Chronic pulmonary aspergillosis

I. What every physician needs to know.

Chronic pulmonary aspergillosis (CPA) is a spectrum of disorders that spans simple aspergilloma and chronic cavitary pulmonary aspergillosis (CCPA). Chronic pulmonary aspergillosis is distinguished from invasive pulmonary aspergillosis (IPA) by disease duration of greater than 3 months. On the end of the spectrum of CPA is chronic necrotizing pulmonary aspergillosis (CNA), which is reserved for quickly progressing disease, especially in immunocompromised patients. This text will focus on CPA including CCPA and simple aspergilloma and IPA will be covered elsewhere.

The immediate cause of these diseases is unclear, but underlying lung disease or damage is a prerequisite for development of CPA. Patients most commonly have a history of COPD, TB or non-TB infection and sometimes fibrotic sarcoidosis or allergic bronchopulmonary aspergillosis (ABPA). Defects in innate immunity and exogenous immunosuppression may contribute to increased susceptibility as well as mechanical impediments to elimination of the Aspergillus organism, frequently seen in chronic pulmonary diseases.

Aspergillus fumigatus is the most common cause of CPA, though there are case reports of Aspergillus niger and Aspergillus flavus also as causes. Inhalation of spores with colonization of underlying lung cavities or diseased lungs is thought to be the method of infection.

Simple aspergilloma is defined as the presence of a mycetoma, or fungus ball, that forms within a pre-existing pulmonary cavity due to sequestration of the fungal spores. Radiographically, it appears as a single, thin-walled cavity of stable size. CCPA can be distinguished from simple aspergilloma by the presence of multiple or expanding cavities in the lung that may have thicker walls and surrounding parenchymal changes.

II. Diagnostic Confirmation: Are you sure your patient has chronic pulmonary aspergillosis?

Diagnosis of CPA is challenging and relies on constellation of findings, including appropriate history, clinical features, radiographic findings, serology, and cultures.

A. History Part I: Pattern Recognition:

Patients with CCPA often present with cough, dyspnea, malaise, fevers, weight loss, chest pain, or hemoptysis. Conversely, patients with simple aspergillomas are usually asymptomatic, and the disease is found incidentally on radiography; however, occasionally these patients may also present with overt hemoptysis. Patients with CCPA are more likely to have systemic symptoms. It is important to note that many of these symptoms may be associated with an exacerbation of the underlying disease predisposing the patient to CPA as described above.

B. History Part 2: Prevalence:

Underlying diseases that may predispose to CPA include pulmonary tuberculosis, COPD, bronchiectasis, sarcoidosis, pneumothorax with bulla formation, and treated lung cancer. The most common underlying pulmonary disease is COPD, followed by TB or non-TB infections, fibrotic sarcoidosis and ABPA.

Aspergilloma and CCPA can occur in immunocompetent patients. More recent studies suggest that immune dysfunction may contribute to risk of disease, including innate, exogenous and mechanical immune dysfunction. Patients with greater degrees of immunosuppression are more prone to CNA or invasive aspergillosis.

C. History Part 3: Competing diagnoses that can mimic chronic pulmonary aspergillosis.

Because many patients with CPA have underlying lung disease, exacerbations of those disorders can be considered. Other causes of hemoptysis include bronchitis, bronchiectasis, tuberculosis, lung abscess, invasive pneumonia, lung cancer, diffuse alveolar hemorrhage, epistaxis, and rheumatalogic disorders such as Wegener’s granulomatosis and Goodpasture’s syndrome.

D. Physical Examination Findings.

Unless the cavity is very large and peripheral, it may be difficult to appreciate on physical exam. The diagnosis is usually made radiographically.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Aspergillus immunoglobulin G (IgG) antibodies, or precipitins, are positive in most cases of CPA and establish sensitization. Total IgE or Aspergillus-specific IgE may also be elevated. Fungal sputum culture, either expectorated or from BAL fluid, may be positive in some cases but is not required to make the diagnosis of CPA. Serum galactomannan can be positive in CCPA due to its invasive nature reaching the blood serum and its sensitivity is improving given newly established cutoffs. On the other hand, 1,3 β-D glucan testing is unreliable and was only positive in 1/5 of patients with CPA. ESR and CRP may be elevated.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

A chest radiograph or CT with a mycetoma, or fungal ball, within a cavity is highly suspicious for simple aspergilloma. It appears as a solid, rounded mass that is separated from the wall of the cavity by an air space.

