and chest discomfort.
- Haemoptysis (in about 50 to 80 percent), from mild to life threatening.
- Fever and night sweats are less common, and signs include clubbing and reduced breath sounds.
- Symptoms of the underlying lung disease, and respiratory failure in advanced disease.
Computed tomography is required for diagnosis and follow up. Findings include:
- Thick walled cavities (wall over 4 mm in many cases), single or multiple, in the upper lobes and apical segments of the lower lobes.
- A fungus ball: a rounded or irregular intracavitary mass that moves with position change (prone and supine imaging), and an air crescent above it.
- Pleural thickening adjacent to a cavity, often an early sign.
- Pericavitary infiltrates, consolidation, and new cavities or enlarging cavities on serial scans over 3 months or more.
- Parenchymal destruction and fibrosis in chronic fibrosing disease.
- Cavitary nodules, tree in bud patterns, and mediastinal nodes less commonly.
Chest radiography is insensitive for early disease but shows cavities and mass lesions.
| Test | Interpretation |
|---|---|
| Aspergillus IgG antibody (immunoassay or precipitins) | The most sensitive test (sensitivity above 90 percent in chronic cavitary disease); a raised level in a patient with a compatible radiological picture is the key microbiological criterion; the level falls with treatment |
| Sputum or bronchoalveolar lavage culture | Positive in about one third to one half of cases (single sputum less sensitive; repeat samples improve yield); a positive result in a patient with cavities is supportive, and a negative one does not exclude disease |
| Galactomannan (bronchoalveolar lavage) | Positive in many cases, and a high index supports the diagnosis; serum galactomannan is usually negative |
| Aspergillus polymerase chain reaction | Respiratory specimens; supportive, with sensitivity similar to culture |
| Total IgE and eosinophil count | Raised in some patients with allergic overlap |
| Beta D glucan | Not useful |
| Histology | Hyphae in the cavity wall; a biopsy shows invasion in subacute invasive disease and fungus ball hyphae in aspergilloma |
| Tests for coexisting disease | Mycobacterial smear, culture, and molecular testing for tuberculosis and non tuberculous mycobacteria (co-infection is frequent), and HIV testing |
| Inflammatory markers | Raised C reactive protein and erythrocyte sedimentation rate, useful for monitoring |
| Condition | Points that separate it |
|---|---|
| Pulmonary tuberculosis, reactivation | Positive smear, culture, and molecular test; both can coexist, and treatment of tuberculosis can leave residual cavities that become colonised |
| Non tuberculous mycobacterial infection | Cavities with nodular bronchiectasis; culture |
| Bacterial lung abscess and necrotising pneumonia | Acute onset and response to antibacterials |
| Lung cancer with cavitation | Histology and PET; Aspergillus nodule can mimic cancer |
| Cavitating histoplasmosis, coccidioidomycosis, paracoccidioidomycosis | Geography, antibody and antigen, culture |
| Nocardiosis and actinomycosis | Culture and histology |
| Granulomatosis with polyangiitis | Autoantibodies and renal involvement |
| Rheumatoid nodules | Rheumatoid disease |
| Allergic bronchopulmonary aspergillosis | Total IgE above 1000 IU per mL, central bronchiectasis, asthma, high attenuation mucus |
| Pulmonary infarct and septic emboli | Clinical context |
Indications
Antifungal treatment is indicated in symptomatic and progressive disease: chronic cavitary and chronic fibrosing disease, subacute invasive disease, and symptomatic aspergilloma. It is also indicated in asymptomatic patients with progressive radiological change.
Observation, with clinical and radiological follow up every 3 to 6 months, is acceptable in asymptomatic simple aspergilloma without haemoptysis, and in patients with stable minor disease.
Antifungal therapy
| Agent | Dose | Notes |
|---|---|---|
| Itraconazole | 200 mg orally twice daily (capsules with food and an acidic drink, or oral solution on an empty stomach); children 5 mg per kg daily in 2 divided doses | First line for most patients; the trough level target is above 0.5 to 1 microgram per mL (by chromatography), checked at 2 weeks; avoid in heart failure; interacts with many drugs including inhaled budesonide and fluticasone (adrenal suppression and Cushing syndrome) |
| Voriconazole | 200 mg orally twice daily (400 mg twice daily on day 1 for loading), adjusted to trough level 1 to 5.5 micrograms per mL | Used where itraconazole fails or is not tolerated, and in subacute invasive disease; monitor liver tests, vision, and skin, and watch for periostitis and squamous cell carcinoma with prolonged courses |
| Posaconazole | Delayed release tablets 300 mg twice daily on day 1, then 300 mg once daily | Alternative for intolerance or failure; trough above 1 microgram per mL |
| Isavuconazonium sulphate | 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses, then 372 mg once daily | Alternative with fewer adverse effects |
| Micafungin | 100 to 150 mg intravenously once daily | Salvage for azole failure or resistance; suppressive or short courses |
| Caspofungin | 70 mg intravenously on day 1, then 50 mg once daily | Salvage |
| Liposomal amphotericin B | 3 to 5 mg per kg intravenously once daily, for 2 to 4 weeks, or 3 times weekly | Salvage for resistance or intolerance; nephrotoxicity |
The usual duration is a minimum of 6 months for chronic cavitary disease. Many patients need 12 months or longer. Those who relapse after stopping, have progressive disease, or have limited lung reserve need long term or lifelong suppression.
Subacute invasive disease is treated with voriconazole 6 mg per kg intravenously every 12 hours for 2 doses, then 4 mg per kg every 12 hours (oral 200 mg twice daily). The initial course is usually 6 to 12 weeks, followed by an oral azole for months.
Monitoring response
Response is judged by symptoms, weight, albumin, C reactive protein, Aspergillus IgG levels (which fall slowly over months), and computed tomography at 3 to 6 months. Look for reduction in pericavitary infiltrate and pleural thickening, with no new cavities.
Treatment failure is cavity growth or new infiltrates despite therapeutic levels. It prompts:
- testing for azole resistance (cyp51A mutations arise during long term azole therapy and occur in about 10 to 20 percent of long term azole treated patients)
- review of adherence and levels
- testing for tuberculosis and non tuberculous mycobacteria
- a change of agent
Haemoptysis and surgery
- Tranexamic acid 1 g orally or intravenously three times daily (adult dose, with caution in renal impairment and in thromboembolic disease) reduces the volume and duration of mild to moderate haemoptysis.
- Bronchial artery embolisation is the first line for moderate to severe haemoptysis, with recurrence rates that are high without antifungal therapy and surgery.
- Surgical resection (lobectomy, segmentectomy, or cavernostomy) is considered for simple aspergilloma with recurrent or severe haemoptysis in patients with adequate lung function. It is also considered for localised chronic cavitary disease after antifungal therapy for a few months. Operative morbidity is considerable (bronchopleural fistula, empyema, and prolonged air leak) and mortality can be several percent, so selection and perioperative antifungal cover are important. Surgery is not appropriate for most patients with poor lung function or extensive disease.
- Intracavitary therapy: percutaneous or endobronchial instillation of amphotericin B has been used for poor surgical candidates with recurrent haemoptysis, with limited evidence.
Supportive care
Supportive measures:
- smoking cessation, nutritional support, and pulmonary rehabilitation
- treatment of the underlying condition (including tuberculosis and non tuberculous mycobacteria)
- vaccination
- review of inhaled and systemic corticosteroids, which increase risk of progression
Drug interactions are reviewed for every patient on an azole. Prophylaxis after surgery or in patients on corticosteroids is considered in selected patients.
Adverse effects
- Itraconazole: hepatotoxicity, negative inotropic effect, hypertension, hypokalaemia, oedema, peripheral neuropathy, and many drug interactions.
- Voriconazole: visual disturbance, hallucinations, hepatotoxicity, photosensitivity, periostitis, and QT prolongation.
- Posaconazole: gastrointestinal upset, hepatotoxicity, hypertension, and hypokalaemia.
- Amphotericin B: infusion reactions and nephrotoxicity.
Untreated chronic cavitary disease progresses to fibrosis, respiratory failure, and death, and haemoptysis can be fatal. With treatment, most patients improve, though relapse after stopping azole therapy is common (about 30 to 50 percent), and long term azole use leads to resistance and toxicity in a minority.