CCPA can present with single or multiple cavities that are thin or thick walled. These usually change over time in either an indolent or rapidly progressive fashion. Discrete mycetomas are only present 25% of the time and pleural thickening is common.

Serial radiographs or computed tomography (CT) scans may be used to follow progression over time.

Histologic confirmation is not commonly pursued but would show evidence of chronic inflammation, possibly granulomas and fungal hyphae within the cavity consistent with Aspergillus.

III. Default Management.

Management of simple aspergilloma and CCPA are different. Consultation with infectious disease and pulmonary specialists can help to guide management.

Simple Aspergilloma

Data guiding management are limited to case series and small studies. In a stable patient without symptoms, no therapy is indicated. Serial radiographs can be used to follow disease progression.

Emergent management of aspergilloma is needed in the setting of massive hemoptysis. This occurs due to invasion or erosion into an adjacent vessel. In the setting of massive hemoptysis, bronchial artery embolization can be attempted to slow bleeding. This procedure is often only temporizing because of collateral vascular channels and recurrent bleeding frequently occurs. Intracavitary instillation of amphotericin B, either via bronchoscopy or percutaneously, has been studied and shows good short-term control of hemoptysis.

Surgical resection is reserved for patients who fail medical management and/or embolization. However, this may be difficult given the risk of complications, including contamination of the pleural space. Surgical resection is more feasible for a single aspergilloma than it is for CCPA.

Medical therapy for aspergilloma can be considered with treatment in the same manner as CCPA (described below), but data to support therapy is more limited.

Chronic cavitary pulmonary aspergillosis

Medical therapy is the mainstay of treatment for CCPA. As above, emergent management of bleeding may require embolization. Surgical outcomes are poorer given the diffuse nature of the disease.

Oral itraconazole and voriconazole are generally used in more stable disease and IV amphotericin or voriconazole is used in more severe disease.

Itraconazole and voriconazole are the preferred drugs for treatment. More data are present for itraconazole, but newer studies support the use of voriconazole. Voriconazole is also available in an intravenous (IV) formulation for patients who are unable to tolerate the oral drug or have more severe disease.

Voriconazole is dosed at 400 mg orally twice daily for 1 day then 200 mg orally twice daily. Itraconazole is dosed at 600 mg orally per day in divided doses for three days then 400 mg orally per day in divided doses.

In patients unable to take an azole due to adverse effects, resistance or treatment failure, amphotericin B or micafungin are other options. Azole resistance is a growing concern in treatment of CPA.

For patients who fail therapy with the above antifungals, there have been some cases of a positive response to IFN- γ, especially if they demonstrate evidence of IFN- γ deficiency.

A. Immediate management.

Immediate management of massive hemoptysis is needed to maintain hemodynamic stability. Bronchial artery embolization can be used for temporary treatment until definite therapy with surgery or antifungals is started. Also, intracavitary amphotericin B can be considered if it can be safely administered.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Aspergillus antibodies (precipitins) can be followed to assess response to therapy, but is not always a reliable end point to treatment. Markers of inflammation such as ESR and CRP can also be followed, but guidelines for expected change with treatment are not well-established. Disease burden should be monitored with chest radiography every 6 months with follow-up CT if new findings develop.

Drug concentrations of azoles should be monitored to ensure therapeutic levels given have variable bioavailability.

D. Long-term management.

Surgical resection can be curative but is not without significant risk.

For aspergillomas, serial radiographs to assess for stability can be used.

If antifungal therapy is used for CCPA, lifelong therapy is usually required.

E. Common Pitfalls and Side-Effects of Management

Treatment failure may occur with inadequate serum concentrations, so drug monitoring is needed. Resistance may develop with low concentrations.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

No dose adjustment is needed for oral voriconazole. Caution should be used with IV voriconazole as the IV vehicle can accumulate. Unless the risk outweighs the benefit, use oral voriconazole if the creatinine clearance is less than 50.

Limited data exist for itraconazole dosing in renal insufficiency, but the IV formulation should not be used if creatinine clearance is less than 30 due to accumulation of the vehicle.

B. Liver Insufficiency.

Patients with mild to moderate cirrhosis should receive the full loading dose but half the daily dose of voriconazole. Use in severe cirrhosis should be avoided unless the benefit outweighs the risk.

Dose adjustment guidelines for itraconazole do not exist.

C. Systolic and Diastolic Heart Failure

Itraconazole has negative ionotropic effects and should be used with significant caution in patients with ventricular dysfunction.